Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin...

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Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling Travis J. Jerde Department of Pharmacology and Toxicology, Indiana University School of Medicine, IU-Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA Correspondence should be addressed to Travis J. Jerde; [email protected] Received 6 April 2015; Revised 6 June 2015; Accepted 1 July 2015 Academic Editor: Matthias Gaestel Copyright © 2015 Travis J. Jerde. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Phosphatase and tensin homologue (PTEN) is a critical cell endogenous inhibitor of phosphoinositide signaling in mammalian cells. PTEN dephosphorylates phosphoinositide trisphosphate (PIP 3 ), and by so doing PTEN has the function of negative regulation of Akt, thereby inhibiting this key intracellular signal transduction pathway. In numerous cell types, PTEN loss-of- function mutations result in unopposed Akt signaling, producing numerous effects on cells. Numerous reports exist regarding mutations in PTEN leading to unregulated Akt and human disease, most notably cancer. However, less is commonly known about nonmutational regulation of PTEN. is review focuses on an emerging literature on the regulation of PTEN at the transcriptional, posttranscriptional, translational, and posttranslational levels. Specifically, a focus is placed on the role developmental signaling pathways play in PTEN regulation; this includes insulin-like growth factor, NOTCH, transforming growth factor, bone morphogenetic protein, wnt, and hedgehog signaling. e regulation of PTEN by developmental mediators affects critical biological processes including neuronal and organ development, stem cell maintenance, cell cycle regulation, inflammation, response to hypoxia, repair and recovery, and cell death and survival. Perturbations of PTEN regulation consequently lead to human diseases such as cancer, chronic inflammatory syndromes, developmental abnormalities, diabetes, and neurodegeneration. 1. Introduction Phosphatase and tensin homolog (PTEN) is a ubiqui- tously expressed protein that functions as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P 3 or PIP 3 ) by catalyzing the dephosphoryla- tion of the 3 phosphate of the inositol ring in PIP 3 [1]. e resulting product of this reaction is the biphosphate product PIP 2 (PtdIns(4,5)P 2 ). Since PIP 3 is a primary activator of the signaling intermediate Akt, dephosphorylation of PIP 3 by PTEN results in inhibition of the AKT signaling pathway. Akt is a serine/threonine-specific protein kinase that is critical for many cellular functions including cell prolifera- tion, apoptosis, transcription, and cell migration and struc- ture [1]. PTEN also functions as a protein phosphatase by dephosphorylating proteins including focal adhesion kinase in the cytosol and Erk, histone H1, RAD51, and CENC-P in the nucleus. erefore, PTEN has effects on cell migration via integrin signaling, chromatin remodeling through its interactions with histones, cell cycle progression and arrest independent of Akt signaling, DNA repair via its modulation of RAD51, and centrosome stability via its role with CENC- P. PTEN’s structure, described in Figure 1, consists of a phosphatase domain harboring the active site and enzymatic function of the protein and a C2 domain responsible for the phospholipid membrane binding site [2]. As such, the C2 domain is responsible for cellular location and allows PTEN localization to membrane-bound PIP 3 ; this promotes PTEN’s phosphoinositide phosphatase function by locating it to the cellular location of its substrates [2]. e functions of the C- terminal and PDZ domains are less defined [2]. Because the downstream signaling pathways that PTEN effects modulate very diverse and dynamic cellular func- tions, PTEN is responsible for regulating the signals of an abundance of mediators including cytokines, growth factors, integrins, and autacoid ligands of G-protein-coupled receptors [3–5]. e cellular mechanistic effects of PTEN function and intrinsic Akt inhibition include modulation Hindawi Publishing Corporation Journal of Signal Transduction Volume 2015, Article ID 282567, 13 pages http://dx.doi.org/10.1155/2015/282567

Transcript of Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin...

Page 1: Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling TravisJ.Jerde Department of Pharmacology

Review ArticlePhosphatase and Tensin Homologue Novel Regulation byDevelopmental Signaling

Travis J Jerde

Department of Pharmacology and Toxicology Indiana University School of Medicine IU-Melvin and Bren Simon Cancer CenterIndianapolis IN 46202 USA

Correspondence should be addressed to Travis J Jerde tjjerdeiupuiedu

Received 6 April 2015 Revised 6 June 2015 Accepted 1 July 2015

Academic Editor Matthias Gaestel

Copyright copy 2015 Travis J JerdeThis is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Phosphatase and tensin homologue (PTEN) is a critical cell endogenous inhibitor of phosphoinositide signaling in mammaliancells PTEN dephosphorylates phosphoinositide trisphosphate (PIP

3) and by so doing PTEN has the function of negative

regulation of Akt thereby inhibiting this key intracellular signal transduction pathway In numerous cell types PTEN loss-of-function mutations result in unopposed Akt signaling producing numerous effects on cells Numerous reports exist regardingmutations in PTEN leading to unregulated Akt and human disease most notably cancer However less is commonly knownabout nonmutational regulation of PTEN This review focuses on an emerging literature on the regulation of PTEN atthe transcriptional posttranscriptional translational and posttranslational levels Specifically a focus is placed on the roledevelopmental signaling pathways play in PTEN regulation this includes insulin-like growth factor NOTCH transforming growthfactor bone morphogenetic protein wnt and hedgehog signaling The regulation of PTEN by developmental mediators affectscritical biological processes including neuronal and organ development stem cell maintenance cell cycle regulation inflammationresponse to hypoxia repair and recovery and cell death and survival Perturbations of PTEN regulation consequently lead to humandiseases such as cancer chronic inflammatory syndromes developmental abnormalities diabetes and neurodegeneration

1 Introduction

Phosphatase and tensin homolog (PTEN) is a ubiqui-tously expressed protein that functions as a phosphatase todephosphorylate phosphatidylinositol (345)-trisphosphate(PtdIns(345)P

3or PIP

3) by catalyzing the dephosphoryla-

tion of the 31015840 phosphate of the inositol ring in PIP3[1] The

resulting product of this reaction is the biphosphate productPIP2(PtdIns(45)P

2) Since PIP

3is a primary activator of

the signaling intermediate Akt dephosphorylation of PIP3

by PTEN results in inhibition of the AKT signaling pathwayAkt is a serinethreonine-specific protein kinase that iscritical for many cellular functions including cell prolifera-tion apoptosis transcription and cell migration and struc-ture [1] PTEN also functions as a protein phosphatase bydephosphorylating proteins including focal adhesion kinasein the cytosol and Erk histone H1 RAD51 and CENC-P inthe nucleus Therefore PTEN has effects on cell migrationvia integrin signaling chromatin remodeling through its

interactions with histones cell cycle progression and arrestindependent of Akt signaling DNA repair via its modulationof RAD51 and centrosome stability via its role with CENC-P PTENrsquos structure described in Figure 1 consists of aphosphatase domain harboring the active site and enzymaticfunction of the protein and a C2 domain responsible for thephospholipid membrane binding site [2] As such the C2domain is responsible for cellular location and allows PTENlocalization tomembrane-bound PIP

3 this promotes PTENrsquos

phosphoinositide phosphatase function by locating it to thecellular location of its substrates [2] The functions of the C-terminal and PDZ domains are less defined [2]

Because the downstream signaling pathways that PTENeffects modulate very diverse and dynamic cellular func-tions PTEN is responsible for regulating the signals ofan abundance of mediators including cytokines growthfactors integrins and autacoid ligands of G-protein-coupledreceptors [3ndash5] The cellular mechanistic effects of PTENfunction and intrinsic Akt inhibition include modulation

Hindawi Publishing CorporationJournal of Signal TransductionVolume 2015 Article ID 282567 13 pageshttpdxdoiorg1011552015282567

2 Journal of Signal Transduction

1 15 186 352 400 403N-term Phosphatase domain C2 domain C-tail PDZ

substratebinding

Phosphataseactivity

Acetylation sitesInhibitory protein

interactions

Cellular locationMembrane association

Protein-protein interactions

Phospho-sitesProtein stability

PIP2

Figure 1 Protein domains of PTEN PTEN has five distinct domains consisting of an N-terminal PIP binding domain the phosphatasedomain responsible for its enzymatic activity and containing acetylation sites responsible for regulating this phosphatase activity theregulatory C2 domain responsible for its cellular location and protein-protein interactions including those that modify enzyme activity orlocalization the less understood C-tail containing phosphorylation sites thought to be critical for PTENrsquos stability and finally the C-terminalPDZ domain

of many pathways this includes cell cycle progression viap27Kip1 [6] Wee1 p21 and cyclin D [7] mTOR-mediatedcellular signaling [8] apoptosis and survival effects mediatedby Bim [9] MDM2-p53 [10] Bcl-2 and Bax [11] cellularstructure regulation mediated by laminins and cytoskeletalprotein expression [12] glycogen and glucose regulation andglycolysis by glycogen synthase 6-phosphofructo-2-kinaseand AS160 [13] Adding to the broad activity of PTEN arethe numerous examples of signaling crosstalk with othertransduction pathways including the Erk p38 and JNKmitogen-activated protein kinases [14] the TGF120573 and BMP-associated SMAD pathways [15] the cytokine-mediated Jak-STAT pathway [16] and IP

3-mediated calcium signaling [17]

Additionally interesting recent findings have demonstratedthat PTEN modulates the DNA damage response and repairvia its inhibition of Akt [18] Because of this diversity anymediators that modulate PTEN expression levels or functionhave substantial effects on cellular function

As a critical cellular protein that modulates numerousprocesses it is expected that PTEN plays a major role inregulating proper development Yet PTEN is still primarilyknown as a tumor suppressormdashthe loss of function of whichleads to tumorigenesisWhile thismay be true the last decadehas seen a greatly enhanced understanding of how PTENis regulated particularly as this relates normal growth anddevelopmentThis review takes a critical look at the literaturefocusing on PTEN regulation the effects of this regulationduring mammalian development and how it is regulated byclassical developmental signal transduction mechanisms

2 PTEN in Developmental Biology

21 Early Embryonic Development PTEN is highly andubiquitously expressed throughout developing embryos Itis expressed as early as the embryonic stem cell stagebeing detectable in embryonic day 35 blastocysts in bothextraembryonic and embryonic tissues [19] PTEN is requiredfor critical hallmarks of developmental biology including cellproliferation growth death and migration In many tissuesPTEN expression coincideswith the need to repress or induce

proliferation or differentiation in cells depending on thetissue need in each location and time point

At an organismal level PTEN plays several critical rolesin the early control of the patterning of embryos FirstPTEN regulation of cell migration is known to controlspecification of the anterior-posterior axis of mouse embryos[20] Embryos that lack PTEN expression exhibit a notableset of morphological defects including the failure to correctlyspecify the anterior-posterior body axis improper separationof body foci and decreased coordinated migration of cellsalong the body axis PTEN is also necessary for gastrulationof embryos PTEN is highly expressed from the midblastulatransition through completion of gastrulation and embryoniclayer separation [21] In this process PTEN coordinates cellcycle elongation and cellular morphogenesis Embryos lack-ing PTEN fail to exhibit proper patterning from the blastulainto the germ layers Lethality of these embryos soon followsAt the postgastrulation stage PTEN localization can be foundthroughout ectodermal endodermal and mesodermal-derived tissue including the developmental precursors of thecentral nervous system and skin the liver and gastrointestinaltract the urogenital sinus heart and skeletal muscle [19 20]Anatomy of PTEN systems effects highlighed in Figure 2Following the separation of the germ layers PTEN exertsdynamic roles throughout development across numerousorgan systems The following highlights recent findings

22 Nervous System Development The high prevalence ofgermline PTENmutations inCowden disease and Bannayan-Riley-Ruvalcaba syndrome Lhermitte-Duclos syndromeautism spectrum disorders and CNS axon regenerationdemonstrates the significance of PTEN in central nervoussystem development and physiology The brain has been themost extensively studied organ in the area of PTENrsquos role indevelopmental biology [22] primarily because of its knownrole in the development of gliomas and medulloblastomasIdentified syndromes associated with germline PTEN inthe CNS include Lhermitte-Duclos disease [23] dysplasticgangliocytoma [24] gray matter heterotopias [25] mentalretardation [26] autism [27] and seizures [28]

Journal of Signal Transduction 3

BrainGangliocytoma

Mental retardationAutism

Seizures

SkinThickening

Melanocyte expansion

Immunitylymphoid hyperplasia NK cell development antibody class-switching recruitment

Mammarygland

Ovary Prostate

Bone

Lungs

UT

GIDevelopment

InvolutionBudding

GrowthOvulation

ElongationMatrix deposition

DevelopmentFunctioning

DevelopmentFunctioning

DevelopmentPhysiology

GrowthDevelopment

Physiology

Figure 2 Precise regulation of PTEN expression activity or localization has profound effects on the development of numerous organ systemsDisruption of PTENat the level of transcriptionmRNA stability protein stability enzymatic function or cellular location results in disruptionof these developmental systems

Cell type-specific mutations of PTEN in animal mod-els demonstrate developmental phenotypes and resultingpathology Glial cell conditional null mutation of the Ptengene promotes seizures and ataxia early in life in miceand promotes premature death [28] Brain size in thesemice increases progressively over time relative to wild-typelittermates and these mutants develop hydrocephalus anduntoward lateral ventricle growth [28]These animals exhibitneural dysplasia thickened internal granule cell layers anda progressive increase in neuronal soma size [28] Furthermice with oligodendrocyte-specific PTEN deletion exhibitdisruption in the myelination of axons [29] Importantlythese murine effects are similar to many common featuresassociated with PTEN mutations in the human CNS [30]

PTEN deletions in terminally differentiated neuronsresult in a number of striking phenotypes Neuronal-specificPTEN deletion promotes soma hypertrophy macroen-cephaly and increased axonal outgrowth This latest find-ing has led to the hypothesis that PTEN inhibition maybe a potential therapeutic mechanism for inducing axonal

outgrowth in spinal injury patients [31] These mice alsoexhibit increased dendritic spine density increased caliberof neuronal projections and alterations in synaptic trans-mission [31] Neurons from these mice exhibit disruptionin Bergmann-glia connections and disorganized cerebellararchitecture [31] Neuronal-conditional PTEN null mice alsodisplay hyperactivity signs of anxiety heightened responseto excitatory stimuli and disrupted social interaction [32]Findings from these studies have prompted the hypothesisthat PTEN expression anomalies may be at least in partresponsible for CNS-related disorders in humans

23 Dermal Development PTEN-mediated signaling haslong been known to be critical for the cytoprotection ofboth epithelial cells and melanocytes in the skin Interest-ingly PTEN has recently been shown to be responsible forregulating the events and timing of epidermal development[19] This may have been predictable given the incidence ofbenign tumors of the skin in Cowdenrsquos syndrome a knownPTEN-driven condition Conditional PTEN deletion induces

4 Journal of Signal Transduction

hyperplasia of squamous cells resulting in mounted skindermis and papillomas [33] Additionally mice with specificmelanocytic PTEN deletion exhibit increased melanocyteexpansion [34]

24 Hematopoietic Development PTEN is necessary forproper development lineage fate and cell function in T cellsB cells myeloid cells NKT cells and hematopoietic stem cells(HSCs) as demonstrated by several elegant studies involvingglobal heterozygous and cell-conditional null PTEN models[35ndash40] It has been known that PTEN (+minus) mice exhibitlymphoid hyperplasia progressing to T-cell lymphoma com-plete with large nodal masses [36] and it has now alsobeen reported that PTEN (+minus) mice develop autoimmunedisorders at an early age due to abrogated PTEN function[37] Cell-type T-cell conditional PTEN null mice exhibitlymphadenopathy splenomegaly and hyperplastic enlargedthymus Similar to the global PTEN heterozygous miceconditional nulls also exhibit autoreactivity evidenced byincreased levels of autoantibodies expanded T-cell prolifer-ation and increased cytokine synthesis and release [38]

Indirect studies show that PTEN-mediated signalingplays a role in natural killer (NK) cells Unfortunatelytrue cell-selective knockout of PTEN in natural killer (NK)cells has not been reported due to the lack of a cell-typespecific promoter However purified NK cells from PTENimmune-system null mice exhibit abrogated maturation andactivation [39] Studies have demonstrated that when thesecells were adoptively transferred intoNK null mice harboringmetastatic melanoma cells the null cells exhibit stronglydecreased protection from metastases relative to wild-typeNKT cells [39 40]These results demonstrate that one criticalrole of NK cells namely tumor targeting is attenuatedin PTEN null NK cells In addition B-cell lineage-specificPTEN null mice exhibit expanded splenocytes mesentericlymph node cells and peritoneal cells [41] B cells deficientin PTEN display enhanced proliferation upon epitope ormitogen stimulation and defective class-switch antibodyrecombination resulting in decreased production of IgA andIgG antibodies and elevated IgM production [41]

Neutrophils isolated from mice with PTEN-null myeloidlineage cells display increased actin polymerization withenhanced membrane ruffling pseudopodia formation che-motaxis and migratory speed [42] Inflammation in thesemice is associated with vastly increased neutrophil recruit-ment [42] Paradoxically these mice are more susceptible toinfection with Leishmania and exhibit a slower clearance ofinfection than wild-type littermates This disconnect appearsto be due to decreased secretion of tumor necrosis factor(TNF) by mutant macrophages in these mice [43] To datelittle else is known about the development of monocytes inmyeloid-specific PTEN null bearing animals

Deletion of PTEN in murine hematopoietic stem cells inmice results in a very rapid onset of myeloproliferative disor-ders and an eventual depletion of the stem cell pool whichdespite their proliferative nature results in the loss of theability of these stem cells to produce all lineages needed forproper immune functioning [44] These myeloproliferativedisorders progressed to acute myeloid leukemia or acute

lymphoblastic leukemia [44] In a demonstration that Akt-signaling is downstream of this phenotype increased HSCproliferation and even the development of myeloproliferativedisorders and leukemia are all rescued when the mice weretreated with rapamycin [44]

25 Visceral OrganDevelopment There are numerous studiesto date examining the developmental effects of organ-specificPTEN mutation in mouse models This review summarizesthe highlights of these studies hereMammary ducts in tissue-specific conditional PTEN null mice exhibit loss of differ-entiation enhanced growth excessive side branching andprecocious budding relative to wild-type controls [45] Thesephenotypes are reported during puberty but also manifesttheir effects during mammary expansion during pregnancyNotably mammary gland involution after pregnancywas alsodefective [45] PTEN is important for the normal physiologyof oocytes as PTEN deficiency in murine oocytes causesthe entire oocyte pool to become activated prematurely [46]This proves to be critical for fertility and reproduction aspremature oocyte activation resulted in females having amaximum of one normal-sized litter before they becameinfertile at 12-13 weeks of age [46]

FabpCre-(Ptenfloxflox) mice exhibit a number of inter-esting phenotypes in the genitourinary system PTEN dele-tion occurs in the bladder ureter kidney colon prostateseminal vesicles and vagina of these mutants [47] Epithelialhyperplasia was omnipresent in these animals As expecteddeletion of PTEN resulted in increased susceptibility tochemically induced carcinogenesis [48] Similarly epithelialhyperplasia is present in organ specific PTEN knockoutsfollowed by intraepithelial neoplasia and ultimately by inva-sion of the cancer cells as invasive adenocarcinoma [49ndash51]Embryonic deletion of PTEN in the lower urinary systemresults in a loss of proper differentiation within affected cells[52] ultimately resulting in loss of proper patterning andgrowth control Based on these data and the collection ofphenotypes observed in PTEN deleted cells and animals it islikely that a loss of differentiation of cells plays a master rolein PTENrsquos role in organ development

Recent reports have demonstrated a critical role for PTENin the branching morphogenesis and nephron patterning ofdeveloping kidneys PTEN has been shown to be indispens-able for developing bud outgrowth mesenchymal invasionand branching morphogenesis in developing kidneys bymediating the signaling downstream of GDNFRET receptortyrosine kinases [53] Again this involves differentiation andchemotaxis of epithelial cells More recently Lindstrom etal have shown that PTEN sits at the center of nephrondevelopment by integrating signaling from BMP and wnt-beta-catenin pathways [54] Disruption of PTEN results in aloss of coordinated signaling and a loss of proper patterningof epithelial cells along the axis of the nephron tubule

Numerous developmental effects of PTEN have beennoted in the gastrointestinal tract In the colon PTEN (+minus)mice develop hamartomatous polyps consistent with dis-rupted control of differentiation of cells [55] Further PTENis critical for colon homeostasis involving inflammatoryrepair and recovery processes that reactivate developmental

Journal of Signal Transduction 5

signalingmechanisms [56] In the liver loss of PTENnot onlyincreases tumor susceptibility but also altersmetabolism [57]In addition hepatomegaly is observed in mice with condi-tional hepatic PTEN knockout as the ratio of liver weightto body weight increased in the mutants when comparedwith wild-type controls [57] Livers harvested from mutantanimals are discolored and show accumulation of triglyc-erides consistent with steatohepatitis associated with severeinflammation Passive diffusion of fatty acids in hepatocyteswas enhanced in PTEN null mice and PTEN-deficienthepatocytes exhibit an increased rate of fatty acid synthesisvia induced fatty acid synthase [57] PTEN-deficient miceexhibit defects in glucose metabolism including decreasedfasting plasma glucose levels and reduced serum insulinlevels [58] Clearance of glucose was accelerated in theabsence of PTEN concurrent with increased liver glycogenstorage

Pancreatic islet beta-cell specific PTEN-deficient miceexhibit increases in islet cell numbers total islet massand an increase in 120573-cell progenitor proliferation duringembryonic development and early postnatal life [59] AdultPTEN mutant mice were hypoglycemic and were resistantto streptozotocin-induced diabetes These mice are signifi-cantly smaller than controls and have a shorter lifespan Insome studies severe hypoglycemia is associated with seizureactivity and premature death before 5 weeks of age [59]In addition PTEN (+minus) mice exhibit protection againstincreased insulin production during reactive oxygen species-dependent type two diabetes and insulin-resistance uponaging [60]

PTENrsquos role in maintaining glucose balance is not limitedto the liver and pancreas but also involves adipocytes andmyocytes Inactivation of PTEN specifically in adipocytesproduces no obvious gross morphological effects on theadipose tissue or adipose tissue mass However this mouseexhibits increased systemic glucose tolerance and insulin sen-sitivity complete with decreased fasting insulin and resistinlevels [61] By controlling serum insulin and resistin levelsPTEN regulates insulin sensitivity and AMP kinase activityin the liver Similarly skeletal and cardiac muscle cell-specificdeletion causes increased systemic glucose tolerance andinsulin sensitivity [62] Interestingly however PTEN loss inthese tissues seems to protect thesemice from streptozotocin-induced diabetes and hyperglycemia indicating that theinsulin hypersensitivity exhibited in tissue-selective PTEN-deficient mice allowed them to maintain proper glucoselevels

PTEN regulates proper lung development Specific lungdeletion of PTEN during embryogenesis results in impairedlungmorphogenesis and early postnatal death [61]The lungsof these neonates exhibit increased epithelial cell proliferationand decreased alveolar cell differentiation Adults exhibitbronchiolar and alveolar epithelial hyperplasia Mutant miceexhibit hypertrophy of alveolar cells derived from bron-chioalveolar stem cells [61] Predictably adenocarcinomawasevident in aged adults Further study of PTENrsquos role inlung development revealed that PTEN-regulated signalingmediates lung endodermal morphogenesis coordinate withthe overall developmental process in the lung and it is central

to the interaction of several signaling pathways including theTGF beta-SMAD and Nkx21 pathways [62]

Normal development of the vascular system is alsodependent on proper PTEN function PTEN knockout inendothelial and endocardial cells in mice results in embry-onic lethality due to increased capillaries and endothelial cellhypertrophy [63] These mutant embryos exhibit pericardialcavity enlargement leakage of blood into the pericardialcavity and enlarged trunk vessels secondary to pericyte andvascular smooth muscle cell recruitment to blood vessels[63] In addition cardiomyocyte-specific deletion of PTENleads to cardiac phenotypes via development of cardiachypertrophy and contractile defect [64] Future studies onPTEN will hopefully be targeted at assessing injury-relatedresponses in the cardiovascular system as deletion of PTENin cardiomyocytes has been shown to protect the heart frommaladaptive remodeling upon biomechanical stress

PTEN regulates developing bone and cartilage by pro-tecting against overgrowth of the skeletal system Mice withdeletion of PTEN in osteochondroprogenitor cells exhibitgrowth plate dysfunction and overgrowth of the vertebrae[65] The bodies of these mice are notably longer than wild-type controls demonstrating a critical defect that resultsin loss of proper skeletal development Interestingly thisincrease in length was not due to bone cell proliferationincreases as might have been expected but rather is due toincreased matrix deposition and cellular hypertrophy [65]In a second model osteoblast-specific knockdown of PTENexpression results in increased bone volume and density[66] Interestingly this mutation is associated with improvedintramembranous and late endochondral fracture healingThis is now an active area of research within the boneremodeling research field

While PTEN remains virtually synonymous with cancerbiology the studies presented here make the importanceof proper PTEN signaling for regulating a wide variety ofdevelopmental processes clearly evident From regulation ofgrowth differentiation glucose maintenance and repair andrecovery to gross effects on organ and systems developmentPTEN is a protein with vast consequence in the field ofdevelopmental biology and the signaling affected by itsexpression is expansiveThe role PTEN plays in developmenthas clear correlates to human disease Further PTENrsquos effectson development acquire greater importance when the rolethat developmental signaling plays in cancer growth andprogression is consideredTherefore an extensive knowledgeof how PTEN is regulated by developmental signaling apartfrom somatic or genetic mutation is required for completeunderstanding of PTENrsquos role in these important physiologi-cal processes

3 PTEN Regulation as Part ofDevelopmental Signaling

31 Intrinsic and Extrinsic PTEN Regulation Most studiesevaluating the role of PTEN in human diseases have beencentered uponmutation in PTEN itself andmost of this workis done in its relationship to cancer initiation and progression

6 Journal of Signal Transduction

BMP Hh JagdeltaNOTCH

NICD

miRNA(17 19 21)

GF

PTEN mRNA

PTEN mRNA

PTENNICD

SMAD2 3

SMAD1 5 8 Gli2

AP -1

NICDAP -1

SMO

SMAD2 3

SMAD1 5 8 Gli2

SALL4

Cyt

p65p50

p65p50

ceRNAAkt

GSK3CK2

PCAF

SIRT1

PIP3 PIP2

PI3 kinase

TGF120573

Figure 3 Summary of regulation mechanisms for PTEN critical for its action in developmental biology PTEN transcription is regulatedby TGF120573 BMP Hh NOTCH and cytokine signaling in cells during development miRNAs and ceRNAs regulate PTEN message stabilityPhosphorylation or acetylation by then can regulate PTENrsquos protein stability enzymatic activity and cellular localization in a positive ornegative manner All told the regulation of PTEN is complex and precise during development and perturbations in this paradigm haveprofound effects

There is no question that mutations of PTEN play a criticalrole in this regard Studies over the last decade howeverhave discovered a tremendous diversity in the regulationof PTEN expression and found that PTEN is tightly con-trolled both transcriptionally and posttranscriptionally [67]Recent studies to date have implicated microRNAs in PTENsuppression [68] and the enzymatic phosphatase activityof PTEN is also regulated posttranslationally via phospho-rylation ubiquitination or oxidation [69 70] This sectionhighlights the multifaceted mechanisms of PTEN regulationsupported by the rapidly expanding literature on PTENrsquos rolein growth and patterning of tissues during development Inaddition special emphasis is given tomediators and pathwaysinvolved in development including insulin-like growth factortransforming growth factor bone morphogenetic proteinsNOTCH forkhead transcription factors (Fox) and othersPTENrsquos complex regulation at the levels of transcriptionmRNA stability posttranslational modifications andmiRNAlevels has become a critical series of mechanisms deserving acomprehensive review (for an overview see Figure 3)

32 Developmental Signaling Regulating PTEN Expressionand Action The regulation of PTEN expression occurs attranscriptional posttranscriptional posttranslational andprotein-protein interaction levels [71] PTENrsquos function isfurther controlled by its cellular location In this sectionwe highlight developmental pathways involved in regulating

PTEN expression at all these regulation points and makespecial reference to connections between signal transductionand development

321 Developmental Pathways in PTEN Gene ExpressionOne critical aspect of PTENrsquos regulation during developmentbegins at the transcriptional level To date PTEN expres-sion has been found to be regulated at the transcriptionallevel by pathways involving p53 PPAR120574 Egr-1 NF-120581Band SMADs and this regulation affects the developmentof proper immune function the vasculature the nervoussystem the gastrointestinal system and the airways [6372 73] While PTEN is constitutively expressed in manynormal adult tissues PTEN expression is altered dramat-ically through the course of development and in patho-logical settings and a primary source of this regulationcomes from bona fide developmental regulators In additionsuppressors of cytokine signaling (SOCS) and SNAIL alsoinduce PTEN and act by countering the growth-promotingactions of cytokines and growth factors in developmentand repair and recovery [74] This mechanism has beenclearly demonstrated in axonal outgrowth during neurondevelopment and regeneration [74] While the physiologicalramifications of this regulation remain unsolved mediatorsthat slow or inhibit cell proliferation are often involved ininducing this protein Developmental mediators includingNOTCH transforming growth factor beta (TGF120573) bone

Journal of Signal Transduction 7

morphogenetic proteins (BMPs) and hedgehogs (Hhs) allparticipate as players in external PTEN regulation [75ndash78] regulating such processes as proliferation and targetedepithelial budding and outgrowth of visceral organs [76 77]and outgrowth in neurons [75] As the direction of cell growthand differentiation balances on the fulcrum between theproliferative and differentiating actions of these mediatorstheir regulation to induce or repress PTEN expression isa critical aspect of their actions during development Thecritical developmental mediator TGF120573 contains both growthpromoting and inhibiting differentiation qualities and TGF120573induces PTEN during differentiation when growth is slowedand inhibits its expression during proliferation In additionthe developmental regulator DJ-1 was recently identified asa novel negative regulator of PTEN by a genetic screen inDrosophila [79] PTEN is also regulated through epigeneticsilencing by methylation of the PTEN promoter [80 81] Aninteresting zinc-finger transcription factor sal-like protein 4(SALL4) has been discovered as a critical negative regulatorof PTEN transcription by recruiting an epigenetic repressorcomplex involving anATPase and a histone deacetylase to thePTENpromoter [80] SALL4 plays a critical role in regulatingdevelopment by modulating self-renewal in stem cells andits function appears to at least partly involve methylation ofthe PTENpromoter andmodulation of its transcriptionDataon this mechanism are still limited but to date this processhas been shown to regulate kidney patterning during devel-opment as well as leukemogenesis [80] Current research inthe area of PTEN transcriptional regulation continues to bedynamic and more novel regulation patterns are likely to bediscovered in the near future

322 PTEN Regulation by Posttranscriptional RegulationRecent studies have identified several interesting develop-mentally expressed miRNAs that regulate PTEN mRNAmessage stability and translatability [82] These miRNAstypically downregulate PTEN mRNA levels by targeting itfor degradation and include miR-17 miR-19 and miR-21 [83ndash85] While several examples of miR-17 and miR-19-mediatedPTENRNA levels have been reported in the cancer literaturemiR-21 has been described to play a critical role in repairand recovery a developmental signaling-related processmiRNAs regulate this mechanism by modulating PTENRNA stability and ultimately downstream Akt signaling Forexample in the pancreas miR-21 regulates injury repair indiabetic models by targeting PTEN RNA for degradationInhibition of miR-21 results in autophagy in this model ina manner dependent on PTEN degradation [85] In anotherexample of novel miR-related PTEN regulation the PTENpseudogene 1 (PTENP1) acts as a decoy for PTEN-targetingmiRNAs and thereby regulates PTEN expression by coding-independent activity through sequestering these miRNAsand effectively inhibiting their effects on PTEN expression[86] Additionally combined bioinformatic and experimentalapproaches have identified ceRNA transcripts that controlPTEN expression by sequestering PTEN-targeting miRNAsduring development of both prostate and skin [87] Becausethis type of PTEN regulation and indeed this field of generegulation in general is in its infancy we are only beginning

to understand the PTEN regulation by coding and noncodingceRNAs Still this novel work provides a platform for furtherstudies investigating posttranscriptional regulation patternsof PTEN expression in both developmental biology anddisease conditions

323 PTENRegulation by PosttranslationalMechanisms Theprotein stability and enzyme activity of PTEN are regulatedin a number of ways at the posttranslational level FirstPTEN is phosphorylated in its C-terminal tail at Ser380Thr382 Thr383 and Ser385 and this functions to inhibitthe critical PTEN phosphatase activity thereby promotinggrowth in prostate and kidney cells [88] However thesephosphorylations also stabilize the PTEN protein by dis-suading ubiquitination While this may seem like a cellulardisconnect this paradoxical phenomenon is explained by thefinding that this closed more stable PTEN conformation isprevented from associating with membranes and thereforeis geographically separated from its substrates [88] PTENcan also be activated by phosphorylation in particular theC2 domain of PTEN is phosphorylated at Ser229 andThr321by RHOA-associated protein kinase (ROCK) [89] a phos-phorylation that results in its association with membranesand phosphoinositide substrates affecting differentiation inleukocytes PTEN is further phosphorylated at Tyr336 by theTyr protein kinase RAK and this phosphorylation resultsin its stabilization [90] Loss of this activity has the effectof promoting breast cell proliferation and migration FinallyPTEN is also phosphorylated at Ser370 and Thr366 by CK2and GSK3120573 [91 92] respectively however the consequencesof this phosphorylation are unclear The likely extensivesignaling networks that regulate these widespread phospho-rylations in PTEN are not fully studied but the TGFBMP-SMADdevelopmental pathways are known to regulate PTENphosphorylation [93 94] Given the widespread applicationof SMAD signaling to developmental biology the presence ofSMAD-regulated PTEN phosphorylation is a critical aspectof developmental regulation in cells

PTEN enzymatic activity is also regulated posttrans-lationally by acetylation [70 95ndash97] PTEN is acetylatedat Lys125ndashLys128 by p300CREB-binding protein- (CBP-)associated factor (PCAF) and at Lys402 by CBP itself [95]Acetylation at these residues inhibits PTENrsquos function as aphosphatase and has been shown to promote the growthof prostate epithelial cells and glial cells [95] In additionthe deacetylase Sirtuin 1 (SIRT1) is involved in excludingPTEN from the nucleus and therefore preventing its newlycharacterized nuclear functions [96]

324 PTEN Regulation by Protein-Protein Interactions Theconformation stability and subcellular distribution of PTENis regulated by critical interactions with other proteins withincells and these proteins are known to be critical for properdevelopment of a number of organ systems The guanylatekinase inverted 2 (MAGI2) and 120573-arrestins cooperate toenhance PTEN activity [98 99] MAGI2 phosphorylatesPTEN on threonine residues at positions 382 and 383 ofPTENrsquos carboxy terminus allowing recruitment to cell-cell

8 Journal of Signal Transduction

junctions [98] Mutations to these residues prevent PTENrecruitment Upon recruitment 120573-arrestins modulate PTENactivity by direct binding to the C2 domain and modulatingits protein phosphatase activity including that at the levelof small GTPases including RhoAROCK [99] In addi-tion Myosin V regulates PTENrsquos movement to and fromthe plasma membrane and this function is required forPTEN to access its phosphoinositide substrates [100] andfor disrupting the proper regulation of neuronal cell sizeThe p85 regulatory subunit of the PI

3kinase enzyme itself

interacts with PTEN in a novel mechanism of repressing thePI3KndashAKT pathway [101] independent of PTENrsquos action as a

phosphatase It is therefore proposed that p85 regulates thePI3KndashAKT pathway bidirectionally both through its binding

to catalytic p110 subunit resulting in the generation of phos-phoinositides and by binding PTEN leading to repressionThis work proposes a novel signaling model for PTEN-p85association in which p85120572 preferentially binds and stabilizesp110 preferentially when p85120572 levels are low but excess p85120572binds to and positively regulates PTEN phosphatase activitywhen p110 is saturated Therefore sustained activation ofPI3K signaling and activated p110-p85 complexing is modu-lated homeostatically by this mechanism

A fascinating group of recent studies have utilizedproteomic library screens to identify further novel PTENinteracting proteins First the Na+H+ exchanger regulatoryfactor (NHERF) binds to and recruits PTEN to the platelet-derived growth factor receptor (PDGFR) This representsanother action that restricts PI

3KndashAKT pathway activation

independent of phosphatase activity [102] This has the effectof inhibiting PDGF-induced cytoskeletal rearrangements andchemotactic migration of developing neurons In additionthe mammalian disks large homologue 1 (DLG1) MAGI-2 and MAST205 proteins directly interact with PTENand enhance PTEN stability and activity [103] Furtherneuregulin 1 (NRG1) has been shown to interact with bothDLG1 and PTEN in a stable complex that has the effect ofregulating myelin sheath thickness in developing mouse sci-atic nerves [104] Additional but less-characterized protein-protein interactions that modulate PTEN function includethe PIP

3-dependent RAC exchanger factor 2a (PREX2a)

[105] shank-interacting protein-like 1 (SIPL1) [106] and 120572-mannosidase 2C1 (MAN2C1) [107]

325 PTEN-Controlled Signal Transduction during Develop-ment PTEN is critically important in regulating signalingpathways involved in cell growth and animal developmentThrough its well-characterized function as a phosphataseof PIP

3 PTEN modulates a network of mitogen-activated

signals transduced through PI3KndashAkt signaling This pri-

mary action of PTEN has tremendous impact on cell growthcell migration cell death and cell differentiationmdashcellularprocesses that are all hallmarks of proper growth andpatterning during development The active phosphorylatedPIP3activates several signaling molecules including the

phosphatidylinositol-dependent kinases (PDKs) followed byAkt S6 kinase and mTOR Beyond this AKTrsquos targetsinclude the apoptotic factor BAD activator and executioner

caspases glycogen synthase kinase-3 (GSK-3) MDM2 p21and p27 forkhead transcription factors (FOXOs) and nuclearreceptors including the androgen and estrogen receptors[108] Akt-mediated phosphorylation of these moleculescauses activation translocation and increased stability

The PTENPI3kinaseAKT signaling cascade crosstalks

to several key signal transduction pathways that are criticalto developmental biology This includes the abovementionedTGF-120573SMAD pathway and the Wnt120573-catenin pathway[109] The TGF-120573SMAD pathway is one of the most seminalpathways in developmental biology and PTEN modulatesTGF120573SMAD signaling by reversing Akt-mediated phospho-rylation of SMAD3 the critical signaling intermediate ofTGF120573SMAD signaling [110] Similarly the Wnt signalingpathway is indispensable for properly regulated developmentcellular proliferation and differentiation [111] PTEN regu-lates this pathway by reversing AKT kinase phosphorylationand inhibition of GSK-3120573 resulting in 120573-catenin nucleartranslocation and activation Finally recent studies demon-strate that PTEN regulates the expression and action of thehomeobox genes NKX31 and hepatic nuclear factor [112]proteins that are critical to organ development

326 PTEN-Regulated Stem Cell Activities The scientificliterature in the field of tissue stem or stem-like ldquoprogen-itorrdquo cells and their role in tissue development growthrecovery and repair has become beyond extensive in recentyears Expansion of stemprogenitor cells is a hallmark ofgrowth and patterning during development and regulationof these cells including their proliferation maintenanceand differentiation is a critical factor of developmentalregulation Because of this a review of the current liter-ature on PTENrsquos role in stem and tissue progenitor cellsis warranted in this review PTEN plays an important rolein regulating the homeostasis of stemprogenitor cells inmultiple tissues Interestingly PTEN regulates both self-renewal and proliferation but paradoxically it also playsa role in stem cell exhaustion For example the FOXOfamily of transcription factors controls stem cell proliferationand survival in hematopoietic stem cells [113] and PTENsignaling is a critical modulator of FOXO activity FOXO3A-deficient HSCs exhibit increased proliferation rate decreasedquiescence and a reduced ability to repopulate bone marrowafter transplantation into recipient mice Additionally thepreviously mentioned Wnt120573-catenin signaling pathway iscritical for HSC self-renewal and its activation is well knownto be modulated by PTEN Interestingly PTEN loss and AKTactivation in HSCs lead to a moderate increase in the levelof unphosphorylated 120573-catenin but this is not sufficient tomaintain Pten-null HSC self-renewal [114] Finally NOTCHsignaling plays a key role in regulating neural stem cellexpansion [115] and as stated previously NOTCH pathwayactivation leads to reduced PTEN expression in neural andhematopoietic stem cells

4 Conclusions

PTEN acts as the key endogenous negative modulatorof phosphoinositide signaling in mammalian cells and

Journal of Signal Transduction 9

therefore its role in normal cell homeostasis proliferationapoptosis and many additional components of cell biologyis extensive Because PTEN regulates cancer progressionmuch of what has been studied regarding PTEN relates totumorigenesis and tumor growth While this is warrantedbecause of the relevance of cancer to humanhealth PTENhassubstantial but underappreciated effects in normal tissue andorgan development immune system development and reg-ulation axonal regeneration glucose regulation and benigngrowth disorders PTEN is often dogmatically thought ofas a constitutive protein that exhibits lost activity duringdiseases butwhat is underappreciated is that PTENhas a verycomplex regulation network that involves signaling path-ways that regulate PTEN transcription transcript stabilityposttranslationalmodifications protein-protein interactionsand cellular location PTEN then in turn regulates numerousdevelopmental signaling networks that are critical to devel-opment and adult tissue maintenance

Abbreviations

Bcl2 B-cell lymphoma 2Bim BCL-2-interacting mediatorCK2 Casein Kinase 2CREB Cyclic AMP response element binding

proteinDLG Disks large homolog 1Egr-1 Early growth response protein 1Erk Extracellular regulated kinaseFOX Forkhead transcription factorsGSK3120573 Glycogen synthase kinase 3JNK Jun-terminal kinaseMAGI2 Membrane-associated guanylate kinase

inverted 2MAN2C1 Mannosidase alpha class 2C member 1MDM2 Mouse double minute 2 homologmTOR Mechanistic target of rapamycinNHERF Sodium-hydrogen antiporter 3

regulator 1NRG1 Neuregulin 1PCAF P300CBP-associated factorPDZ Postsynaptic density proteinmdashDisc

large tumor suppressormdashZonulaoccludens-1 protein

PIP3 Phosphoinositide triphosphatePPAR120574 Peroxisome proliferating antigen

receptorPREX2a Phosphatidylinositol-345-

trisphosphate-dependent Rac exchangefactor A

PTEN Phosphatase and Tensin homologueROCK Rho-associated coiled-coil-containing

protein kinaseSALL Spalt-like transcription factor-1SIPL1 Shank-interacting protein-like 1SIRT1 Sirtuin 1SMAD Small mothers against decapentaplegicSOCS Suppressor of cytokine signalingTGF120573 Transforming growth factor-beta

Disclosure

Travis J Jerde carried out the extensive literature reviewrequired to write this paper and have written the entirepaper The author has therefore read and approved the papersubmitted

Conflict of Interests

The author has no financial or nonfinancial conflict ofinterests with the submission of this paper

Acknowledgments

The author gratefully acknowledges the financial supportof the Indiana University School of Medicine Departmentof Pharmacology and Toxicology and the Melvin and BrynSimon Cancer Center The author also gratefully acknowl-edges this paper as part of his training made possible byNational Institutes of Health-NIDDK (DK092366-01A1)

References

[1] M Milella I Falcone F Conciatori et al ldquoPTEN multiplefunctions in human malignant tumorsrdquo Frontiers in Oncologyvol 5 article 24 2015

[2] J-O Lee H Yang M-M Georgescu et al ldquoCrystal structure ofthe PTEN tumor suppressor implications for its phosphoinosi-tide phosphatase activity and membrane associationrdquo Cell vol99 no 3 pp 323ndash334 1999

[3] W-L Yang G Jin C-F Li et al ldquoCycles of ubiquitinationand deubiquitination critically regulate growth factor-mediatedactivation of Akt signalingrdquo Science Signaling vol 6 no 257article ra3 2013

[4] J Gu S Nada M Okada and K Sekiguchi ldquoCsk regulatesintegrin-mediated signals involvement of differential activa-tion of ERK and Aktrdquo Biochemical and Biophysical ResearchCommunications vol 303 no 3 pp 973ndash977 2003

[5] A Clerk and P H Sugden ldquoActivation of protein kinase cas-cades in the heart by hypertrophic G protein-coupled receptoragonistsrdquoTheAmerican Journal of Cardiology vol 83 no 12 pp64Hndash69H 1999

[6] I Tonic W-N Yu Y Park C-C Chen and N Hay ldquoAktactivation emulates Chk1 inhibition and Bcl2 overexpressionand abrogates G2 cell cycle checkpoint by inhibiting BRCA1focirdquo The Journal of Biological Chemistry vol 285 no 31 pp23790ndash23798 2010

[7] S Fatrai L Elghazi N Balcazar et al ldquoAkt induces 120573-cellproliferation by regulating cyclin D1 cyclin D2 and p21 levelsand cyclin-dependent kinase-4 activityrdquo Diabetes vol 55 no 2pp 318ndash325 2006

[8] M Aoki E Blazek and P K Vogt ldquoA role of the kinase mTORin cellular transformation induced by the oncoproteins P3k andAktrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 98 no 1 pp 136ndash141 2001

[9] H Guan L Song J Cai et al ldquoSphingosine kinase 1 regulatesthe AktFOXO3aBim pathway and contributes to apoptosisresistance in glioma cellsrdquo PLoS ONE vol 6 no 5 Article IDe19946 2011

[10] T D Dung C H Day T V Binh et al ldquoPP2Amediates diosminp53 activation to block HA22T cell proliferation and tumor

10 Journal of Signal Transduction

growth in xenografted nude mice through PI3K-Akt-MDM2signaling suppressionrdquo Food and Chemical Toxicology vol 50no 5 pp 1802ndash1810 2012

[11] K Shanmugasundaram K Block B K Nayak C B Livi MA Venkatachalam and S Sudarshan ldquoPI3K regulation of theSKP-2p27 axis through mTORC2rdquo Oncogene vol 32 no 16pp 2027ndash2036 2013

[12] J-C Chang H-H Chang C-T Lin and S J Lo ldquoThe integrin12057261205731modulation of PI3K andCdc42 activities induces dynamicfilopodium formation in humanplateletsrdquo Journal of BiomedicalScience vol 12 no 6 pp 881ndash898 2005

[13] E Hajduch G J Litherland and H S Hundal ldquoProtein kinaseB (PKBAkt)mdasha key regulator of glucose transportrdquo FEBSLetters vol 492 no 3 pp 199ndash203 2001

[14] M M Martin J A Buckenberger J Jiang et al ldquoTGF-beta1stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[15] M M Martin J A Buckenberger J Jiang et al ldquoTGF-1205731stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[16] K Abell and C J Watson ldquoThe JakStat pathway a novel wayto regulate PI3K activityrdquo Cell Cycle vol 4 no 7 pp 897ndash9002005

[17] J-Y Hwang R S Duncan C Madry M Singh and P KoulenldquoProgesterone potentiates calcium release through IP3 recep-tors by an Akt-mediated mechanism in hippocampal neuronsrdquoCell Calcium vol 45 no 3 pp 233ndash242 2009

[18] G Pappas L A Zumstein A Munshi M Hobbs and R EMeyn ldquoAdenoviral-mediated PTEN expression radiosensitizesnon-small cell lung cancer cells by suppressing DNA repaircapacityrdquoCancer GeneTherapy vol 14 no 6 pp 543ndash549 2007

[19] A Di Cristofano B Pesce C Cordon-Cardo and P P PandolfildquoPten is essential for embryonic development and tumoursuppressionrdquo Nature Genetics vol 19 no 4 pp 348ndash355 1998

[20] J Bloomekatz J Grego-Bessa I Migeotte and K V AndersonldquoPten regulates collective cell migration during specification ofthe anterior-posterior axis of the mouse embryordquo Developmen-tal Biology vol 364 no 2 pp 192ndash201 2012

[21] S Ueno R Kono andY Iwao ldquoPTEN is required for the normalprogression of gastrulation by repressing cell proliferation afterMBT in Xenopus embryosrdquoDevelopmental Biology vol 297 no1 pp 274ndash283 2006

[22] C B Knobbe A Merlo and G Reifenberger ldquoPten signaling ingliomasrdquo Neuro Oncology vol 4 pp 196ndash211 2002

[23] E Kirches J Steiner T Schneider et al ldquoLhermitte-Duclosdisease caused by a novel germline PTEN mutation R173P in apatient presenting with psychosisrdquoNeuropathology and AppliedNeurobiology vol 36 no 1 pp 86ndash89 2010

[24] J-I Murata M Tada Y Sawamura K Mitsumori H Abe andK Nagashima ldquoDysplastic gangliocytoma (Lhermitte-Duclosdisease) associated with Cowden disease report of a case andreview of the literature for the genetic relationship between thetwo diseasesrdquo Journal of Neuro-Oncology vol 41 no 2 pp 129ndash136 1999

[25] G Zhu L M L Chow I T Bayazitov et al ldquoPten deletioncauses mTorc1-dependent ectopic neuroblast differentiation

without causing uniform migration defectsrdquo Development vol139 no 18 pp 3422ndash3431 2012

[26] K L McBride E A Varga M T Pastore et al ldquoConfirmationstudy of PTEN mutations among individuals with autism ordevelopmental delaysmental retardation and macrocephalyrdquoAutism Research vol 3 no 3 pp 137ndash141 2010

[27] J Zhou and L F Parada ldquoPTEN signaling in autism spectrumdisordersrdquo Current Opinion in Neurobiology vol 22 no 5 pp873ndash879 2012

[28] S A Backman V Stambolic A Suzuki et al ldquoDeletion of Ptenin mouse brain causes seizures ataxia and defects in soma sizeresembling Lhermitte-Duclos diseaserdquo Nature Genetics vol 29no 4 pp 396ndash403 2001

[29] L Cotter M Ozcelik C Jacob et al ldquoDlg1-PTEN interactionregulates myelin thickness to prevent damaging peripheralnerve overmyelinationrdquo Science vol 328 no 5984 pp 1415ndash1418 2010

[30] S Ogawa C-H Kwon J Zhou D Koovakkattu L F Paradaand C M Sinton ldquoA seizure-prone phenotype is associatedwith altered free-running rhythm in Pten mutant micerdquo BrainResearch vol 1168 no 1 pp 112ndash123 2007

[31] C-H Kwon X Zhu J Zhang and S J Baker ldquomTor isrequired for hypertrophy of Pten-deficient neuronal soma invivordquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 22 pp 12923ndash12928 2003

[32] C-H Kwon B W Luikart C M Powell et al ldquoPten regulatesneuronal arborization and social interaction in micerdquo Neuronvol 50 no 3 pp 377ndash388 2006

[33] A Suzuki S Itami M Ohishi et al ldquoKeratinocyte-specific Ptendeficiency results in epidermal hyperplasia accelerated hairfollicle morphogenesis and tumor formationrdquo Cancer Researchvol 63 no 3 pp 674ndash681 2003

[34] T Inoue-Narita K Hamada T Sasaki et al ldquoPten deficiency inmelanocytes results in resistance to hair graying and susceptibil-ity to carcinogen-induced melanomagenesisrdquo Cancer Researchvol 68 no 14 pp 5760ndash5768 2008

[35] R K Patel and C Mohan ldquoPI3KAKT signaling and systemicautoimmunityrdquo Immunologic Research vol 31 no 1 pp 47ndash552005

[36] K Podsypanina L H Ellenson A Nemes et al ldquoMutationof PtenMmac1 in mice causes neoplasia in multiple organsystemsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 4 pp 1563ndash1568 1999

[37] M Kashiwada P Lu and P B Rothman ldquoPIP3 pathway inregulatory T cells and autoimmunityrdquo Immunologic Researchvol 39 no 1ndash3 pp 194ndash224 2007

[38] A Suzuki M T Yamaguchi T Ohteki et al ldquoT cell-specificloss of Pten leads to defects in central and peripheral tolerancerdquoImmunity vol 14 no 5 pp 523ndash534 2001

[39] Y Yamanaka H Tagawa N Takahashi et al ldquoAberrant over-expression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lym-phomaleukemiardquo Blood vol 114 no 15 pp 3265ndash3275 2009

[40] H Kishimoto T Ohteki N Yajima et al ldquoThe PtenPI3Kpathway governs the homeostasis of V12057214iNKT cellsrdquo Bloodvol 109 no 8 pp 3316ndash3324 2007

[41] A Suzuki T Kaisho M Ohishi et al ldquoCritical roles ofPten in B cell homeostasis and immunoglobulin class switchrecombinationrdquo Journal of Experimental Medicine vol 197 no5 pp 657ndash667 2003

Journal of Signal Transduction 11

[42] M Nishio K-IWatanabe J Sasaki et al ldquoControl of cell polar-ity and motility by the PtdIns(345)P

3phosphatase SHIP1rdquo

Nature Cell Biology vol 9 no 1 pp 36ndash44 2007[43] S Kuroda M Nishio T Sasaki et al ldquoEffective clearance

of intracellular Leishmania major in vivo requires Pten inmacrophagesrdquo European Journal of Immunology vol 38 no 5pp 1331ndash1340 2008

[44] O H Yilmaz R Valdez B K Theisen et al ldquoPten depen-dence distinguishes haematopoietic stem cells from leukaemia-initiating cellsrdquo Nature vol 441 no 7092 pp 475ndash482 2006

[45] Y Li K Podsypanina X Liu et al ldquoDeficiency of Ptenaccelerates mammary oncogenesis in MMTV-Wnt-1 transgenicmicerdquo BMCMolecular Biology vol 2 article 2 2001

[46] P Reddy L Liu D Adhikari et al ldquoOocyte-specific deletion ofpten causes premature activation of the primordial follicle poolrdquoScience vol 319 no 5863 pp 611ndash613 2008

[47] H Tsuruta H Kishimoto T Sasaki et al ldquoHyperplasia andcarcinomas in Pten-deficient mice and reduced PTEN proteinin human bladder cancer patientsrdquoCancer Research vol 66 no17 pp 8389ndash8396 2006

[48] L I Yoo D W Liu S Le Vu R T Bronson H Wu and JYuan ldquoPten deficiency activates distinct downstream signalingpathways in a tissue-specific mannerrdquo Cancer Research vol 66no 4 pp 1929ndash1939 2006

[49] J Li C Yen D Liaw et al ldquoPTEN a putative protein tyrosinephosphatase gene mutated in human brain breast and prostatecancerrdquo Science vol 275 no 5308 pp 1943ndash1947 1997

[50] N D Deocampo H Huang and D J Tindall ldquoThe role ofPTEN in the progression and survival of prostate cancerrdquoMinerva Endocrinologica vol 28 no 2 pp 145ndash153 2003

[51] S A Backman D Ghazarian K So et al ldquoEarly onset ofneoplasia in the prostate and skin of mice with tissue-specificdeletion of Ptenrdquo Proceedings of the National Academy ofSciences of the United States of America vol 101 no 6 pp 1725ndash1730 2004

[52] X Wu K Xu L Zhang et al ldquoDifferentiation of the ductalepithelium and smooth muscle in the prostate gland areregulated by the NotchPTEN-dependent mechanismrdquo Devel-opmental Biology vol 356 no 2 pp 337ndash349 2011

[53] D Kim and G R Dressler ldquoPTEN modulates GDNFRETmediated chemotaxis and branching morphogenesis in thedeveloping kidneyrdquo Developmental Biology vol 307 no 2 pp290ndash299 2007

[54] N O Lindstrom M L Lawrence S F Burn et al ldquoIntegrated120573-catenin BMP PTEN and notch signalling patterns thenephronrdquo eLife no 4 Article ID e04000 2015

[55] V Marsh D J Winton G T Williams et al ldquoEpithelialPten is dispensable for intestinal homeostasis but suppressesadenoma development and progression after Apc mutationrdquoNature Genetics vol 40 no 12 pp 1436ndash1444 2008

[56] S Matsuda M Kobayashi and Y Kitagishi ldquoRoles forPI3KAKTPTEN pathway in cell signaling of nonalcoholicfatty liver diseaserdquo ISRN Endocrinology vol 2013 Article ID472432 7 pages 2013

[57] X Qi J Xu P Gu X Yang and X Gao ldquoPTEN in smoothmuscle cells is essential for colonic immune homeostasisrdquoInternational Journal of Biochemistry and Cell Biology vol 53pp 108ndash114 2014

[58] A Pal T M Barber M Van de Bunt et al ldquoPTENmutations asa cause of constitutive insulin sensitivity and obesityrdquoThe NewEngland Journal of Medicine vol 367 no 11 pp 1002ndash1011 2012

[59] B L Stiles C Kuralwalla-Martinez W Guo et al ldquoSelectivedeletion of Pten in pancreatic 120573 cells leads to increased isletmass and resistance to STZ-induced diabetesrdquo Molecular andCellular Biology vol 26 no 7 pp 2772ndash2781 2006

[60] LWang C T Luk E P Cai et al ldquoPTEN deletion in pancreatic120572-cells protects against high-fat diet-induced hyperglucagone-mia and insulin resistancerdquo Diabetes vol 64 no 1 pp 147ndash1572015

[61] C Kurlawalla-Martinez B Stiles Y Wang S U Devaskar BB Kahn and H Wu ldquoInsulin hypersensitivity and resistanceto streptozotocin-induced diabetes in mice lacking PTEN inadipose tissuerdquo Molecular and Cellular Biology vol 25 no 6pp 2498ndash2510 2005

[62] N Wijesekara D Konrad M Eweida et al ldquoMuscle-specificPten deletion protects against insulin resistance and diabetesrdquoMolecular and Cellular Biology vol 25 no 3 pp 1135ndash11452005

[63] K Hamada T Sasaki P A Koni et al ldquoThe PTENPI3Kpathway governs normal vascular development and tumorangiogenesisrdquo Genes and Development vol 19 no 17 pp 2054ndash2065 2005

[64] N D Roe X Xu M R Kandadi et al ldquoTargeted deletionof PTEN in cardiomyocytes renders cardiac contractile dys-function through interruption of Pink1-AMPK signaling andautophagyrdquo Biochimica et Biophysica Acta Molecular Basis ofDisease vol 1852 no 2 pp 290ndash298 2015

[65] A F Ford-Hutchinson Z Ali S E Lines B HallgrımssonS K Boyd and F R Jirik ldquoInactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnor-malities and skeletal overgrowthrdquo Journal of Bone and MineralResearch vol 22 no 8 pp 1245ndash1259 2007

[66] T A Burgers M F Hoffmann C J Collins et al ldquoMice lackingpten in osteoblasts have improved intramembranous and lateendochondral fracture healingrdquo PLoS ONE vol 8 no 5 ArticleID e63857 2013

[67] N R Leslie L Spinelli P Tibarewal et al ldquoIndirect mecha-nisms of carcinogenesis via downregulation of PTEN functionrdquoAdvances in Enzyme Regulation vol 50 no 1 pp 112ndash118 2010

[68] L He ldquoPosttranscriptional regulation of PTEN dosage bynoncoding RNAsrdquo Science Signaling vol 3 no 146 article pe392010

[69] F Vazquez S R Grossman Y Takahashi M V Rokas NNakamura andWR Sellers ldquoPhosphorylation of the PTEN tailacts as an inhibitory switch by preventing its recruitment into aprotein complexrdquo The Journal of Biological Chemistry vol 276no 52 pp 48627ndash48630 2001

[70] X Wang L C Trotman T Koppie et al ldquoNEDD4-1 is a proto-oncogenic ubiquitin ligase for PTENrdquo Cell vol 128 no 1 pp129ndash139 2007

[71] N R Leslie and M Foti ldquoNon-genomic loss of PTEN functionin cancer not in my genesrdquo Trends in Pharmacological Sciencesvol 32 no 3 pp 131ndash140 2011

[72] Y Xing C Li L Hu et al ldquoMechanisms of TGF120573 inhibition ofLUNG endodermal morphogenesis the role of T120573RII SmadsNkx21 and Ptenrdquo Developmental Biology vol 320 no 2 pp340ndash350 2008

[73] J P Luyendyk G A Schabbauer M Tencati T Holscher RPawlinski and N Mackman ldquoGenetic analysis of the role ofthe PI3K-Akt pathway in lipopolysaccharide-induced cytokineand tissue factor gene expression in monocytesmacrophagesrdquoJournal of Immunology vol 180 no 6 pp 4218ndash4226 2008

12 Journal of Signal Transduction

[74] F Sun K K Park S Belin et al ldquoSustained axon regenerationinduced by co-deletion of PTEN and SOCS3rdquo Nature vol 480no 7377 pp 372ndash375 2011

[75] C B Knobbe V Lapin A Suzuki and T W Mak ldquoThe roles ofPTEN in development physiology and tumorigenesis in mousemodels a tissue-by-tissue surveyrdquo Oncogene vol 27 no 41 pp5398ndash5415 2008

[76] S J Assinder Q Dong Z Kovacevic and D R RichardsonldquoThe TGF-beta PI3KAkt and PTEN pathways establishedand proposed biochemical integration in prostate cancerrdquoBiochemical Journal vol 417 no 2 pp 411ndash421 2009

[77] K A Waite and C Eng ldquoFrom developmental disorder toheritable cancer itrsquos all in the BMPTGF-120573 familyrdquo NatureReviews Genetics vol 4 no 10 pp 763ndash773 2003

[78] H B Newton ldquoMolecular neuro-oncology and developmentof targeted therapeutic strategies for brain tumors Part2 PI3KAktPTEN mTOR SHHPTCH and angiogenesisrdquoExpert Review of Anticancer Therapy vol 4 no 1 pp 105ndash1282004

[79] R H KimM Peters Y Jang et al ldquoDJ-1 a novel regulator of thetumor suppressor PTENrdquo Cancer Cell vol 7 no 3 pp 263ndash2732005

[80] J Lu H W Jeong N Kong et al ldquoStem cell factor SALL4represses the transcriptions of PTEN and SALL1 through anepigenetic repressor complexrdquo PLoS ONE vol 4 no 5 ArticleID e5577 2009

[81] M M A Rizvi M S Alam A Ali S J Mehdi S Batra andA KMandal ldquoAberrant promotermethylation and inactivationof PTEN gene in cervical carcinoma from Indian populationrdquoJournal of Cancer Research and Clinical Oncology vol 137 no 8pp 1255ndash1262 2011

[82] J Liu ldquoControl of protein synthesis and mRNA degradation bymicroRNAsrdquo Current Opinion in Cell Biology vol 20 no 2 pp214ndash221 2008

[83] S W Shan L Fang T Shatseva et al ldquoMature miR-17-5pand passenger miR-17-3p induce hepatocellular carcinoma bytargeting PTEN GalNT7 and vimentin in different signalpathwaysrdquo Journal of Cell Science vol 126 part 6 pp 1517ndash15302013

[84] Z Liang Y Li K Huang N Wagar and H Shim ldquoRegulationof miR-19 to breast cancer chemoresistance through targetingPTENrdquo Pharmaceutical Research vol 28 no 12 pp 3091ndash31002011

[85] X Lu Q Fan L Xu et al ldquoUrsolic acid attenuates diabeticmesangial cell injury through the up-regulation of autophagyvia miRNA-21PTENAktmTOR suppressionrdquo PLoS ONE vol10 no 2 Article ID e0117400 2015

[86] L Poliseno L Salmena J Zhang B Carver W J Havemanand P P Pandolfi ldquoA coding-independent function of geneand pseudogenemRNAs regulates tumour biologyrdquoNature vol465 no 7301 pp 1033ndash1038 2010

[87] Y Tay L Kats L Salmena et al ldquoCoding-independent regula-tion of the tumor suppressor PTEN by competing endogenousmRNAsrdquo Cell vol 147 no 2 pp 344ndash357 2011

[88] L Odriozola G Singh T Hoang and A M Chan ldquoRegula-tion of PTEN activity by its carboxyl-terminal autoinhibitorydomainrdquo The Journal of Biological Chemistry vol 282 no 32pp 23306ndash23315 2007

[89] Z Li X Dong Z Wang et al ldquoRegulation of PTEN by Rhosmall GTPasesrdquo Nature Cell Biology vol 7 no 4 pp 399ndash4042005

[90] E-K Yim G Peng H Dai et al ldquoRak functions as a tumorsuppressor by regulating PTEN protein stability and functionrdquoCancer Cell vol 15 no 4 pp 304ndash314 2009

[91] AMAl-Khouri YMa SH Togo SWilliams andTMustelinldquoCooperative phosphorylation of the tumor suppressor phos-phatase and tensin homologue (PTEN) by casein kinasesand glycogen synthase kinase 3120573rdquo The Journal of BiologicalChemistry vol 280 no 42 pp 35195ndash35202 2005

[92] H Maccario N M Perera L Davidson C P Downes and NR Leslie ldquoPTEN is destabilized by phosphorylation onThr366rdquoBiochemical Journal vol 405 no 3 pp 439ndash444 2007

[93] K A Waite and C Eng ldquoBMP2 exposure results in decreasedPTEN protein degradation and increased PTEN levelsrdquoHumanMolecular Genetics vol 12 no 6 pp 679ndash684 2003

[94] T J Jerde Z Wu D Theodorescu and W Bushman ldquoRegu-lation of phosphatase homologue of tensin protein expressionby bone morphogenetic proteins in prostate epithelial cellsrdquoProstate vol 71 no 8 pp 791ndash800 2011

[95] G Singh and A M Chan ldquoPost-translational modificationsof PTEN and their potential therapeutic implicationsrdquo CurrentCancer Drug Targets vol 11 no 5 pp 536ndash547 2011

[96] T Ikenoue K Inoki B Zhao and K-L Guan ldquoPTEN acety-lation modulates its interaction with PDZ domainrdquo CancerResearch vol 68 no 17 pp 6908ndash6912 2008

[97] L C Trotman X Wang A Alimonti et al ldquoUbiquitinationregulates PTEN nuclear import and tumor suppressionrdquo Cellvol 128 no 1 pp 141ndash156 2007

[98] T Tolkacheva M Boddapati A Sanfiz K Tsuchida A CKimmelman and AM-L Chan ldquoRegulation of PTEN bindingto MAGI-2 by two putative phosphorylation sites at threonine382 and 383rdquo Cancer Research vol 61 no 13 pp 4985ndash49892001

[99] E Lima-Fernandes H Enslen E Camand et al ldquoDistinct func-tional outputs of PTEN signalling are controlled by dynamicassociation with 120573-arrestinsrdquoThe EMBO Journal vol 30 no 13pp 2557ndash2568 2011

[100] M T van Diepen M Parsons C P Downes N R Leslie RHindges and B J Eickholt ldquoMyosinV controls PTEN functionand neuronal cell sizerdquo Nature Cell Biology vol 11 no 10 pp1191ndash1196 2009

[101] R B Chagpar P H Links M C Pastor et al ldquoDirect positiveregulation of PTEN by the p85 subunit of phosphatidylinositol3-kinaserdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 107 no 12 pp 5471ndash5476 2010

[102] Y Takahashi F C Morales E L Kreimann and M-MGeorgescu ldquoPTEN tumor suppressor associates with NHERFproteins to attenuate PDGF receptor signalingrdquo The EMBOJournal vol 25 no 4 pp 910ndash920 2006

[103] M Valiente A Andres-Pons B Gomar et al ldquoBinding ofPTEN to specific PDZ domains contributes to PTEN proteinstability and phosphorylation by microtubule-associated ser-inethreonine kinasesrdquoThe Journal of Biological Chemistry vol280 no 32 pp 28936ndash28943 2005

[104] SQuintes SGoebbels G SaherMH Schwab andK-ANaveldquoNeuron-glia signaling and the protection of axon function bySchwann cellsrdquo Journal of the Peripheral Nervous System vol 15no 1 pp 10ndash16 2010

[105] B Fine C Hodakoski S Koujak et al ldquoActivation of the PI3Kpathway in cancer through inhibition of PTEN by exchangefactor P-REX2ardquo Science vol 325 no 5945 pp 1261ndash1265 2009

Journal of Signal Transduction 13

[106] L He A Ingram A P Rybak and D Tang ldquoShank-interactingprotein-like 1 promotes tumorigenesis via PTEN inhibition inhuman tumor cellsrdquo The Journal of Clinical Investigation vol120 no 6 pp 2094ndash2108 2010

[107] L He C Fan A Kapoor et al ldquo120572-Mannosidase 2C1 attenuatesPTEN function in prostate cancer cellsrdquo Nature Communica-tions vol 2 no 1 article 307 2011

[108] Z Radisavljevic ldquoAKT as locus of cancer positive feedbackloops and extreme robustnessrdquo Journal of Cellular Physiologyvol 228 no 3 pp 522ndash524 2013

[109] M Y Lee HW Lim S H Lee andH J Han ldquoSmad PI3KAktand wnt-dependent signaling pathways are involved in BMP-4-induced ESC self-renewalrdquo Stem Cells vol 27 no 8 pp 1858ndash1868 2009

[110] K Song S C Cornelius M Reiss and D Danielpour ldquoInsulin-like growth factor-I inhibits transcriptional responses of trans-forming growth factor-120573 by phosphatidylinositol 3-kinaseAkt-dependent suppression of the activation of Smad3 but notSmad2rdquoThe Journal of Biological Chemistry vol 278 no 40 pp38342ndash38351 2003

[111] D Fang D Hawke Y Zheng et al ldquoPhosphorylation of 120573-catenin by AKT promotes 120573-catenin transcriptional activityrdquoThe Journal of Biological Chemistry vol 282 no 15 pp 11221ndash11229 2007

[112] Q Lei J Jiao L Xin et al ldquoNKX31 stabilizes p53 inhibitsAKT activation and blocks prostate cancer initiation caused byPTEN lossrdquo Cancer Cell vol 9 no 5 pp 367ndash378 2006

[113] A Sengupta J D Molkentin J-H Paik R A DePinho and KE Yutzey ldquoFoxO transcription factors promote cardiomyocytesurvival upon induction of oxidative stressrdquo The Journal ofBiological Chemistry vol 286 no 9 pp 7468ndash7478 2011

[114] C H M Jamieson L E Ailles S J Dylla et al ldquoGranulocyte-macrophage progenitors as candidate leukemic stem cells inblast-crisis CMLrdquoTheNewEngland Journal ofMedicine vol 351no 7 pp 657ndash667 2004

[115] A Androutsellis-Theotokis R R Leker F Soldner et al ldquoNotchsignalling regulates stem cell numbers in vitro and in vivordquoNature vol 442 no 7104 pp 823ndash826 2006

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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International Journal of

Volume 2014

Zoology

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Signal TransductionJournal of

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International Journal of

Microbiology

Page 2: Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling TravisJ.Jerde Department of Pharmacology

2 Journal of Signal Transduction

1 15 186 352 400 403N-term Phosphatase domain C2 domain C-tail PDZ

substratebinding

Phosphataseactivity

Acetylation sitesInhibitory protein

interactions

Cellular locationMembrane association

Protein-protein interactions

Phospho-sitesProtein stability

PIP2

Figure 1 Protein domains of PTEN PTEN has five distinct domains consisting of an N-terminal PIP binding domain the phosphatasedomain responsible for its enzymatic activity and containing acetylation sites responsible for regulating this phosphatase activity theregulatory C2 domain responsible for its cellular location and protein-protein interactions including those that modify enzyme activity orlocalization the less understood C-tail containing phosphorylation sites thought to be critical for PTENrsquos stability and finally the C-terminalPDZ domain

of many pathways this includes cell cycle progression viap27Kip1 [6] Wee1 p21 and cyclin D [7] mTOR-mediatedcellular signaling [8] apoptosis and survival effects mediatedby Bim [9] MDM2-p53 [10] Bcl-2 and Bax [11] cellularstructure regulation mediated by laminins and cytoskeletalprotein expression [12] glycogen and glucose regulation andglycolysis by glycogen synthase 6-phosphofructo-2-kinaseand AS160 [13] Adding to the broad activity of PTEN arethe numerous examples of signaling crosstalk with othertransduction pathways including the Erk p38 and JNKmitogen-activated protein kinases [14] the TGF120573 and BMP-associated SMAD pathways [15] the cytokine-mediated Jak-STAT pathway [16] and IP

3-mediated calcium signaling [17]

Additionally interesting recent findings have demonstratedthat PTEN modulates the DNA damage response and repairvia its inhibition of Akt [18] Because of this diversity anymediators that modulate PTEN expression levels or functionhave substantial effects on cellular function

As a critical cellular protein that modulates numerousprocesses it is expected that PTEN plays a major role inregulating proper development Yet PTEN is still primarilyknown as a tumor suppressormdashthe loss of function of whichleads to tumorigenesisWhile thismay be true the last decadehas seen a greatly enhanced understanding of how PTENis regulated particularly as this relates normal growth anddevelopmentThis review takes a critical look at the literaturefocusing on PTEN regulation the effects of this regulationduring mammalian development and how it is regulated byclassical developmental signal transduction mechanisms

2 PTEN in Developmental Biology

21 Early Embryonic Development PTEN is highly andubiquitously expressed throughout developing embryos Itis expressed as early as the embryonic stem cell stagebeing detectable in embryonic day 35 blastocysts in bothextraembryonic and embryonic tissues [19] PTEN is requiredfor critical hallmarks of developmental biology including cellproliferation growth death and migration In many tissuesPTEN expression coincideswith the need to repress or induce

proliferation or differentiation in cells depending on thetissue need in each location and time point

At an organismal level PTEN plays several critical rolesin the early control of the patterning of embryos FirstPTEN regulation of cell migration is known to controlspecification of the anterior-posterior axis of mouse embryos[20] Embryos that lack PTEN expression exhibit a notableset of morphological defects including the failure to correctlyspecify the anterior-posterior body axis improper separationof body foci and decreased coordinated migration of cellsalong the body axis PTEN is also necessary for gastrulationof embryos PTEN is highly expressed from the midblastulatransition through completion of gastrulation and embryoniclayer separation [21] In this process PTEN coordinates cellcycle elongation and cellular morphogenesis Embryos lack-ing PTEN fail to exhibit proper patterning from the blastulainto the germ layers Lethality of these embryos soon followsAt the postgastrulation stage PTEN localization can be foundthroughout ectodermal endodermal and mesodermal-derived tissue including the developmental precursors of thecentral nervous system and skin the liver and gastrointestinaltract the urogenital sinus heart and skeletal muscle [19 20]Anatomy of PTEN systems effects highlighed in Figure 2Following the separation of the germ layers PTEN exertsdynamic roles throughout development across numerousorgan systems The following highlights recent findings

22 Nervous System Development The high prevalence ofgermline PTENmutations inCowden disease and Bannayan-Riley-Ruvalcaba syndrome Lhermitte-Duclos syndromeautism spectrum disorders and CNS axon regenerationdemonstrates the significance of PTEN in central nervoussystem development and physiology The brain has been themost extensively studied organ in the area of PTENrsquos role indevelopmental biology [22] primarily because of its knownrole in the development of gliomas and medulloblastomasIdentified syndromes associated with germline PTEN inthe CNS include Lhermitte-Duclos disease [23] dysplasticgangliocytoma [24] gray matter heterotopias [25] mentalretardation [26] autism [27] and seizures [28]

Journal of Signal Transduction 3

BrainGangliocytoma

Mental retardationAutism

Seizures

SkinThickening

Melanocyte expansion

Immunitylymphoid hyperplasia NK cell development antibody class-switching recruitment

Mammarygland

Ovary Prostate

Bone

Lungs

UT

GIDevelopment

InvolutionBudding

GrowthOvulation

ElongationMatrix deposition

DevelopmentFunctioning

DevelopmentFunctioning

DevelopmentPhysiology

GrowthDevelopment

Physiology

Figure 2 Precise regulation of PTEN expression activity or localization has profound effects on the development of numerous organ systemsDisruption of PTENat the level of transcriptionmRNA stability protein stability enzymatic function or cellular location results in disruptionof these developmental systems

Cell type-specific mutations of PTEN in animal mod-els demonstrate developmental phenotypes and resultingpathology Glial cell conditional null mutation of the Ptengene promotes seizures and ataxia early in life in miceand promotes premature death [28] Brain size in thesemice increases progressively over time relative to wild-typelittermates and these mutants develop hydrocephalus anduntoward lateral ventricle growth [28]These animals exhibitneural dysplasia thickened internal granule cell layers anda progressive increase in neuronal soma size [28] Furthermice with oligodendrocyte-specific PTEN deletion exhibitdisruption in the myelination of axons [29] Importantlythese murine effects are similar to many common featuresassociated with PTEN mutations in the human CNS [30]

PTEN deletions in terminally differentiated neuronsresult in a number of striking phenotypes Neuronal-specificPTEN deletion promotes soma hypertrophy macroen-cephaly and increased axonal outgrowth This latest find-ing has led to the hypothesis that PTEN inhibition maybe a potential therapeutic mechanism for inducing axonal

outgrowth in spinal injury patients [31] These mice alsoexhibit increased dendritic spine density increased caliberof neuronal projections and alterations in synaptic trans-mission [31] Neurons from these mice exhibit disruptionin Bergmann-glia connections and disorganized cerebellararchitecture [31] Neuronal-conditional PTEN null mice alsodisplay hyperactivity signs of anxiety heightened responseto excitatory stimuli and disrupted social interaction [32]Findings from these studies have prompted the hypothesisthat PTEN expression anomalies may be at least in partresponsible for CNS-related disorders in humans

23 Dermal Development PTEN-mediated signaling haslong been known to be critical for the cytoprotection ofboth epithelial cells and melanocytes in the skin Interest-ingly PTEN has recently been shown to be responsible forregulating the events and timing of epidermal development[19] This may have been predictable given the incidence ofbenign tumors of the skin in Cowdenrsquos syndrome a knownPTEN-driven condition Conditional PTEN deletion induces

4 Journal of Signal Transduction

hyperplasia of squamous cells resulting in mounted skindermis and papillomas [33] Additionally mice with specificmelanocytic PTEN deletion exhibit increased melanocyteexpansion [34]

24 Hematopoietic Development PTEN is necessary forproper development lineage fate and cell function in T cellsB cells myeloid cells NKT cells and hematopoietic stem cells(HSCs) as demonstrated by several elegant studies involvingglobal heterozygous and cell-conditional null PTEN models[35ndash40] It has been known that PTEN (+minus) mice exhibitlymphoid hyperplasia progressing to T-cell lymphoma com-plete with large nodal masses [36] and it has now alsobeen reported that PTEN (+minus) mice develop autoimmunedisorders at an early age due to abrogated PTEN function[37] Cell-type T-cell conditional PTEN null mice exhibitlymphadenopathy splenomegaly and hyperplastic enlargedthymus Similar to the global PTEN heterozygous miceconditional nulls also exhibit autoreactivity evidenced byincreased levels of autoantibodies expanded T-cell prolifer-ation and increased cytokine synthesis and release [38]

Indirect studies show that PTEN-mediated signalingplays a role in natural killer (NK) cells Unfortunatelytrue cell-selective knockout of PTEN in natural killer (NK)cells has not been reported due to the lack of a cell-typespecific promoter However purified NK cells from PTENimmune-system null mice exhibit abrogated maturation andactivation [39] Studies have demonstrated that when thesecells were adoptively transferred intoNK null mice harboringmetastatic melanoma cells the null cells exhibit stronglydecreased protection from metastases relative to wild-typeNKT cells [39 40]These results demonstrate that one criticalrole of NK cells namely tumor targeting is attenuatedin PTEN null NK cells In addition B-cell lineage-specificPTEN null mice exhibit expanded splenocytes mesentericlymph node cells and peritoneal cells [41] B cells deficientin PTEN display enhanced proliferation upon epitope ormitogen stimulation and defective class-switch antibodyrecombination resulting in decreased production of IgA andIgG antibodies and elevated IgM production [41]

Neutrophils isolated from mice with PTEN-null myeloidlineage cells display increased actin polymerization withenhanced membrane ruffling pseudopodia formation che-motaxis and migratory speed [42] Inflammation in thesemice is associated with vastly increased neutrophil recruit-ment [42] Paradoxically these mice are more susceptible toinfection with Leishmania and exhibit a slower clearance ofinfection than wild-type littermates This disconnect appearsto be due to decreased secretion of tumor necrosis factor(TNF) by mutant macrophages in these mice [43] To datelittle else is known about the development of monocytes inmyeloid-specific PTEN null bearing animals

Deletion of PTEN in murine hematopoietic stem cells inmice results in a very rapid onset of myeloproliferative disor-ders and an eventual depletion of the stem cell pool whichdespite their proliferative nature results in the loss of theability of these stem cells to produce all lineages needed forproper immune functioning [44] These myeloproliferativedisorders progressed to acute myeloid leukemia or acute

lymphoblastic leukemia [44] In a demonstration that Akt-signaling is downstream of this phenotype increased HSCproliferation and even the development of myeloproliferativedisorders and leukemia are all rescued when the mice weretreated with rapamycin [44]

25 Visceral OrganDevelopment There are numerous studiesto date examining the developmental effects of organ-specificPTEN mutation in mouse models This review summarizesthe highlights of these studies hereMammary ducts in tissue-specific conditional PTEN null mice exhibit loss of differ-entiation enhanced growth excessive side branching andprecocious budding relative to wild-type controls [45] Thesephenotypes are reported during puberty but also manifesttheir effects during mammary expansion during pregnancyNotably mammary gland involution after pregnancywas alsodefective [45] PTEN is important for the normal physiologyof oocytes as PTEN deficiency in murine oocytes causesthe entire oocyte pool to become activated prematurely [46]This proves to be critical for fertility and reproduction aspremature oocyte activation resulted in females having amaximum of one normal-sized litter before they becameinfertile at 12-13 weeks of age [46]

FabpCre-(Ptenfloxflox) mice exhibit a number of inter-esting phenotypes in the genitourinary system PTEN dele-tion occurs in the bladder ureter kidney colon prostateseminal vesicles and vagina of these mutants [47] Epithelialhyperplasia was omnipresent in these animals As expecteddeletion of PTEN resulted in increased susceptibility tochemically induced carcinogenesis [48] Similarly epithelialhyperplasia is present in organ specific PTEN knockoutsfollowed by intraepithelial neoplasia and ultimately by inva-sion of the cancer cells as invasive adenocarcinoma [49ndash51]Embryonic deletion of PTEN in the lower urinary systemresults in a loss of proper differentiation within affected cells[52] ultimately resulting in loss of proper patterning andgrowth control Based on these data and the collection ofphenotypes observed in PTEN deleted cells and animals it islikely that a loss of differentiation of cells plays a master rolein PTENrsquos role in organ development

Recent reports have demonstrated a critical role for PTENin the branching morphogenesis and nephron patterning ofdeveloping kidneys PTEN has been shown to be indispens-able for developing bud outgrowth mesenchymal invasionand branching morphogenesis in developing kidneys bymediating the signaling downstream of GDNFRET receptortyrosine kinases [53] Again this involves differentiation andchemotaxis of epithelial cells More recently Lindstrom etal have shown that PTEN sits at the center of nephrondevelopment by integrating signaling from BMP and wnt-beta-catenin pathways [54] Disruption of PTEN results in aloss of coordinated signaling and a loss of proper patterningof epithelial cells along the axis of the nephron tubule

Numerous developmental effects of PTEN have beennoted in the gastrointestinal tract In the colon PTEN (+minus)mice develop hamartomatous polyps consistent with dis-rupted control of differentiation of cells [55] Further PTENis critical for colon homeostasis involving inflammatoryrepair and recovery processes that reactivate developmental

Journal of Signal Transduction 5

signalingmechanisms [56] In the liver loss of PTENnot onlyincreases tumor susceptibility but also altersmetabolism [57]In addition hepatomegaly is observed in mice with condi-tional hepatic PTEN knockout as the ratio of liver weightto body weight increased in the mutants when comparedwith wild-type controls [57] Livers harvested from mutantanimals are discolored and show accumulation of triglyc-erides consistent with steatohepatitis associated with severeinflammation Passive diffusion of fatty acids in hepatocyteswas enhanced in PTEN null mice and PTEN-deficienthepatocytes exhibit an increased rate of fatty acid synthesisvia induced fatty acid synthase [57] PTEN-deficient miceexhibit defects in glucose metabolism including decreasedfasting plasma glucose levels and reduced serum insulinlevels [58] Clearance of glucose was accelerated in theabsence of PTEN concurrent with increased liver glycogenstorage

Pancreatic islet beta-cell specific PTEN-deficient miceexhibit increases in islet cell numbers total islet massand an increase in 120573-cell progenitor proliferation duringembryonic development and early postnatal life [59] AdultPTEN mutant mice were hypoglycemic and were resistantto streptozotocin-induced diabetes These mice are signifi-cantly smaller than controls and have a shorter lifespan Insome studies severe hypoglycemia is associated with seizureactivity and premature death before 5 weeks of age [59]In addition PTEN (+minus) mice exhibit protection againstincreased insulin production during reactive oxygen species-dependent type two diabetes and insulin-resistance uponaging [60]

PTENrsquos role in maintaining glucose balance is not limitedto the liver and pancreas but also involves adipocytes andmyocytes Inactivation of PTEN specifically in adipocytesproduces no obvious gross morphological effects on theadipose tissue or adipose tissue mass However this mouseexhibits increased systemic glucose tolerance and insulin sen-sitivity complete with decreased fasting insulin and resistinlevels [61] By controlling serum insulin and resistin levelsPTEN regulates insulin sensitivity and AMP kinase activityin the liver Similarly skeletal and cardiac muscle cell-specificdeletion causes increased systemic glucose tolerance andinsulin sensitivity [62] Interestingly however PTEN loss inthese tissues seems to protect thesemice from streptozotocin-induced diabetes and hyperglycemia indicating that theinsulin hypersensitivity exhibited in tissue-selective PTEN-deficient mice allowed them to maintain proper glucoselevels

PTEN regulates proper lung development Specific lungdeletion of PTEN during embryogenesis results in impairedlungmorphogenesis and early postnatal death [61]The lungsof these neonates exhibit increased epithelial cell proliferationand decreased alveolar cell differentiation Adults exhibitbronchiolar and alveolar epithelial hyperplasia Mutant miceexhibit hypertrophy of alveolar cells derived from bron-chioalveolar stem cells [61] Predictably adenocarcinomawasevident in aged adults Further study of PTENrsquos role inlung development revealed that PTEN-regulated signalingmediates lung endodermal morphogenesis coordinate withthe overall developmental process in the lung and it is central

to the interaction of several signaling pathways including theTGF beta-SMAD and Nkx21 pathways [62]

Normal development of the vascular system is alsodependent on proper PTEN function PTEN knockout inendothelial and endocardial cells in mice results in embry-onic lethality due to increased capillaries and endothelial cellhypertrophy [63] These mutant embryos exhibit pericardialcavity enlargement leakage of blood into the pericardialcavity and enlarged trunk vessels secondary to pericyte andvascular smooth muscle cell recruitment to blood vessels[63] In addition cardiomyocyte-specific deletion of PTENleads to cardiac phenotypes via development of cardiachypertrophy and contractile defect [64] Future studies onPTEN will hopefully be targeted at assessing injury-relatedresponses in the cardiovascular system as deletion of PTENin cardiomyocytes has been shown to protect the heart frommaladaptive remodeling upon biomechanical stress

PTEN regulates developing bone and cartilage by pro-tecting against overgrowth of the skeletal system Mice withdeletion of PTEN in osteochondroprogenitor cells exhibitgrowth plate dysfunction and overgrowth of the vertebrae[65] The bodies of these mice are notably longer than wild-type controls demonstrating a critical defect that resultsin loss of proper skeletal development Interestingly thisincrease in length was not due to bone cell proliferationincreases as might have been expected but rather is due toincreased matrix deposition and cellular hypertrophy [65]In a second model osteoblast-specific knockdown of PTENexpression results in increased bone volume and density[66] Interestingly this mutation is associated with improvedintramembranous and late endochondral fracture healingThis is now an active area of research within the boneremodeling research field

While PTEN remains virtually synonymous with cancerbiology the studies presented here make the importanceof proper PTEN signaling for regulating a wide variety ofdevelopmental processes clearly evident From regulation ofgrowth differentiation glucose maintenance and repair andrecovery to gross effects on organ and systems developmentPTEN is a protein with vast consequence in the field ofdevelopmental biology and the signaling affected by itsexpression is expansiveThe role PTEN plays in developmenthas clear correlates to human disease Further PTENrsquos effectson development acquire greater importance when the rolethat developmental signaling plays in cancer growth andprogression is consideredTherefore an extensive knowledgeof how PTEN is regulated by developmental signaling apartfrom somatic or genetic mutation is required for completeunderstanding of PTENrsquos role in these important physiologi-cal processes

3 PTEN Regulation as Part ofDevelopmental Signaling

31 Intrinsic and Extrinsic PTEN Regulation Most studiesevaluating the role of PTEN in human diseases have beencentered uponmutation in PTEN itself andmost of this workis done in its relationship to cancer initiation and progression

6 Journal of Signal Transduction

BMP Hh JagdeltaNOTCH

NICD

miRNA(17 19 21)

GF

PTEN mRNA

PTEN mRNA

PTENNICD

SMAD2 3

SMAD1 5 8 Gli2

AP -1

NICDAP -1

SMO

SMAD2 3

SMAD1 5 8 Gli2

SALL4

Cyt

p65p50

p65p50

ceRNAAkt

GSK3CK2

PCAF

SIRT1

PIP3 PIP2

PI3 kinase

TGF120573

Figure 3 Summary of regulation mechanisms for PTEN critical for its action in developmental biology PTEN transcription is regulatedby TGF120573 BMP Hh NOTCH and cytokine signaling in cells during development miRNAs and ceRNAs regulate PTEN message stabilityPhosphorylation or acetylation by then can regulate PTENrsquos protein stability enzymatic activity and cellular localization in a positive ornegative manner All told the regulation of PTEN is complex and precise during development and perturbations in this paradigm haveprofound effects

There is no question that mutations of PTEN play a criticalrole in this regard Studies over the last decade howeverhave discovered a tremendous diversity in the regulationof PTEN expression and found that PTEN is tightly con-trolled both transcriptionally and posttranscriptionally [67]Recent studies to date have implicated microRNAs in PTENsuppression [68] and the enzymatic phosphatase activityof PTEN is also regulated posttranslationally via phospho-rylation ubiquitination or oxidation [69 70] This sectionhighlights the multifaceted mechanisms of PTEN regulationsupported by the rapidly expanding literature on PTENrsquos rolein growth and patterning of tissues during development Inaddition special emphasis is given tomediators and pathwaysinvolved in development including insulin-like growth factortransforming growth factor bone morphogenetic proteinsNOTCH forkhead transcription factors (Fox) and othersPTENrsquos complex regulation at the levels of transcriptionmRNA stability posttranslational modifications andmiRNAlevels has become a critical series of mechanisms deserving acomprehensive review (for an overview see Figure 3)

32 Developmental Signaling Regulating PTEN Expressionand Action The regulation of PTEN expression occurs attranscriptional posttranscriptional posttranslational andprotein-protein interaction levels [71] PTENrsquos function isfurther controlled by its cellular location In this sectionwe highlight developmental pathways involved in regulating

PTEN expression at all these regulation points and makespecial reference to connections between signal transductionand development

321 Developmental Pathways in PTEN Gene ExpressionOne critical aspect of PTENrsquos regulation during developmentbegins at the transcriptional level To date PTEN expres-sion has been found to be regulated at the transcriptionallevel by pathways involving p53 PPAR120574 Egr-1 NF-120581Band SMADs and this regulation affects the developmentof proper immune function the vasculature the nervoussystem the gastrointestinal system and the airways [6372 73] While PTEN is constitutively expressed in manynormal adult tissues PTEN expression is altered dramat-ically through the course of development and in patho-logical settings and a primary source of this regulationcomes from bona fide developmental regulators In additionsuppressors of cytokine signaling (SOCS) and SNAIL alsoinduce PTEN and act by countering the growth-promotingactions of cytokines and growth factors in developmentand repair and recovery [74] This mechanism has beenclearly demonstrated in axonal outgrowth during neurondevelopment and regeneration [74] While the physiologicalramifications of this regulation remain unsolved mediatorsthat slow or inhibit cell proliferation are often involved ininducing this protein Developmental mediators includingNOTCH transforming growth factor beta (TGF120573) bone

Journal of Signal Transduction 7

morphogenetic proteins (BMPs) and hedgehogs (Hhs) allparticipate as players in external PTEN regulation [75ndash78] regulating such processes as proliferation and targetedepithelial budding and outgrowth of visceral organs [76 77]and outgrowth in neurons [75] As the direction of cell growthand differentiation balances on the fulcrum between theproliferative and differentiating actions of these mediatorstheir regulation to induce or repress PTEN expression isa critical aspect of their actions during development Thecritical developmental mediator TGF120573 contains both growthpromoting and inhibiting differentiation qualities and TGF120573induces PTEN during differentiation when growth is slowedand inhibits its expression during proliferation In additionthe developmental regulator DJ-1 was recently identified asa novel negative regulator of PTEN by a genetic screen inDrosophila [79] PTEN is also regulated through epigeneticsilencing by methylation of the PTEN promoter [80 81] Aninteresting zinc-finger transcription factor sal-like protein 4(SALL4) has been discovered as a critical negative regulatorof PTEN transcription by recruiting an epigenetic repressorcomplex involving anATPase and a histone deacetylase to thePTENpromoter [80] SALL4 plays a critical role in regulatingdevelopment by modulating self-renewal in stem cells andits function appears to at least partly involve methylation ofthe PTENpromoter andmodulation of its transcriptionDataon this mechanism are still limited but to date this processhas been shown to regulate kidney patterning during devel-opment as well as leukemogenesis [80] Current research inthe area of PTEN transcriptional regulation continues to bedynamic and more novel regulation patterns are likely to bediscovered in the near future

322 PTEN Regulation by Posttranscriptional RegulationRecent studies have identified several interesting develop-mentally expressed miRNAs that regulate PTEN mRNAmessage stability and translatability [82] These miRNAstypically downregulate PTEN mRNA levels by targeting itfor degradation and include miR-17 miR-19 and miR-21 [83ndash85] While several examples of miR-17 and miR-19-mediatedPTENRNA levels have been reported in the cancer literaturemiR-21 has been described to play a critical role in repairand recovery a developmental signaling-related processmiRNAs regulate this mechanism by modulating PTENRNA stability and ultimately downstream Akt signaling Forexample in the pancreas miR-21 regulates injury repair indiabetic models by targeting PTEN RNA for degradationInhibition of miR-21 results in autophagy in this model ina manner dependent on PTEN degradation [85] In anotherexample of novel miR-related PTEN regulation the PTENpseudogene 1 (PTENP1) acts as a decoy for PTEN-targetingmiRNAs and thereby regulates PTEN expression by coding-independent activity through sequestering these miRNAsand effectively inhibiting their effects on PTEN expression[86] Additionally combined bioinformatic and experimentalapproaches have identified ceRNA transcripts that controlPTEN expression by sequestering PTEN-targeting miRNAsduring development of both prostate and skin [87] Becausethis type of PTEN regulation and indeed this field of generegulation in general is in its infancy we are only beginning

to understand the PTEN regulation by coding and noncodingceRNAs Still this novel work provides a platform for furtherstudies investigating posttranscriptional regulation patternsof PTEN expression in both developmental biology anddisease conditions

323 PTENRegulation by PosttranslationalMechanisms Theprotein stability and enzyme activity of PTEN are regulatedin a number of ways at the posttranslational level FirstPTEN is phosphorylated in its C-terminal tail at Ser380Thr382 Thr383 and Ser385 and this functions to inhibitthe critical PTEN phosphatase activity thereby promotinggrowth in prostate and kidney cells [88] However thesephosphorylations also stabilize the PTEN protein by dis-suading ubiquitination While this may seem like a cellulardisconnect this paradoxical phenomenon is explained by thefinding that this closed more stable PTEN conformation isprevented from associating with membranes and thereforeis geographically separated from its substrates [88] PTENcan also be activated by phosphorylation in particular theC2 domain of PTEN is phosphorylated at Ser229 andThr321by RHOA-associated protein kinase (ROCK) [89] a phos-phorylation that results in its association with membranesand phosphoinositide substrates affecting differentiation inleukocytes PTEN is further phosphorylated at Tyr336 by theTyr protein kinase RAK and this phosphorylation resultsin its stabilization [90] Loss of this activity has the effectof promoting breast cell proliferation and migration FinallyPTEN is also phosphorylated at Ser370 and Thr366 by CK2and GSK3120573 [91 92] respectively however the consequencesof this phosphorylation are unclear The likely extensivesignaling networks that regulate these widespread phospho-rylations in PTEN are not fully studied but the TGFBMP-SMADdevelopmental pathways are known to regulate PTENphosphorylation [93 94] Given the widespread applicationof SMAD signaling to developmental biology the presence ofSMAD-regulated PTEN phosphorylation is a critical aspectof developmental regulation in cells

PTEN enzymatic activity is also regulated posttrans-lationally by acetylation [70 95ndash97] PTEN is acetylatedat Lys125ndashLys128 by p300CREB-binding protein- (CBP-)associated factor (PCAF) and at Lys402 by CBP itself [95]Acetylation at these residues inhibits PTENrsquos function as aphosphatase and has been shown to promote the growthof prostate epithelial cells and glial cells [95] In additionthe deacetylase Sirtuin 1 (SIRT1) is involved in excludingPTEN from the nucleus and therefore preventing its newlycharacterized nuclear functions [96]

324 PTEN Regulation by Protein-Protein Interactions Theconformation stability and subcellular distribution of PTENis regulated by critical interactions with other proteins withincells and these proteins are known to be critical for properdevelopment of a number of organ systems The guanylatekinase inverted 2 (MAGI2) and 120573-arrestins cooperate toenhance PTEN activity [98 99] MAGI2 phosphorylatesPTEN on threonine residues at positions 382 and 383 ofPTENrsquos carboxy terminus allowing recruitment to cell-cell

8 Journal of Signal Transduction

junctions [98] Mutations to these residues prevent PTENrecruitment Upon recruitment 120573-arrestins modulate PTENactivity by direct binding to the C2 domain and modulatingits protein phosphatase activity including that at the levelof small GTPases including RhoAROCK [99] In addi-tion Myosin V regulates PTENrsquos movement to and fromthe plasma membrane and this function is required forPTEN to access its phosphoinositide substrates [100] andfor disrupting the proper regulation of neuronal cell sizeThe p85 regulatory subunit of the PI

3kinase enzyme itself

interacts with PTEN in a novel mechanism of repressing thePI3KndashAKT pathway [101] independent of PTENrsquos action as a

phosphatase It is therefore proposed that p85 regulates thePI3KndashAKT pathway bidirectionally both through its binding

to catalytic p110 subunit resulting in the generation of phos-phoinositides and by binding PTEN leading to repressionThis work proposes a novel signaling model for PTEN-p85association in which p85120572 preferentially binds and stabilizesp110 preferentially when p85120572 levels are low but excess p85120572binds to and positively regulates PTEN phosphatase activitywhen p110 is saturated Therefore sustained activation ofPI3K signaling and activated p110-p85 complexing is modu-lated homeostatically by this mechanism

A fascinating group of recent studies have utilizedproteomic library screens to identify further novel PTENinteracting proteins First the Na+H+ exchanger regulatoryfactor (NHERF) binds to and recruits PTEN to the platelet-derived growth factor receptor (PDGFR) This representsanother action that restricts PI

3KndashAKT pathway activation

independent of phosphatase activity [102] This has the effectof inhibiting PDGF-induced cytoskeletal rearrangements andchemotactic migration of developing neurons In additionthe mammalian disks large homologue 1 (DLG1) MAGI-2 and MAST205 proteins directly interact with PTENand enhance PTEN stability and activity [103] Furtherneuregulin 1 (NRG1) has been shown to interact with bothDLG1 and PTEN in a stable complex that has the effect ofregulating myelin sheath thickness in developing mouse sci-atic nerves [104] Additional but less-characterized protein-protein interactions that modulate PTEN function includethe PIP

3-dependent RAC exchanger factor 2a (PREX2a)

[105] shank-interacting protein-like 1 (SIPL1) [106] and 120572-mannosidase 2C1 (MAN2C1) [107]

325 PTEN-Controlled Signal Transduction during Develop-ment PTEN is critically important in regulating signalingpathways involved in cell growth and animal developmentThrough its well-characterized function as a phosphataseof PIP

3 PTEN modulates a network of mitogen-activated

signals transduced through PI3KndashAkt signaling This pri-

mary action of PTEN has tremendous impact on cell growthcell migration cell death and cell differentiationmdashcellularprocesses that are all hallmarks of proper growth andpatterning during development The active phosphorylatedPIP3activates several signaling molecules including the

phosphatidylinositol-dependent kinases (PDKs) followed byAkt S6 kinase and mTOR Beyond this AKTrsquos targetsinclude the apoptotic factor BAD activator and executioner

caspases glycogen synthase kinase-3 (GSK-3) MDM2 p21and p27 forkhead transcription factors (FOXOs) and nuclearreceptors including the androgen and estrogen receptors[108] Akt-mediated phosphorylation of these moleculescauses activation translocation and increased stability

The PTENPI3kinaseAKT signaling cascade crosstalks

to several key signal transduction pathways that are criticalto developmental biology This includes the abovementionedTGF-120573SMAD pathway and the Wnt120573-catenin pathway[109] The TGF-120573SMAD pathway is one of the most seminalpathways in developmental biology and PTEN modulatesTGF120573SMAD signaling by reversing Akt-mediated phospho-rylation of SMAD3 the critical signaling intermediate ofTGF120573SMAD signaling [110] Similarly the Wnt signalingpathway is indispensable for properly regulated developmentcellular proliferation and differentiation [111] PTEN regu-lates this pathway by reversing AKT kinase phosphorylationand inhibition of GSK-3120573 resulting in 120573-catenin nucleartranslocation and activation Finally recent studies demon-strate that PTEN regulates the expression and action of thehomeobox genes NKX31 and hepatic nuclear factor [112]proteins that are critical to organ development

326 PTEN-Regulated Stem Cell Activities The scientificliterature in the field of tissue stem or stem-like ldquoprogen-itorrdquo cells and their role in tissue development growthrecovery and repair has become beyond extensive in recentyears Expansion of stemprogenitor cells is a hallmark ofgrowth and patterning during development and regulationof these cells including their proliferation maintenanceand differentiation is a critical factor of developmentalregulation Because of this a review of the current liter-ature on PTENrsquos role in stem and tissue progenitor cellsis warranted in this review PTEN plays an important rolein regulating the homeostasis of stemprogenitor cells inmultiple tissues Interestingly PTEN regulates both self-renewal and proliferation but paradoxically it also playsa role in stem cell exhaustion For example the FOXOfamily of transcription factors controls stem cell proliferationand survival in hematopoietic stem cells [113] and PTENsignaling is a critical modulator of FOXO activity FOXO3A-deficient HSCs exhibit increased proliferation rate decreasedquiescence and a reduced ability to repopulate bone marrowafter transplantation into recipient mice Additionally thepreviously mentioned Wnt120573-catenin signaling pathway iscritical for HSC self-renewal and its activation is well knownto be modulated by PTEN Interestingly PTEN loss and AKTactivation in HSCs lead to a moderate increase in the levelof unphosphorylated 120573-catenin but this is not sufficient tomaintain Pten-null HSC self-renewal [114] Finally NOTCHsignaling plays a key role in regulating neural stem cellexpansion [115] and as stated previously NOTCH pathwayactivation leads to reduced PTEN expression in neural andhematopoietic stem cells

4 Conclusions

PTEN acts as the key endogenous negative modulatorof phosphoinositide signaling in mammalian cells and

Journal of Signal Transduction 9

therefore its role in normal cell homeostasis proliferationapoptosis and many additional components of cell biologyis extensive Because PTEN regulates cancer progressionmuch of what has been studied regarding PTEN relates totumorigenesis and tumor growth While this is warrantedbecause of the relevance of cancer to humanhealth PTENhassubstantial but underappreciated effects in normal tissue andorgan development immune system development and reg-ulation axonal regeneration glucose regulation and benigngrowth disorders PTEN is often dogmatically thought ofas a constitutive protein that exhibits lost activity duringdiseases butwhat is underappreciated is that PTENhas a verycomplex regulation network that involves signaling path-ways that regulate PTEN transcription transcript stabilityposttranslationalmodifications protein-protein interactionsand cellular location PTEN then in turn regulates numerousdevelopmental signaling networks that are critical to devel-opment and adult tissue maintenance

Abbreviations

Bcl2 B-cell lymphoma 2Bim BCL-2-interacting mediatorCK2 Casein Kinase 2CREB Cyclic AMP response element binding

proteinDLG Disks large homolog 1Egr-1 Early growth response protein 1Erk Extracellular regulated kinaseFOX Forkhead transcription factorsGSK3120573 Glycogen synthase kinase 3JNK Jun-terminal kinaseMAGI2 Membrane-associated guanylate kinase

inverted 2MAN2C1 Mannosidase alpha class 2C member 1MDM2 Mouse double minute 2 homologmTOR Mechanistic target of rapamycinNHERF Sodium-hydrogen antiporter 3

regulator 1NRG1 Neuregulin 1PCAF P300CBP-associated factorPDZ Postsynaptic density proteinmdashDisc

large tumor suppressormdashZonulaoccludens-1 protein

PIP3 Phosphoinositide triphosphatePPAR120574 Peroxisome proliferating antigen

receptorPREX2a Phosphatidylinositol-345-

trisphosphate-dependent Rac exchangefactor A

PTEN Phosphatase and Tensin homologueROCK Rho-associated coiled-coil-containing

protein kinaseSALL Spalt-like transcription factor-1SIPL1 Shank-interacting protein-like 1SIRT1 Sirtuin 1SMAD Small mothers against decapentaplegicSOCS Suppressor of cytokine signalingTGF120573 Transforming growth factor-beta

Disclosure

Travis J Jerde carried out the extensive literature reviewrequired to write this paper and have written the entirepaper The author has therefore read and approved the papersubmitted

Conflict of Interests

The author has no financial or nonfinancial conflict ofinterests with the submission of this paper

Acknowledgments

The author gratefully acknowledges the financial supportof the Indiana University School of Medicine Departmentof Pharmacology and Toxicology and the Melvin and BrynSimon Cancer Center The author also gratefully acknowl-edges this paper as part of his training made possible byNational Institutes of Health-NIDDK (DK092366-01A1)

References

[1] M Milella I Falcone F Conciatori et al ldquoPTEN multiplefunctions in human malignant tumorsrdquo Frontiers in Oncologyvol 5 article 24 2015

[2] J-O Lee H Yang M-M Georgescu et al ldquoCrystal structure ofthe PTEN tumor suppressor implications for its phosphoinosi-tide phosphatase activity and membrane associationrdquo Cell vol99 no 3 pp 323ndash334 1999

[3] W-L Yang G Jin C-F Li et al ldquoCycles of ubiquitinationand deubiquitination critically regulate growth factor-mediatedactivation of Akt signalingrdquo Science Signaling vol 6 no 257article ra3 2013

[4] J Gu S Nada M Okada and K Sekiguchi ldquoCsk regulatesintegrin-mediated signals involvement of differential activa-tion of ERK and Aktrdquo Biochemical and Biophysical ResearchCommunications vol 303 no 3 pp 973ndash977 2003

[5] A Clerk and P H Sugden ldquoActivation of protein kinase cas-cades in the heart by hypertrophic G protein-coupled receptoragonistsrdquoTheAmerican Journal of Cardiology vol 83 no 12 pp64Hndash69H 1999

[6] I Tonic W-N Yu Y Park C-C Chen and N Hay ldquoAktactivation emulates Chk1 inhibition and Bcl2 overexpressionand abrogates G2 cell cycle checkpoint by inhibiting BRCA1focirdquo The Journal of Biological Chemistry vol 285 no 31 pp23790ndash23798 2010

[7] S Fatrai L Elghazi N Balcazar et al ldquoAkt induces 120573-cellproliferation by regulating cyclin D1 cyclin D2 and p21 levelsand cyclin-dependent kinase-4 activityrdquo Diabetes vol 55 no 2pp 318ndash325 2006

[8] M Aoki E Blazek and P K Vogt ldquoA role of the kinase mTORin cellular transformation induced by the oncoproteins P3k andAktrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 98 no 1 pp 136ndash141 2001

[9] H Guan L Song J Cai et al ldquoSphingosine kinase 1 regulatesthe AktFOXO3aBim pathway and contributes to apoptosisresistance in glioma cellsrdquo PLoS ONE vol 6 no 5 Article IDe19946 2011

[10] T D Dung C H Day T V Binh et al ldquoPP2Amediates diosminp53 activation to block HA22T cell proliferation and tumor

10 Journal of Signal Transduction

growth in xenografted nude mice through PI3K-Akt-MDM2signaling suppressionrdquo Food and Chemical Toxicology vol 50no 5 pp 1802ndash1810 2012

[11] K Shanmugasundaram K Block B K Nayak C B Livi MA Venkatachalam and S Sudarshan ldquoPI3K regulation of theSKP-2p27 axis through mTORC2rdquo Oncogene vol 32 no 16pp 2027ndash2036 2013

[12] J-C Chang H-H Chang C-T Lin and S J Lo ldquoThe integrin12057261205731modulation of PI3K andCdc42 activities induces dynamicfilopodium formation in humanplateletsrdquo Journal of BiomedicalScience vol 12 no 6 pp 881ndash898 2005

[13] E Hajduch G J Litherland and H S Hundal ldquoProtein kinaseB (PKBAkt)mdasha key regulator of glucose transportrdquo FEBSLetters vol 492 no 3 pp 199ndash203 2001

[14] M M Martin J A Buckenberger J Jiang et al ldquoTGF-beta1stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[15] M M Martin J A Buckenberger J Jiang et al ldquoTGF-1205731stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[16] K Abell and C J Watson ldquoThe JakStat pathway a novel wayto regulate PI3K activityrdquo Cell Cycle vol 4 no 7 pp 897ndash9002005

[17] J-Y Hwang R S Duncan C Madry M Singh and P KoulenldquoProgesterone potentiates calcium release through IP3 recep-tors by an Akt-mediated mechanism in hippocampal neuronsrdquoCell Calcium vol 45 no 3 pp 233ndash242 2009

[18] G Pappas L A Zumstein A Munshi M Hobbs and R EMeyn ldquoAdenoviral-mediated PTEN expression radiosensitizesnon-small cell lung cancer cells by suppressing DNA repaircapacityrdquoCancer GeneTherapy vol 14 no 6 pp 543ndash549 2007

[19] A Di Cristofano B Pesce C Cordon-Cardo and P P PandolfildquoPten is essential for embryonic development and tumoursuppressionrdquo Nature Genetics vol 19 no 4 pp 348ndash355 1998

[20] J Bloomekatz J Grego-Bessa I Migeotte and K V AndersonldquoPten regulates collective cell migration during specification ofthe anterior-posterior axis of the mouse embryordquo Developmen-tal Biology vol 364 no 2 pp 192ndash201 2012

[21] S Ueno R Kono andY Iwao ldquoPTEN is required for the normalprogression of gastrulation by repressing cell proliferation afterMBT in Xenopus embryosrdquoDevelopmental Biology vol 297 no1 pp 274ndash283 2006

[22] C B Knobbe A Merlo and G Reifenberger ldquoPten signaling ingliomasrdquo Neuro Oncology vol 4 pp 196ndash211 2002

[23] E Kirches J Steiner T Schneider et al ldquoLhermitte-Duclosdisease caused by a novel germline PTEN mutation R173P in apatient presenting with psychosisrdquoNeuropathology and AppliedNeurobiology vol 36 no 1 pp 86ndash89 2010

[24] J-I Murata M Tada Y Sawamura K Mitsumori H Abe andK Nagashima ldquoDysplastic gangliocytoma (Lhermitte-Duclosdisease) associated with Cowden disease report of a case andreview of the literature for the genetic relationship between thetwo diseasesrdquo Journal of Neuro-Oncology vol 41 no 2 pp 129ndash136 1999

[25] G Zhu L M L Chow I T Bayazitov et al ldquoPten deletioncauses mTorc1-dependent ectopic neuroblast differentiation

without causing uniform migration defectsrdquo Development vol139 no 18 pp 3422ndash3431 2012

[26] K L McBride E A Varga M T Pastore et al ldquoConfirmationstudy of PTEN mutations among individuals with autism ordevelopmental delaysmental retardation and macrocephalyrdquoAutism Research vol 3 no 3 pp 137ndash141 2010

[27] J Zhou and L F Parada ldquoPTEN signaling in autism spectrumdisordersrdquo Current Opinion in Neurobiology vol 22 no 5 pp873ndash879 2012

[28] S A Backman V Stambolic A Suzuki et al ldquoDeletion of Ptenin mouse brain causes seizures ataxia and defects in soma sizeresembling Lhermitte-Duclos diseaserdquo Nature Genetics vol 29no 4 pp 396ndash403 2001

[29] L Cotter M Ozcelik C Jacob et al ldquoDlg1-PTEN interactionregulates myelin thickness to prevent damaging peripheralnerve overmyelinationrdquo Science vol 328 no 5984 pp 1415ndash1418 2010

[30] S Ogawa C-H Kwon J Zhou D Koovakkattu L F Paradaand C M Sinton ldquoA seizure-prone phenotype is associatedwith altered free-running rhythm in Pten mutant micerdquo BrainResearch vol 1168 no 1 pp 112ndash123 2007

[31] C-H Kwon X Zhu J Zhang and S J Baker ldquomTor isrequired for hypertrophy of Pten-deficient neuronal soma invivordquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 22 pp 12923ndash12928 2003

[32] C-H Kwon B W Luikart C M Powell et al ldquoPten regulatesneuronal arborization and social interaction in micerdquo Neuronvol 50 no 3 pp 377ndash388 2006

[33] A Suzuki S Itami M Ohishi et al ldquoKeratinocyte-specific Ptendeficiency results in epidermal hyperplasia accelerated hairfollicle morphogenesis and tumor formationrdquo Cancer Researchvol 63 no 3 pp 674ndash681 2003

[34] T Inoue-Narita K Hamada T Sasaki et al ldquoPten deficiency inmelanocytes results in resistance to hair graying and susceptibil-ity to carcinogen-induced melanomagenesisrdquo Cancer Researchvol 68 no 14 pp 5760ndash5768 2008

[35] R K Patel and C Mohan ldquoPI3KAKT signaling and systemicautoimmunityrdquo Immunologic Research vol 31 no 1 pp 47ndash552005

[36] K Podsypanina L H Ellenson A Nemes et al ldquoMutationof PtenMmac1 in mice causes neoplasia in multiple organsystemsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 4 pp 1563ndash1568 1999

[37] M Kashiwada P Lu and P B Rothman ldquoPIP3 pathway inregulatory T cells and autoimmunityrdquo Immunologic Researchvol 39 no 1ndash3 pp 194ndash224 2007

[38] A Suzuki M T Yamaguchi T Ohteki et al ldquoT cell-specificloss of Pten leads to defects in central and peripheral tolerancerdquoImmunity vol 14 no 5 pp 523ndash534 2001

[39] Y Yamanaka H Tagawa N Takahashi et al ldquoAberrant over-expression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lym-phomaleukemiardquo Blood vol 114 no 15 pp 3265ndash3275 2009

[40] H Kishimoto T Ohteki N Yajima et al ldquoThe PtenPI3Kpathway governs the homeostasis of V12057214iNKT cellsrdquo Bloodvol 109 no 8 pp 3316ndash3324 2007

[41] A Suzuki T Kaisho M Ohishi et al ldquoCritical roles ofPten in B cell homeostasis and immunoglobulin class switchrecombinationrdquo Journal of Experimental Medicine vol 197 no5 pp 657ndash667 2003

Journal of Signal Transduction 11

[42] M Nishio K-IWatanabe J Sasaki et al ldquoControl of cell polar-ity and motility by the PtdIns(345)P

3phosphatase SHIP1rdquo

Nature Cell Biology vol 9 no 1 pp 36ndash44 2007[43] S Kuroda M Nishio T Sasaki et al ldquoEffective clearance

of intracellular Leishmania major in vivo requires Pten inmacrophagesrdquo European Journal of Immunology vol 38 no 5pp 1331ndash1340 2008

[44] O H Yilmaz R Valdez B K Theisen et al ldquoPten depen-dence distinguishes haematopoietic stem cells from leukaemia-initiating cellsrdquo Nature vol 441 no 7092 pp 475ndash482 2006

[45] Y Li K Podsypanina X Liu et al ldquoDeficiency of Ptenaccelerates mammary oncogenesis in MMTV-Wnt-1 transgenicmicerdquo BMCMolecular Biology vol 2 article 2 2001

[46] P Reddy L Liu D Adhikari et al ldquoOocyte-specific deletion ofpten causes premature activation of the primordial follicle poolrdquoScience vol 319 no 5863 pp 611ndash613 2008

[47] H Tsuruta H Kishimoto T Sasaki et al ldquoHyperplasia andcarcinomas in Pten-deficient mice and reduced PTEN proteinin human bladder cancer patientsrdquoCancer Research vol 66 no17 pp 8389ndash8396 2006

[48] L I Yoo D W Liu S Le Vu R T Bronson H Wu and JYuan ldquoPten deficiency activates distinct downstream signalingpathways in a tissue-specific mannerrdquo Cancer Research vol 66no 4 pp 1929ndash1939 2006

[49] J Li C Yen D Liaw et al ldquoPTEN a putative protein tyrosinephosphatase gene mutated in human brain breast and prostatecancerrdquo Science vol 275 no 5308 pp 1943ndash1947 1997

[50] N D Deocampo H Huang and D J Tindall ldquoThe role ofPTEN in the progression and survival of prostate cancerrdquoMinerva Endocrinologica vol 28 no 2 pp 145ndash153 2003

[51] S A Backman D Ghazarian K So et al ldquoEarly onset ofneoplasia in the prostate and skin of mice with tissue-specificdeletion of Ptenrdquo Proceedings of the National Academy ofSciences of the United States of America vol 101 no 6 pp 1725ndash1730 2004

[52] X Wu K Xu L Zhang et al ldquoDifferentiation of the ductalepithelium and smooth muscle in the prostate gland areregulated by the NotchPTEN-dependent mechanismrdquo Devel-opmental Biology vol 356 no 2 pp 337ndash349 2011

[53] D Kim and G R Dressler ldquoPTEN modulates GDNFRETmediated chemotaxis and branching morphogenesis in thedeveloping kidneyrdquo Developmental Biology vol 307 no 2 pp290ndash299 2007

[54] N O Lindstrom M L Lawrence S F Burn et al ldquoIntegrated120573-catenin BMP PTEN and notch signalling patterns thenephronrdquo eLife no 4 Article ID e04000 2015

[55] V Marsh D J Winton G T Williams et al ldquoEpithelialPten is dispensable for intestinal homeostasis but suppressesadenoma development and progression after Apc mutationrdquoNature Genetics vol 40 no 12 pp 1436ndash1444 2008

[56] S Matsuda M Kobayashi and Y Kitagishi ldquoRoles forPI3KAKTPTEN pathway in cell signaling of nonalcoholicfatty liver diseaserdquo ISRN Endocrinology vol 2013 Article ID472432 7 pages 2013

[57] X Qi J Xu P Gu X Yang and X Gao ldquoPTEN in smoothmuscle cells is essential for colonic immune homeostasisrdquoInternational Journal of Biochemistry and Cell Biology vol 53pp 108ndash114 2014

[58] A Pal T M Barber M Van de Bunt et al ldquoPTENmutations asa cause of constitutive insulin sensitivity and obesityrdquoThe NewEngland Journal of Medicine vol 367 no 11 pp 1002ndash1011 2012

[59] B L Stiles C Kuralwalla-Martinez W Guo et al ldquoSelectivedeletion of Pten in pancreatic 120573 cells leads to increased isletmass and resistance to STZ-induced diabetesrdquo Molecular andCellular Biology vol 26 no 7 pp 2772ndash2781 2006

[60] LWang C T Luk E P Cai et al ldquoPTEN deletion in pancreatic120572-cells protects against high-fat diet-induced hyperglucagone-mia and insulin resistancerdquo Diabetes vol 64 no 1 pp 147ndash1572015

[61] C Kurlawalla-Martinez B Stiles Y Wang S U Devaskar BB Kahn and H Wu ldquoInsulin hypersensitivity and resistanceto streptozotocin-induced diabetes in mice lacking PTEN inadipose tissuerdquo Molecular and Cellular Biology vol 25 no 6pp 2498ndash2510 2005

[62] N Wijesekara D Konrad M Eweida et al ldquoMuscle-specificPten deletion protects against insulin resistance and diabetesrdquoMolecular and Cellular Biology vol 25 no 3 pp 1135ndash11452005

[63] K Hamada T Sasaki P A Koni et al ldquoThe PTENPI3Kpathway governs normal vascular development and tumorangiogenesisrdquo Genes and Development vol 19 no 17 pp 2054ndash2065 2005

[64] N D Roe X Xu M R Kandadi et al ldquoTargeted deletionof PTEN in cardiomyocytes renders cardiac contractile dys-function through interruption of Pink1-AMPK signaling andautophagyrdquo Biochimica et Biophysica Acta Molecular Basis ofDisease vol 1852 no 2 pp 290ndash298 2015

[65] A F Ford-Hutchinson Z Ali S E Lines B HallgrımssonS K Boyd and F R Jirik ldquoInactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnor-malities and skeletal overgrowthrdquo Journal of Bone and MineralResearch vol 22 no 8 pp 1245ndash1259 2007

[66] T A Burgers M F Hoffmann C J Collins et al ldquoMice lackingpten in osteoblasts have improved intramembranous and lateendochondral fracture healingrdquo PLoS ONE vol 8 no 5 ArticleID e63857 2013

[67] N R Leslie L Spinelli P Tibarewal et al ldquoIndirect mecha-nisms of carcinogenesis via downregulation of PTEN functionrdquoAdvances in Enzyme Regulation vol 50 no 1 pp 112ndash118 2010

[68] L He ldquoPosttranscriptional regulation of PTEN dosage bynoncoding RNAsrdquo Science Signaling vol 3 no 146 article pe392010

[69] F Vazquez S R Grossman Y Takahashi M V Rokas NNakamura andWR Sellers ldquoPhosphorylation of the PTEN tailacts as an inhibitory switch by preventing its recruitment into aprotein complexrdquo The Journal of Biological Chemistry vol 276no 52 pp 48627ndash48630 2001

[70] X Wang L C Trotman T Koppie et al ldquoNEDD4-1 is a proto-oncogenic ubiquitin ligase for PTENrdquo Cell vol 128 no 1 pp129ndash139 2007

[71] N R Leslie and M Foti ldquoNon-genomic loss of PTEN functionin cancer not in my genesrdquo Trends in Pharmacological Sciencesvol 32 no 3 pp 131ndash140 2011

[72] Y Xing C Li L Hu et al ldquoMechanisms of TGF120573 inhibition ofLUNG endodermal morphogenesis the role of T120573RII SmadsNkx21 and Ptenrdquo Developmental Biology vol 320 no 2 pp340ndash350 2008

[73] J P Luyendyk G A Schabbauer M Tencati T Holscher RPawlinski and N Mackman ldquoGenetic analysis of the role ofthe PI3K-Akt pathway in lipopolysaccharide-induced cytokineand tissue factor gene expression in monocytesmacrophagesrdquoJournal of Immunology vol 180 no 6 pp 4218ndash4226 2008

12 Journal of Signal Transduction

[74] F Sun K K Park S Belin et al ldquoSustained axon regenerationinduced by co-deletion of PTEN and SOCS3rdquo Nature vol 480no 7377 pp 372ndash375 2011

[75] C B Knobbe V Lapin A Suzuki and T W Mak ldquoThe roles ofPTEN in development physiology and tumorigenesis in mousemodels a tissue-by-tissue surveyrdquo Oncogene vol 27 no 41 pp5398ndash5415 2008

[76] S J Assinder Q Dong Z Kovacevic and D R RichardsonldquoThe TGF-beta PI3KAkt and PTEN pathways establishedand proposed biochemical integration in prostate cancerrdquoBiochemical Journal vol 417 no 2 pp 411ndash421 2009

[77] K A Waite and C Eng ldquoFrom developmental disorder toheritable cancer itrsquos all in the BMPTGF-120573 familyrdquo NatureReviews Genetics vol 4 no 10 pp 763ndash773 2003

[78] H B Newton ldquoMolecular neuro-oncology and developmentof targeted therapeutic strategies for brain tumors Part2 PI3KAktPTEN mTOR SHHPTCH and angiogenesisrdquoExpert Review of Anticancer Therapy vol 4 no 1 pp 105ndash1282004

[79] R H KimM Peters Y Jang et al ldquoDJ-1 a novel regulator of thetumor suppressor PTENrdquo Cancer Cell vol 7 no 3 pp 263ndash2732005

[80] J Lu H W Jeong N Kong et al ldquoStem cell factor SALL4represses the transcriptions of PTEN and SALL1 through anepigenetic repressor complexrdquo PLoS ONE vol 4 no 5 ArticleID e5577 2009

[81] M M A Rizvi M S Alam A Ali S J Mehdi S Batra andA KMandal ldquoAberrant promotermethylation and inactivationof PTEN gene in cervical carcinoma from Indian populationrdquoJournal of Cancer Research and Clinical Oncology vol 137 no 8pp 1255ndash1262 2011

[82] J Liu ldquoControl of protein synthesis and mRNA degradation bymicroRNAsrdquo Current Opinion in Cell Biology vol 20 no 2 pp214ndash221 2008

[83] S W Shan L Fang T Shatseva et al ldquoMature miR-17-5pand passenger miR-17-3p induce hepatocellular carcinoma bytargeting PTEN GalNT7 and vimentin in different signalpathwaysrdquo Journal of Cell Science vol 126 part 6 pp 1517ndash15302013

[84] Z Liang Y Li K Huang N Wagar and H Shim ldquoRegulationof miR-19 to breast cancer chemoresistance through targetingPTENrdquo Pharmaceutical Research vol 28 no 12 pp 3091ndash31002011

[85] X Lu Q Fan L Xu et al ldquoUrsolic acid attenuates diabeticmesangial cell injury through the up-regulation of autophagyvia miRNA-21PTENAktmTOR suppressionrdquo PLoS ONE vol10 no 2 Article ID e0117400 2015

[86] L Poliseno L Salmena J Zhang B Carver W J Havemanand P P Pandolfi ldquoA coding-independent function of geneand pseudogenemRNAs regulates tumour biologyrdquoNature vol465 no 7301 pp 1033ndash1038 2010

[87] Y Tay L Kats L Salmena et al ldquoCoding-independent regula-tion of the tumor suppressor PTEN by competing endogenousmRNAsrdquo Cell vol 147 no 2 pp 344ndash357 2011

[88] L Odriozola G Singh T Hoang and A M Chan ldquoRegula-tion of PTEN activity by its carboxyl-terminal autoinhibitorydomainrdquo The Journal of Biological Chemistry vol 282 no 32pp 23306ndash23315 2007

[89] Z Li X Dong Z Wang et al ldquoRegulation of PTEN by Rhosmall GTPasesrdquo Nature Cell Biology vol 7 no 4 pp 399ndash4042005

[90] E-K Yim G Peng H Dai et al ldquoRak functions as a tumorsuppressor by regulating PTEN protein stability and functionrdquoCancer Cell vol 15 no 4 pp 304ndash314 2009

[91] AMAl-Khouri YMa SH Togo SWilliams andTMustelinldquoCooperative phosphorylation of the tumor suppressor phos-phatase and tensin homologue (PTEN) by casein kinasesand glycogen synthase kinase 3120573rdquo The Journal of BiologicalChemistry vol 280 no 42 pp 35195ndash35202 2005

[92] H Maccario N M Perera L Davidson C P Downes and NR Leslie ldquoPTEN is destabilized by phosphorylation onThr366rdquoBiochemical Journal vol 405 no 3 pp 439ndash444 2007

[93] K A Waite and C Eng ldquoBMP2 exposure results in decreasedPTEN protein degradation and increased PTEN levelsrdquoHumanMolecular Genetics vol 12 no 6 pp 679ndash684 2003

[94] T J Jerde Z Wu D Theodorescu and W Bushman ldquoRegu-lation of phosphatase homologue of tensin protein expressionby bone morphogenetic proteins in prostate epithelial cellsrdquoProstate vol 71 no 8 pp 791ndash800 2011

[95] G Singh and A M Chan ldquoPost-translational modificationsof PTEN and their potential therapeutic implicationsrdquo CurrentCancer Drug Targets vol 11 no 5 pp 536ndash547 2011

[96] T Ikenoue K Inoki B Zhao and K-L Guan ldquoPTEN acety-lation modulates its interaction with PDZ domainrdquo CancerResearch vol 68 no 17 pp 6908ndash6912 2008

[97] L C Trotman X Wang A Alimonti et al ldquoUbiquitinationregulates PTEN nuclear import and tumor suppressionrdquo Cellvol 128 no 1 pp 141ndash156 2007

[98] T Tolkacheva M Boddapati A Sanfiz K Tsuchida A CKimmelman and AM-L Chan ldquoRegulation of PTEN bindingto MAGI-2 by two putative phosphorylation sites at threonine382 and 383rdquo Cancer Research vol 61 no 13 pp 4985ndash49892001

[99] E Lima-Fernandes H Enslen E Camand et al ldquoDistinct func-tional outputs of PTEN signalling are controlled by dynamicassociation with 120573-arrestinsrdquoThe EMBO Journal vol 30 no 13pp 2557ndash2568 2011

[100] M T van Diepen M Parsons C P Downes N R Leslie RHindges and B J Eickholt ldquoMyosinV controls PTEN functionand neuronal cell sizerdquo Nature Cell Biology vol 11 no 10 pp1191ndash1196 2009

[101] R B Chagpar P H Links M C Pastor et al ldquoDirect positiveregulation of PTEN by the p85 subunit of phosphatidylinositol3-kinaserdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 107 no 12 pp 5471ndash5476 2010

[102] Y Takahashi F C Morales E L Kreimann and M-MGeorgescu ldquoPTEN tumor suppressor associates with NHERFproteins to attenuate PDGF receptor signalingrdquo The EMBOJournal vol 25 no 4 pp 910ndash920 2006

[103] M Valiente A Andres-Pons B Gomar et al ldquoBinding ofPTEN to specific PDZ domains contributes to PTEN proteinstability and phosphorylation by microtubule-associated ser-inethreonine kinasesrdquoThe Journal of Biological Chemistry vol280 no 32 pp 28936ndash28943 2005

[104] SQuintes SGoebbels G SaherMH Schwab andK-ANaveldquoNeuron-glia signaling and the protection of axon function bySchwann cellsrdquo Journal of the Peripheral Nervous System vol 15no 1 pp 10ndash16 2010

[105] B Fine C Hodakoski S Koujak et al ldquoActivation of the PI3Kpathway in cancer through inhibition of PTEN by exchangefactor P-REX2ardquo Science vol 325 no 5945 pp 1261ndash1265 2009

Journal of Signal Transduction 13

[106] L He A Ingram A P Rybak and D Tang ldquoShank-interactingprotein-like 1 promotes tumorigenesis via PTEN inhibition inhuman tumor cellsrdquo The Journal of Clinical Investigation vol120 no 6 pp 2094ndash2108 2010

[107] L He C Fan A Kapoor et al ldquo120572-Mannosidase 2C1 attenuatesPTEN function in prostate cancer cellsrdquo Nature Communica-tions vol 2 no 1 article 307 2011

[108] Z Radisavljevic ldquoAKT as locus of cancer positive feedbackloops and extreme robustnessrdquo Journal of Cellular Physiologyvol 228 no 3 pp 522ndash524 2013

[109] M Y Lee HW Lim S H Lee andH J Han ldquoSmad PI3KAktand wnt-dependent signaling pathways are involved in BMP-4-induced ESC self-renewalrdquo Stem Cells vol 27 no 8 pp 1858ndash1868 2009

[110] K Song S C Cornelius M Reiss and D Danielpour ldquoInsulin-like growth factor-I inhibits transcriptional responses of trans-forming growth factor-120573 by phosphatidylinositol 3-kinaseAkt-dependent suppression of the activation of Smad3 but notSmad2rdquoThe Journal of Biological Chemistry vol 278 no 40 pp38342ndash38351 2003

[111] D Fang D Hawke Y Zheng et al ldquoPhosphorylation of 120573-catenin by AKT promotes 120573-catenin transcriptional activityrdquoThe Journal of Biological Chemistry vol 282 no 15 pp 11221ndash11229 2007

[112] Q Lei J Jiao L Xin et al ldquoNKX31 stabilizes p53 inhibitsAKT activation and blocks prostate cancer initiation caused byPTEN lossrdquo Cancer Cell vol 9 no 5 pp 367ndash378 2006

[113] A Sengupta J D Molkentin J-H Paik R A DePinho and KE Yutzey ldquoFoxO transcription factors promote cardiomyocytesurvival upon induction of oxidative stressrdquo The Journal ofBiological Chemistry vol 286 no 9 pp 7468ndash7478 2011

[114] C H M Jamieson L E Ailles S J Dylla et al ldquoGranulocyte-macrophage progenitors as candidate leukemic stem cells inblast-crisis CMLrdquoTheNewEngland Journal ofMedicine vol 351no 7 pp 657ndash667 2004

[115] A Androutsellis-Theotokis R R Leker F Soldner et al ldquoNotchsignalling regulates stem cell numbers in vitro and in vivordquoNature vol 442 no 7104 pp 823ndash826 2006

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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International Journal of

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Microbiology

Page 3: Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling TravisJ.Jerde Department of Pharmacology

Journal of Signal Transduction 3

BrainGangliocytoma

Mental retardationAutism

Seizures

SkinThickening

Melanocyte expansion

Immunitylymphoid hyperplasia NK cell development antibody class-switching recruitment

Mammarygland

Ovary Prostate

Bone

Lungs

UT

GIDevelopment

InvolutionBudding

GrowthOvulation

ElongationMatrix deposition

DevelopmentFunctioning

DevelopmentFunctioning

DevelopmentPhysiology

GrowthDevelopment

Physiology

Figure 2 Precise regulation of PTEN expression activity or localization has profound effects on the development of numerous organ systemsDisruption of PTENat the level of transcriptionmRNA stability protein stability enzymatic function or cellular location results in disruptionof these developmental systems

Cell type-specific mutations of PTEN in animal mod-els demonstrate developmental phenotypes and resultingpathology Glial cell conditional null mutation of the Ptengene promotes seizures and ataxia early in life in miceand promotes premature death [28] Brain size in thesemice increases progressively over time relative to wild-typelittermates and these mutants develop hydrocephalus anduntoward lateral ventricle growth [28]These animals exhibitneural dysplasia thickened internal granule cell layers anda progressive increase in neuronal soma size [28] Furthermice with oligodendrocyte-specific PTEN deletion exhibitdisruption in the myelination of axons [29] Importantlythese murine effects are similar to many common featuresassociated with PTEN mutations in the human CNS [30]

PTEN deletions in terminally differentiated neuronsresult in a number of striking phenotypes Neuronal-specificPTEN deletion promotes soma hypertrophy macroen-cephaly and increased axonal outgrowth This latest find-ing has led to the hypothesis that PTEN inhibition maybe a potential therapeutic mechanism for inducing axonal

outgrowth in spinal injury patients [31] These mice alsoexhibit increased dendritic spine density increased caliberof neuronal projections and alterations in synaptic trans-mission [31] Neurons from these mice exhibit disruptionin Bergmann-glia connections and disorganized cerebellararchitecture [31] Neuronal-conditional PTEN null mice alsodisplay hyperactivity signs of anxiety heightened responseto excitatory stimuli and disrupted social interaction [32]Findings from these studies have prompted the hypothesisthat PTEN expression anomalies may be at least in partresponsible for CNS-related disorders in humans

23 Dermal Development PTEN-mediated signaling haslong been known to be critical for the cytoprotection ofboth epithelial cells and melanocytes in the skin Interest-ingly PTEN has recently been shown to be responsible forregulating the events and timing of epidermal development[19] This may have been predictable given the incidence ofbenign tumors of the skin in Cowdenrsquos syndrome a knownPTEN-driven condition Conditional PTEN deletion induces

4 Journal of Signal Transduction

hyperplasia of squamous cells resulting in mounted skindermis and papillomas [33] Additionally mice with specificmelanocytic PTEN deletion exhibit increased melanocyteexpansion [34]

24 Hematopoietic Development PTEN is necessary forproper development lineage fate and cell function in T cellsB cells myeloid cells NKT cells and hematopoietic stem cells(HSCs) as demonstrated by several elegant studies involvingglobal heterozygous and cell-conditional null PTEN models[35ndash40] It has been known that PTEN (+minus) mice exhibitlymphoid hyperplasia progressing to T-cell lymphoma com-plete with large nodal masses [36] and it has now alsobeen reported that PTEN (+minus) mice develop autoimmunedisorders at an early age due to abrogated PTEN function[37] Cell-type T-cell conditional PTEN null mice exhibitlymphadenopathy splenomegaly and hyperplastic enlargedthymus Similar to the global PTEN heterozygous miceconditional nulls also exhibit autoreactivity evidenced byincreased levels of autoantibodies expanded T-cell prolifer-ation and increased cytokine synthesis and release [38]

Indirect studies show that PTEN-mediated signalingplays a role in natural killer (NK) cells Unfortunatelytrue cell-selective knockout of PTEN in natural killer (NK)cells has not been reported due to the lack of a cell-typespecific promoter However purified NK cells from PTENimmune-system null mice exhibit abrogated maturation andactivation [39] Studies have demonstrated that when thesecells were adoptively transferred intoNK null mice harboringmetastatic melanoma cells the null cells exhibit stronglydecreased protection from metastases relative to wild-typeNKT cells [39 40]These results demonstrate that one criticalrole of NK cells namely tumor targeting is attenuatedin PTEN null NK cells In addition B-cell lineage-specificPTEN null mice exhibit expanded splenocytes mesentericlymph node cells and peritoneal cells [41] B cells deficientin PTEN display enhanced proliferation upon epitope ormitogen stimulation and defective class-switch antibodyrecombination resulting in decreased production of IgA andIgG antibodies and elevated IgM production [41]

Neutrophils isolated from mice with PTEN-null myeloidlineage cells display increased actin polymerization withenhanced membrane ruffling pseudopodia formation che-motaxis and migratory speed [42] Inflammation in thesemice is associated with vastly increased neutrophil recruit-ment [42] Paradoxically these mice are more susceptible toinfection with Leishmania and exhibit a slower clearance ofinfection than wild-type littermates This disconnect appearsto be due to decreased secretion of tumor necrosis factor(TNF) by mutant macrophages in these mice [43] To datelittle else is known about the development of monocytes inmyeloid-specific PTEN null bearing animals

Deletion of PTEN in murine hematopoietic stem cells inmice results in a very rapid onset of myeloproliferative disor-ders and an eventual depletion of the stem cell pool whichdespite their proliferative nature results in the loss of theability of these stem cells to produce all lineages needed forproper immune functioning [44] These myeloproliferativedisorders progressed to acute myeloid leukemia or acute

lymphoblastic leukemia [44] In a demonstration that Akt-signaling is downstream of this phenotype increased HSCproliferation and even the development of myeloproliferativedisorders and leukemia are all rescued when the mice weretreated with rapamycin [44]

25 Visceral OrganDevelopment There are numerous studiesto date examining the developmental effects of organ-specificPTEN mutation in mouse models This review summarizesthe highlights of these studies hereMammary ducts in tissue-specific conditional PTEN null mice exhibit loss of differ-entiation enhanced growth excessive side branching andprecocious budding relative to wild-type controls [45] Thesephenotypes are reported during puberty but also manifesttheir effects during mammary expansion during pregnancyNotably mammary gland involution after pregnancywas alsodefective [45] PTEN is important for the normal physiologyof oocytes as PTEN deficiency in murine oocytes causesthe entire oocyte pool to become activated prematurely [46]This proves to be critical for fertility and reproduction aspremature oocyte activation resulted in females having amaximum of one normal-sized litter before they becameinfertile at 12-13 weeks of age [46]

FabpCre-(Ptenfloxflox) mice exhibit a number of inter-esting phenotypes in the genitourinary system PTEN dele-tion occurs in the bladder ureter kidney colon prostateseminal vesicles and vagina of these mutants [47] Epithelialhyperplasia was omnipresent in these animals As expecteddeletion of PTEN resulted in increased susceptibility tochemically induced carcinogenesis [48] Similarly epithelialhyperplasia is present in organ specific PTEN knockoutsfollowed by intraepithelial neoplasia and ultimately by inva-sion of the cancer cells as invasive adenocarcinoma [49ndash51]Embryonic deletion of PTEN in the lower urinary systemresults in a loss of proper differentiation within affected cells[52] ultimately resulting in loss of proper patterning andgrowth control Based on these data and the collection ofphenotypes observed in PTEN deleted cells and animals it islikely that a loss of differentiation of cells plays a master rolein PTENrsquos role in organ development

Recent reports have demonstrated a critical role for PTENin the branching morphogenesis and nephron patterning ofdeveloping kidneys PTEN has been shown to be indispens-able for developing bud outgrowth mesenchymal invasionand branching morphogenesis in developing kidneys bymediating the signaling downstream of GDNFRET receptortyrosine kinases [53] Again this involves differentiation andchemotaxis of epithelial cells More recently Lindstrom etal have shown that PTEN sits at the center of nephrondevelopment by integrating signaling from BMP and wnt-beta-catenin pathways [54] Disruption of PTEN results in aloss of coordinated signaling and a loss of proper patterningof epithelial cells along the axis of the nephron tubule

Numerous developmental effects of PTEN have beennoted in the gastrointestinal tract In the colon PTEN (+minus)mice develop hamartomatous polyps consistent with dis-rupted control of differentiation of cells [55] Further PTENis critical for colon homeostasis involving inflammatoryrepair and recovery processes that reactivate developmental

Journal of Signal Transduction 5

signalingmechanisms [56] In the liver loss of PTENnot onlyincreases tumor susceptibility but also altersmetabolism [57]In addition hepatomegaly is observed in mice with condi-tional hepatic PTEN knockout as the ratio of liver weightto body weight increased in the mutants when comparedwith wild-type controls [57] Livers harvested from mutantanimals are discolored and show accumulation of triglyc-erides consistent with steatohepatitis associated with severeinflammation Passive diffusion of fatty acids in hepatocyteswas enhanced in PTEN null mice and PTEN-deficienthepatocytes exhibit an increased rate of fatty acid synthesisvia induced fatty acid synthase [57] PTEN-deficient miceexhibit defects in glucose metabolism including decreasedfasting plasma glucose levels and reduced serum insulinlevels [58] Clearance of glucose was accelerated in theabsence of PTEN concurrent with increased liver glycogenstorage

Pancreatic islet beta-cell specific PTEN-deficient miceexhibit increases in islet cell numbers total islet massand an increase in 120573-cell progenitor proliferation duringembryonic development and early postnatal life [59] AdultPTEN mutant mice were hypoglycemic and were resistantto streptozotocin-induced diabetes These mice are signifi-cantly smaller than controls and have a shorter lifespan Insome studies severe hypoglycemia is associated with seizureactivity and premature death before 5 weeks of age [59]In addition PTEN (+minus) mice exhibit protection againstincreased insulin production during reactive oxygen species-dependent type two diabetes and insulin-resistance uponaging [60]

PTENrsquos role in maintaining glucose balance is not limitedto the liver and pancreas but also involves adipocytes andmyocytes Inactivation of PTEN specifically in adipocytesproduces no obvious gross morphological effects on theadipose tissue or adipose tissue mass However this mouseexhibits increased systemic glucose tolerance and insulin sen-sitivity complete with decreased fasting insulin and resistinlevels [61] By controlling serum insulin and resistin levelsPTEN regulates insulin sensitivity and AMP kinase activityin the liver Similarly skeletal and cardiac muscle cell-specificdeletion causes increased systemic glucose tolerance andinsulin sensitivity [62] Interestingly however PTEN loss inthese tissues seems to protect thesemice from streptozotocin-induced diabetes and hyperglycemia indicating that theinsulin hypersensitivity exhibited in tissue-selective PTEN-deficient mice allowed them to maintain proper glucoselevels

PTEN regulates proper lung development Specific lungdeletion of PTEN during embryogenesis results in impairedlungmorphogenesis and early postnatal death [61]The lungsof these neonates exhibit increased epithelial cell proliferationand decreased alveolar cell differentiation Adults exhibitbronchiolar and alveolar epithelial hyperplasia Mutant miceexhibit hypertrophy of alveolar cells derived from bron-chioalveolar stem cells [61] Predictably adenocarcinomawasevident in aged adults Further study of PTENrsquos role inlung development revealed that PTEN-regulated signalingmediates lung endodermal morphogenesis coordinate withthe overall developmental process in the lung and it is central

to the interaction of several signaling pathways including theTGF beta-SMAD and Nkx21 pathways [62]

Normal development of the vascular system is alsodependent on proper PTEN function PTEN knockout inendothelial and endocardial cells in mice results in embry-onic lethality due to increased capillaries and endothelial cellhypertrophy [63] These mutant embryos exhibit pericardialcavity enlargement leakage of blood into the pericardialcavity and enlarged trunk vessels secondary to pericyte andvascular smooth muscle cell recruitment to blood vessels[63] In addition cardiomyocyte-specific deletion of PTENleads to cardiac phenotypes via development of cardiachypertrophy and contractile defect [64] Future studies onPTEN will hopefully be targeted at assessing injury-relatedresponses in the cardiovascular system as deletion of PTENin cardiomyocytes has been shown to protect the heart frommaladaptive remodeling upon biomechanical stress

PTEN regulates developing bone and cartilage by pro-tecting against overgrowth of the skeletal system Mice withdeletion of PTEN in osteochondroprogenitor cells exhibitgrowth plate dysfunction and overgrowth of the vertebrae[65] The bodies of these mice are notably longer than wild-type controls demonstrating a critical defect that resultsin loss of proper skeletal development Interestingly thisincrease in length was not due to bone cell proliferationincreases as might have been expected but rather is due toincreased matrix deposition and cellular hypertrophy [65]In a second model osteoblast-specific knockdown of PTENexpression results in increased bone volume and density[66] Interestingly this mutation is associated with improvedintramembranous and late endochondral fracture healingThis is now an active area of research within the boneremodeling research field

While PTEN remains virtually synonymous with cancerbiology the studies presented here make the importanceof proper PTEN signaling for regulating a wide variety ofdevelopmental processes clearly evident From regulation ofgrowth differentiation glucose maintenance and repair andrecovery to gross effects on organ and systems developmentPTEN is a protein with vast consequence in the field ofdevelopmental biology and the signaling affected by itsexpression is expansiveThe role PTEN plays in developmenthas clear correlates to human disease Further PTENrsquos effectson development acquire greater importance when the rolethat developmental signaling plays in cancer growth andprogression is consideredTherefore an extensive knowledgeof how PTEN is regulated by developmental signaling apartfrom somatic or genetic mutation is required for completeunderstanding of PTENrsquos role in these important physiologi-cal processes

3 PTEN Regulation as Part ofDevelopmental Signaling

31 Intrinsic and Extrinsic PTEN Regulation Most studiesevaluating the role of PTEN in human diseases have beencentered uponmutation in PTEN itself andmost of this workis done in its relationship to cancer initiation and progression

6 Journal of Signal Transduction

BMP Hh JagdeltaNOTCH

NICD

miRNA(17 19 21)

GF

PTEN mRNA

PTEN mRNA

PTENNICD

SMAD2 3

SMAD1 5 8 Gli2

AP -1

NICDAP -1

SMO

SMAD2 3

SMAD1 5 8 Gli2

SALL4

Cyt

p65p50

p65p50

ceRNAAkt

GSK3CK2

PCAF

SIRT1

PIP3 PIP2

PI3 kinase

TGF120573

Figure 3 Summary of regulation mechanisms for PTEN critical for its action in developmental biology PTEN transcription is regulatedby TGF120573 BMP Hh NOTCH and cytokine signaling in cells during development miRNAs and ceRNAs regulate PTEN message stabilityPhosphorylation or acetylation by then can regulate PTENrsquos protein stability enzymatic activity and cellular localization in a positive ornegative manner All told the regulation of PTEN is complex and precise during development and perturbations in this paradigm haveprofound effects

There is no question that mutations of PTEN play a criticalrole in this regard Studies over the last decade howeverhave discovered a tremendous diversity in the regulationof PTEN expression and found that PTEN is tightly con-trolled both transcriptionally and posttranscriptionally [67]Recent studies to date have implicated microRNAs in PTENsuppression [68] and the enzymatic phosphatase activityof PTEN is also regulated posttranslationally via phospho-rylation ubiquitination or oxidation [69 70] This sectionhighlights the multifaceted mechanisms of PTEN regulationsupported by the rapidly expanding literature on PTENrsquos rolein growth and patterning of tissues during development Inaddition special emphasis is given tomediators and pathwaysinvolved in development including insulin-like growth factortransforming growth factor bone morphogenetic proteinsNOTCH forkhead transcription factors (Fox) and othersPTENrsquos complex regulation at the levels of transcriptionmRNA stability posttranslational modifications andmiRNAlevels has become a critical series of mechanisms deserving acomprehensive review (for an overview see Figure 3)

32 Developmental Signaling Regulating PTEN Expressionand Action The regulation of PTEN expression occurs attranscriptional posttranscriptional posttranslational andprotein-protein interaction levels [71] PTENrsquos function isfurther controlled by its cellular location In this sectionwe highlight developmental pathways involved in regulating

PTEN expression at all these regulation points and makespecial reference to connections between signal transductionand development

321 Developmental Pathways in PTEN Gene ExpressionOne critical aspect of PTENrsquos regulation during developmentbegins at the transcriptional level To date PTEN expres-sion has been found to be regulated at the transcriptionallevel by pathways involving p53 PPAR120574 Egr-1 NF-120581Band SMADs and this regulation affects the developmentof proper immune function the vasculature the nervoussystem the gastrointestinal system and the airways [6372 73] While PTEN is constitutively expressed in manynormal adult tissues PTEN expression is altered dramat-ically through the course of development and in patho-logical settings and a primary source of this regulationcomes from bona fide developmental regulators In additionsuppressors of cytokine signaling (SOCS) and SNAIL alsoinduce PTEN and act by countering the growth-promotingactions of cytokines and growth factors in developmentand repair and recovery [74] This mechanism has beenclearly demonstrated in axonal outgrowth during neurondevelopment and regeneration [74] While the physiologicalramifications of this regulation remain unsolved mediatorsthat slow or inhibit cell proliferation are often involved ininducing this protein Developmental mediators includingNOTCH transforming growth factor beta (TGF120573) bone

Journal of Signal Transduction 7

morphogenetic proteins (BMPs) and hedgehogs (Hhs) allparticipate as players in external PTEN regulation [75ndash78] regulating such processes as proliferation and targetedepithelial budding and outgrowth of visceral organs [76 77]and outgrowth in neurons [75] As the direction of cell growthand differentiation balances on the fulcrum between theproliferative and differentiating actions of these mediatorstheir regulation to induce or repress PTEN expression isa critical aspect of their actions during development Thecritical developmental mediator TGF120573 contains both growthpromoting and inhibiting differentiation qualities and TGF120573induces PTEN during differentiation when growth is slowedand inhibits its expression during proliferation In additionthe developmental regulator DJ-1 was recently identified asa novel negative regulator of PTEN by a genetic screen inDrosophila [79] PTEN is also regulated through epigeneticsilencing by methylation of the PTEN promoter [80 81] Aninteresting zinc-finger transcription factor sal-like protein 4(SALL4) has been discovered as a critical negative regulatorof PTEN transcription by recruiting an epigenetic repressorcomplex involving anATPase and a histone deacetylase to thePTENpromoter [80] SALL4 plays a critical role in regulatingdevelopment by modulating self-renewal in stem cells andits function appears to at least partly involve methylation ofthe PTENpromoter andmodulation of its transcriptionDataon this mechanism are still limited but to date this processhas been shown to regulate kidney patterning during devel-opment as well as leukemogenesis [80] Current research inthe area of PTEN transcriptional regulation continues to bedynamic and more novel regulation patterns are likely to bediscovered in the near future

322 PTEN Regulation by Posttranscriptional RegulationRecent studies have identified several interesting develop-mentally expressed miRNAs that regulate PTEN mRNAmessage stability and translatability [82] These miRNAstypically downregulate PTEN mRNA levels by targeting itfor degradation and include miR-17 miR-19 and miR-21 [83ndash85] While several examples of miR-17 and miR-19-mediatedPTENRNA levels have been reported in the cancer literaturemiR-21 has been described to play a critical role in repairand recovery a developmental signaling-related processmiRNAs regulate this mechanism by modulating PTENRNA stability and ultimately downstream Akt signaling Forexample in the pancreas miR-21 regulates injury repair indiabetic models by targeting PTEN RNA for degradationInhibition of miR-21 results in autophagy in this model ina manner dependent on PTEN degradation [85] In anotherexample of novel miR-related PTEN regulation the PTENpseudogene 1 (PTENP1) acts as a decoy for PTEN-targetingmiRNAs and thereby regulates PTEN expression by coding-independent activity through sequestering these miRNAsand effectively inhibiting their effects on PTEN expression[86] Additionally combined bioinformatic and experimentalapproaches have identified ceRNA transcripts that controlPTEN expression by sequestering PTEN-targeting miRNAsduring development of both prostate and skin [87] Becausethis type of PTEN regulation and indeed this field of generegulation in general is in its infancy we are only beginning

to understand the PTEN regulation by coding and noncodingceRNAs Still this novel work provides a platform for furtherstudies investigating posttranscriptional regulation patternsof PTEN expression in both developmental biology anddisease conditions

323 PTENRegulation by PosttranslationalMechanisms Theprotein stability and enzyme activity of PTEN are regulatedin a number of ways at the posttranslational level FirstPTEN is phosphorylated in its C-terminal tail at Ser380Thr382 Thr383 and Ser385 and this functions to inhibitthe critical PTEN phosphatase activity thereby promotinggrowth in prostate and kidney cells [88] However thesephosphorylations also stabilize the PTEN protein by dis-suading ubiquitination While this may seem like a cellulardisconnect this paradoxical phenomenon is explained by thefinding that this closed more stable PTEN conformation isprevented from associating with membranes and thereforeis geographically separated from its substrates [88] PTENcan also be activated by phosphorylation in particular theC2 domain of PTEN is phosphorylated at Ser229 andThr321by RHOA-associated protein kinase (ROCK) [89] a phos-phorylation that results in its association with membranesand phosphoinositide substrates affecting differentiation inleukocytes PTEN is further phosphorylated at Tyr336 by theTyr protein kinase RAK and this phosphorylation resultsin its stabilization [90] Loss of this activity has the effectof promoting breast cell proliferation and migration FinallyPTEN is also phosphorylated at Ser370 and Thr366 by CK2and GSK3120573 [91 92] respectively however the consequencesof this phosphorylation are unclear The likely extensivesignaling networks that regulate these widespread phospho-rylations in PTEN are not fully studied but the TGFBMP-SMADdevelopmental pathways are known to regulate PTENphosphorylation [93 94] Given the widespread applicationof SMAD signaling to developmental biology the presence ofSMAD-regulated PTEN phosphorylation is a critical aspectof developmental regulation in cells

PTEN enzymatic activity is also regulated posttrans-lationally by acetylation [70 95ndash97] PTEN is acetylatedat Lys125ndashLys128 by p300CREB-binding protein- (CBP-)associated factor (PCAF) and at Lys402 by CBP itself [95]Acetylation at these residues inhibits PTENrsquos function as aphosphatase and has been shown to promote the growthof prostate epithelial cells and glial cells [95] In additionthe deacetylase Sirtuin 1 (SIRT1) is involved in excludingPTEN from the nucleus and therefore preventing its newlycharacterized nuclear functions [96]

324 PTEN Regulation by Protein-Protein Interactions Theconformation stability and subcellular distribution of PTENis regulated by critical interactions with other proteins withincells and these proteins are known to be critical for properdevelopment of a number of organ systems The guanylatekinase inverted 2 (MAGI2) and 120573-arrestins cooperate toenhance PTEN activity [98 99] MAGI2 phosphorylatesPTEN on threonine residues at positions 382 and 383 ofPTENrsquos carboxy terminus allowing recruitment to cell-cell

8 Journal of Signal Transduction

junctions [98] Mutations to these residues prevent PTENrecruitment Upon recruitment 120573-arrestins modulate PTENactivity by direct binding to the C2 domain and modulatingits protein phosphatase activity including that at the levelof small GTPases including RhoAROCK [99] In addi-tion Myosin V regulates PTENrsquos movement to and fromthe plasma membrane and this function is required forPTEN to access its phosphoinositide substrates [100] andfor disrupting the proper regulation of neuronal cell sizeThe p85 regulatory subunit of the PI

3kinase enzyme itself

interacts with PTEN in a novel mechanism of repressing thePI3KndashAKT pathway [101] independent of PTENrsquos action as a

phosphatase It is therefore proposed that p85 regulates thePI3KndashAKT pathway bidirectionally both through its binding

to catalytic p110 subunit resulting in the generation of phos-phoinositides and by binding PTEN leading to repressionThis work proposes a novel signaling model for PTEN-p85association in which p85120572 preferentially binds and stabilizesp110 preferentially when p85120572 levels are low but excess p85120572binds to and positively regulates PTEN phosphatase activitywhen p110 is saturated Therefore sustained activation ofPI3K signaling and activated p110-p85 complexing is modu-lated homeostatically by this mechanism

A fascinating group of recent studies have utilizedproteomic library screens to identify further novel PTENinteracting proteins First the Na+H+ exchanger regulatoryfactor (NHERF) binds to and recruits PTEN to the platelet-derived growth factor receptor (PDGFR) This representsanother action that restricts PI

3KndashAKT pathway activation

independent of phosphatase activity [102] This has the effectof inhibiting PDGF-induced cytoskeletal rearrangements andchemotactic migration of developing neurons In additionthe mammalian disks large homologue 1 (DLG1) MAGI-2 and MAST205 proteins directly interact with PTENand enhance PTEN stability and activity [103] Furtherneuregulin 1 (NRG1) has been shown to interact with bothDLG1 and PTEN in a stable complex that has the effect ofregulating myelin sheath thickness in developing mouse sci-atic nerves [104] Additional but less-characterized protein-protein interactions that modulate PTEN function includethe PIP

3-dependent RAC exchanger factor 2a (PREX2a)

[105] shank-interacting protein-like 1 (SIPL1) [106] and 120572-mannosidase 2C1 (MAN2C1) [107]

325 PTEN-Controlled Signal Transduction during Develop-ment PTEN is critically important in regulating signalingpathways involved in cell growth and animal developmentThrough its well-characterized function as a phosphataseof PIP

3 PTEN modulates a network of mitogen-activated

signals transduced through PI3KndashAkt signaling This pri-

mary action of PTEN has tremendous impact on cell growthcell migration cell death and cell differentiationmdashcellularprocesses that are all hallmarks of proper growth andpatterning during development The active phosphorylatedPIP3activates several signaling molecules including the

phosphatidylinositol-dependent kinases (PDKs) followed byAkt S6 kinase and mTOR Beyond this AKTrsquos targetsinclude the apoptotic factor BAD activator and executioner

caspases glycogen synthase kinase-3 (GSK-3) MDM2 p21and p27 forkhead transcription factors (FOXOs) and nuclearreceptors including the androgen and estrogen receptors[108] Akt-mediated phosphorylation of these moleculescauses activation translocation and increased stability

The PTENPI3kinaseAKT signaling cascade crosstalks

to several key signal transduction pathways that are criticalto developmental biology This includes the abovementionedTGF-120573SMAD pathway and the Wnt120573-catenin pathway[109] The TGF-120573SMAD pathway is one of the most seminalpathways in developmental biology and PTEN modulatesTGF120573SMAD signaling by reversing Akt-mediated phospho-rylation of SMAD3 the critical signaling intermediate ofTGF120573SMAD signaling [110] Similarly the Wnt signalingpathway is indispensable for properly regulated developmentcellular proliferation and differentiation [111] PTEN regu-lates this pathway by reversing AKT kinase phosphorylationand inhibition of GSK-3120573 resulting in 120573-catenin nucleartranslocation and activation Finally recent studies demon-strate that PTEN regulates the expression and action of thehomeobox genes NKX31 and hepatic nuclear factor [112]proteins that are critical to organ development

326 PTEN-Regulated Stem Cell Activities The scientificliterature in the field of tissue stem or stem-like ldquoprogen-itorrdquo cells and their role in tissue development growthrecovery and repair has become beyond extensive in recentyears Expansion of stemprogenitor cells is a hallmark ofgrowth and patterning during development and regulationof these cells including their proliferation maintenanceand differentiation is a critical factor of developmentalregulation Because of this a review of the current liter-ature on PTENrsquos role in stem and tissue progenitor cellsis warranted in this review PTEN plays an important rolein regulating the homeostasis of stemprogenitor cells inmultiple tissues Interestingly PTEN regulates both self-renewal and proliferation but paradoxically it also playsa role in stem cell exhaustion For example the FOXOfamily of transcription factors controls stem cell proliferationand survival in hematopoietic stem cells [113] and PTENsignaling is a critical modulator of FOXO activity FOXO3A-deficient HSCs exhibit increased proliferation rate decreasedquiescence and a reduced ability to repopulate bone marrowafter transplantation into recipient mice Additionally thepreviously mentioned Wnt120573-catenin signaling pathway iscritical for HSC self-renewal and its activation is well knownto be modulated by PTEN Interestingly PTEN loss and AKTactivation in HSCs lead to a moderate increase in the levelof unphosphorylated 120573-catenin but this is not sufficient tomaintain Pten-null HSC self-renewal [114] Finally NOTCHsignaling plays a key role in regulating neural stem cellexpansion [115] and as stated previously NOTCH pathwayactivation leads to reduced PTEN expression in neural andhematopoietic stem cells

4 Conclusions

PTEN acts as the key endogenous negative modulatorof phosphoinositide signaling in mammalian cells and

Journal of Signal Transduction 9

therefore its role in normal cell homeostasis proliferationapoptosis and many additional components of cell biologyis extensive Because PTEN regulates cancer progressionmuch of what has been studied regarding PTEN relates totumorigenesis and tumor growth While this is warrantedbecause of the relevance of cancer to humanhealth PTENhassubstantial but underappreciated effects in normal tissue andorgan development immune system development and reg-ulation axonal regeneration glucose regulation and benigngrowth disorders PTEN is often dogmatically thought ofas a constitutive protein that exhibits lost activity duringdiseases butwhat is underappreciated is that PTENhas a verycomplex regulation network that involves signaling path-ways that regulate PTEN transcription transcript stabilityposttranslationalmodifications protein-protein interactionsand cellular location PTEN then in turn regulates numerousdevelopmental signaling networks that are critical to devel-opment and adult tissue maintenance

Abbreviations

Bcl2 B-cell lymphoma 2Bim BCL-2-interacting mediatorCK2 Casein Kinase 2CREB Cyclic AMP response element binding

proteinDLG Disks large homolog 1Egr-1 Early growth response protein 1Erk Extracellular regulated kinaseFOX Forkhead transcription factorsGSK3120573 Glycogen synthase kinase 3JNK Jun-terminal kinaseMAGI2 Membrane-associated guanylate kinase

inverted 2MAN2C1 Mannosidase alpha class 2C member 1MDM2 Mouse double minute 2 homologmTOR Mechanistic target of rapamycinNHERF Sodium-hydrogen antiporter 3

regulator 1NRG1 Neuregulin 1PCAF P300CBP-associated factorPDZ Postsynaptic density proteinmdashDisc

large tumor suppressormdashZonulaoccludens-1 protein

PIP3 Phosphoinositide triphosphatePPAR120574 Peroxisome proliferating antigen

receptorPREX2a Phosphatidylinositol-345-

trisphosphate-dependent Rac exchangefactor A

PTEN Phosphatase and Tensin homologueROCK Rho-associated coiled-coil-containing

protein kinaseSALL Spalt-like transcription factor-1SIPL1 Shank-interacting protein-like 1SIRT1 Sirtuin 1SMAD Small mothers against decapentaplegicSOCS Suppressor of cytokine signalingTGF120573 Transforming growth factor-beta

Disclosure

Travis J Jerde carried out the extensive literature reviewrequired to write this paper and have written the entirepaper The author has therefore read and approved the papersubmitted

Conflict of Interests

The author has no financial or nonfinancial conflict ofinterests with the submission of this paper

Acknowledgments

The author gratefully acknowledges the financial supportof the Indiana University School of Medicine Departmentof Pharmacology and Toxicology and the Melvin and BrynSimon Cancer Center The author also gratefully acknowl-edges this paper as part of his training made possible byNational Institutes of Health-NIDDK (DK092366-01A1)

References

[1] M Milella I Falcone F Conciatori et al ldquoPTEN multiplefunctions in human malignant tumorsrdquo Frontiers in Oncologyvol 5 article 24 2015

[2] J-O Lee H Yang M-M Georgescu et al ldquoCrystal structure ofthe PTEN tumor suppressor implications for its phosphoinosi-tide phosphatase activity and membrane associationrdquo Cell vol99 no 3 pp 323ndash334 1999

[3] W-L Yang G Jin C-F Li et al ldquoCycles of ubiquitinationand deubiquitination critically regulate growth factor-mediatedactivation of Akt signalingrdquo Science Signaling vol 6 no 257article ra3 2013

[4] J Gu S Nada M Okada and K Sekiguchi ldquoCsk regulatesintegrin-mediated signals involvement of differential activa-tion of ERK and Aktrdquo Biochemical and Biophysical ResearchCommunications vol 303 no 3 pp 973ndash977 2003

[5] A Clerk and P H Sugden ldquoActivation of protein kinase cas-cades in the heart by hypertrophic G protein-coupled receptoragonistsrdquoTheAmerican Journal of Cardiology vol 83 no 12 pp64Hndash69H 1999

[6] I Tonic W-N Yu Y Park C-C Chen and N Hay ldquoAktactivation emulates Chk1 inhibition and Bcl2 overexpressionand abrogates G2 cell cycle checkpoint by inhibiting BRCA1focirdquo The Journal of Biological Chemistry vol 285 no 31 pp23790ndash23798 2010

[7] S Fatrai L Elghazi N Balcazar et al ldquoAkt induces 120573-cellproliferation by regulating cyclin D1 cyclin D2 and p21 levelsand cyclin-dependent kinase-4 activityrdquo Diabetes vol 55 no 2pp 318ndash325 2006

[8] M Aoki E Blazek and P K Vogt ldquoA role of the kinase mTORin cellular transformation induced by the oncoproteins P3k andAktrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 98 no 1 pp 136ndash141 2001

[9] H Guan L Song J Cai et al ldquoSphingosine kinase 1 regulatesthe AktFOXO3aBim pathway and contributes to apoptosisresistance in glioma cellsrdquo PLoS ONE vol 6 no 5 Article IDe19946 2011

[10] T D Dung C H Day T V Binh et al ldquoPP2Amediates diosminp53 activation to block HA22T cell proliferation and tumor

10 Journal of Signal Transduction

growth in xenografted nude mice through PI3K-Akt-MDM2signaling suppressionrdquo Food and Chemical Toxicology vol 50no 5 pp 1802ndash1810 2012

[11] K Shanmugasundaram K Block B K Nayak C B Livi MA Venkatachalam and S Sudarshan ldquoPI3K regulation of theSKP-2p27 axis through mTORC2rdquo Oncogene vol 32 no 16pp 2027ndash2036 2013

[12] J-C Chang H-H Chang C-T Lin and S J Lo ldquoThe integrin12057261205731modulation of PI3K andCdc42 activities induces dynamicfilopodium formation in humanplateletsrdquo Journal of BiomedicalScience vol 12 no 6 pp 881ndash898 2005

[13] E Hajduch G J Litherland and H S Hundal ldquoProtein kinaseB (PKBAkt)mdasha key regulator of glucose transportrdquo FEBSLetters vol 492 no 3 pp 199ndash203 2001

[14] M M Martin J A Buckenberger J Jiang et al ldquoTGF-beta1stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[15] M M Martin J A Buckenberger J Jiang et al ldquoTGF-1205731stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[16] K Abell and C J Watson ldquoThe JakStat pathway a novel wayto regulate PI3K activityrdquo Cell Cycle vol 4 no 7 pp 897ndash9002005

[17] J-Y Hwang R S Duncan C Madry M Singh and P KoulenldquoProgesterone potentiates calcium release through IP3 recep-tors by an Akt-mediated mechanism in hippocampal neuronsrdquoCell Calcium vol 45 no 3 pp 233ndash242 2009

[18] G Pappas L A Zumstein A Munshi M Hobbs and R EMeyn ldquoAdenoviral-mediated PTEN expression radiosensitizesnon-small cell lung cancer cells by suppressing DNA repaircapacityrdquoCancer GeneTherapy vol 14 no 6 pp 543ndash549 2007

[19] A Di Cristofano B Pesce C Cordon-Cardo and P P PandolfildquoPten is essential for embryonic development and tumoursuppressionrdquo Nature Genetics vol 19 no 4 pp 348ndash355 1998

[20] J Bloomekatz J Grego-Bessa I Migeotte and K V AndersonldquoPten regulates collective cell migration during specification ofthe anterior-posterior axis of the mouse embryordquo Developmen-tal Biology vol 364 no 2 pp 192ndash201 2012

[21] S Ueno R Kono andY Iwao ldquoPTEN is required for the normalprogression of gastrulation by repressing cell proliferation afterMBT in Xenopus embryosrdquoDevelopmental Biology vol 297 no1 pp 274ndash283 2006

[22] C B Knobbe A Merlo and G Reifenberger ldquoPten signaling ingliomasrdquo Neuro Oncology vol 4 pp 196ndash211 2002

[23] E Kirches J Steiner T Schneider et al ldquoLhermitte-Duclosdisease caused by a novel germline PTEN mutation R173P in apatient presenting with psychosisrdquoNeuropathology and AppliedNeurobiology vol 36 no 1 pp 86ndash89 2010

[24] J-I Murata M Tada Y Sawamura K Mitsumori H Abe andK Nagashima ldquoDysplastic gangliocytoma (Lhermitte-Duclosdisease) associated with Cowden disease report of a case andreview of the literature for the genetic relationship between thetwo diseasesrdquo Journal of Neuro-Oncology vol 41 no 2 pp 129ndash136 1999

[25] G Zhu L M L Chow I T Bayazitov et al ldquoPten deletioncauses mTorc1-dependent ectopic neuroblast differentiation

without causing uniform migration defectsrdquo Development vol139 no 18 pp 3422ndash3431 2012

[26] K L McBride E A Varga M T Pastore et al ldquoConfirmationstudy of PTEN mutations among individuals with autism ordevelopmental delaysmental retardation and macrocephalyrdquoAutism Research vol 3 no 3 pp 137ndash141 2010

[27] J Zhou and L F Parada ldquoPTEN signaling in autism spectrumdisordersrdquo Current Opinion in Neurobiology vol 22 no 5 pp873ndash879 2012

[28] S A Backman V Stambolic A Suzuki et al ldquoDeletion of Ptenin mouse brain causes seizures ataxia and defects in soma sizeresembling Lhermitte-Duclos diseaserdquo Nature Genetics vol 29no 4 pp 396ndash403 2001

[29] L Cotter M Ozcelik C Jacob et al ldquoDlg1-PTEN interactionregulates myelin thickness to prevent damaging peripheralnerve overmyelinationrdquo Science vol 328 no 5984 pp 1415ndash1418 2010

[30] S Ogawa C-H Kwon J Zhou D Koovakkattu L F Paradaand C M Sinton ldquoA seizure-prone phenotype is associatedwith altered free-running rhythm in Pten mutant micerdquo BrainResearch vol 1168 no 1 pp 112ndash123 2007

[31] C-H Kwon X Zhu J Zhang and S J Baker ldquomTor isrequired for hypertrophy of Pten-deficient neuronal soma invivordquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 22 pp 12923ndash12928 2003

[32] C-H Kwon B W Luikart C M Powell et al ldquoPten regulatesneuronal arborization and social interaction in micerdquo Neuronvol 50 no 3 pp 377ndash388 2006

[33] A Suzuki S Itami M Ohishi et al ldquoKeratinocyte-specific Ptendeficiency results in epidermal hyperplasia accelerated hairfollicle morphogenesis and tumor formationrdquo Cancer Researchvol 63 no 3 pp 674ndash681 2003

[34] T Inoue-Narita K Hamada T Sasaki et al ldquoPten deficiency inmelanocytes results in resistance to hair graying and susceptibil-ity to carcinogen-induced melanomagenesisrdquo Cancer Researchvol 68 no 14 pp 5760ndash5768 2008

[35] R K Patel and C Mohan ldquoPI3KAKT signaling and systemicautoimmunityrdquo Immunologic Research vol 31 no 1 pp 47ndash552005

[36] K Podsypanina L H Ellenson A Nemes et al ldquoMutationof PtenMmac1 in mice causes neoplasia in multiple organsystemsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 4 pp 1563ndash1568 1999

[37] M Kashiwada P Lu and P B Rothman ldquoPIP3 pathway inregulatory T cells and autoimmunityrdquo Immunologic Researchvol 39 no 1ndash3 pp 194ndash224 2007

[38] A Suzuki M T Yamaguchi T Ohteki et al ldquoT cell-specificloss of Pten leads to defects in central and peripheral tolerancerdquoImmunity vol 14 no 5 pp 523ndash534 2001

[39] Y Yamanaka H Tagawa N Takahashi et al ldquoAberrant over-expression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lym-phomaleukemiardquo Blood vol 114 no 15 pp 3265ndash3275 2009

[40] H Kishimoto T Ohteki N Yajima et al ldquoThe PtenPI3Kpathway governs the homeostasis of V12057214iNKT cellsrdquo Bloodvol 109 no 8 pp 3316ndash3324 2007

[41] A Suzuki T Kaisho M Ohishi et al ldquoCritical roles ofPten in B cell homeostasis and immunoglobulin class switchrecombinationrdquo Journal of Experimental Medicine vol 197 no5 pp 657ndash667 2003

Journal of Signal Transduction 11

[42] M Nishio K-IWatanabe J Sasaki et al ldquoControl of cell polar-ity and motility by the PtdIns(345)P

3phosphatase SHIP1rdquo

Nature Cell Biology vol 9 no 1 pp 36ndash44 2007[43] S Kuroda M Nishio T Sasaki et al ldquoEffective clearance

of intracellular Leishmania major in vivo requires Pten inmacrophagesrdquo European Journal of Immunology vol 38 no 5pp 1331ndash1340 2008

[44] O H Yilmaz R Valdez B K Theisen et al ldquoPten depen-dence distinguishes haematopoietic stem cells from leukaemia-initiating cellsrdquo Nature vol 441 no 7092 pp 475ndash482 2006

[45] Y Li K Podsypanina X Liu et al ldquoDeficiency of Ptenaccelerates mammary oncogenesis in MMTV-Wnt-1 transgenicmicerdquo BMCMolecular Biology vol 2 article 2 2001

[46] P Reddy L Liu D Adhikari et al ldquoOocyte-specific deletion ofpten causes premature activation of the primordial follicle poolrdquoScience vol 319 no 5863 pp 611ndash613 2008

[47] H Tsuruta H Kishimoto T Sasaki et al ldquoHyperplasia andcarcinomas in Pten-deficient mice and reduced PTEN proteinin human bladder cancer patientsrdquoCancer Research vol 66 no17 pp 8389ndash8396 2006

[48] L I Yoo D W Liu S Le Vu R T Bronson H Wu and JYuan ldquoPten deficiency activates distinct downstream signalingpathways in a tissue-specific mannerrdquo Cancer Research vol 66no 4 pp 1929ndash1939 2006

[49] J Li C Yen D Liaw et al ldquoPTEN a putative protein tyrosinephosphatase gene mutated in human brain breast and prostatecancerrdquo Science vol 275 no 5308 pp 1943ndash1947 1997

[50] N D Deocampo H Huang and D J Tindall ldquoThe role ofPTEN in the progression and survival of prostate cancerrdquoMinerva Endocrinologica vol 28 no 2 pp 145ndash153 2003

[51] S A Backman D Ghazarian K So et al ldquoEarly onset ofneoplasia in the prostate and skin of mice with tissue-specificdeletion of Ptenrdquo Proceedings of the National Academy ofSciences of the United States of America vol 101 no 6 pp 1725ndash1730 2004

[52] X Wu K Xu L Zhang et al ldquoDifferentiation of the ductalepithelium and smooth muscle in the prostate gland areregulated by the NotchPTEN-dependent mechanismrdquo Devel-opmental Biology vol 356 no 2 pp 337ndash349 2011

[53] D Kim and G R Dressler ldquoPTEN modulates GDNFRETmediated chemotaxis and branching morphogenesis in thedeveloping kidneyrdquo Developmental Biology vol 307 no 2 pp290ndash299 2007

[54] N O Lindstrom M L Lawrence S F Burn et al ldquoIntegrated120573-catenin BMP PTEN and notch signalling patterns thenephronrdquo eLife no 4 Article ID e04000 2015

[55] V Marsh D J Winton G T Williams et al ldquoEpithelialPten is dispensable for intestinal homeostasis but suppressesadenoma development and progression after Apc mutationrdquoNature Genetics vol 40 no 12 pp 1436ndash1444 2008

[56] S Matsuda M Kobayashi and Y Kitagishi ldquoRoles forPI3KAKTPTEN pathway in cell signaling of nonalcoholicfatty liver diseaserdquo ISRN Endocrinology vol 2013 Article ID472432 7 pages 2013

[57] X Qi J Xu P Gu X Yang and X Gao ldquoPTEN in smoothmuscle cells is essential for colonic immune homeostasisrdquoInternational Journal of Biochemistry and Cell Biology vol 53pp 108ndash114 2014

[58] A Pal T M Barber M Van de Bunt et al ldquoPTENmutations asa cause of constitutive insulin sensitivity and obesityrdquoThe NewEngland Journal of Medicine vol 367 no 11 pp 1002ndash1011 2012

[59] B L Stiles C Kuralwalla-Martinez W Guo et al ldquoSelectivedeletion of Pten in pancreatic 120573 cells leads to increased isletmass and resistance to STZ-induced diabetesrdquo Molecular andCellular Biology vol 26 no 7 pp 2772ndash2781 2006

[60] LWang C T Luk E P Cai et al ldquoPTEN deletion in pancreatic120572-cells protects against high-fat diet-induced hyperglucagone-mia and insulin resistancerdquo Diabetes vol 64 no 1 pp 147ndash1572015

[61] C Kurlawalla-Martinez B Stiles Y Wang S U Devaskar BB Kahn and H Wu ldquoInsulin hypersensitivity and resistanceto streptozotocin-induced diabetes in mice lacking PTEN inadipose tissuerdquo Molecular and Cellular Biology vol 25 no 6pp 2498ndash2510 2005

[62] N Wijesekara D Konrad M Eweida et al ldquoMuscle-specificPten deletion protects against insulin resistance and diabetesrdquoMolecular and Cellular Biology vol 25 no 3 pp 1135ndash11452005

[63] K Hamada T Sasaki P A Koni et al ldquoThe PTENPI3Kpathway governs normal vascular development and tumorangiogenesisrdquo Genes and Development vol 19 no 17 pp 2054ndash2065 2005

[64] N D Roe X Xu M R Kandadi et al ldquoTargeted deletionof PTEN in cardiomyocytes renders cardiac contractile dys-function through interruption of Pink1-AMPK signaling andautophagyrdquo Biochimica et Biophysica Acta Molecular Basis ofDisease vol 1852 no 2 pp 290ndash298 2015

[65] A F Ford-Hutchinson Z Ali S E Lines B HallgrımssonS K Boyd and F R Jirik ldquoInactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnor-malities and skeletal overgrowthrdquo Journal of Bone and MineralResearch vol 22 no 8 pp 1245ndash1259 2007

[66] T A Burgers M F Hoffmann C J Collins et al ldquoMice lackingpten in osteoblasts have improved intramembranous and lateendochondral fracture healingrdquo PLoS ONE vol 8 no 5 ArticleID e63857 2013

[67] N R Leslie L Spinelli P Tibarewal et al ldquoIndirect mecha-nisms of carcinogenesis via downregulation of PTEN functionrdquoAdvances in Enzyme Regulation vol 50 no 1 pp 112ndash118 2010

[68] L He ldquoPosttranscriptional regulation of PTEN dosage bynoncoding RNAsrdquo Science Signaling vol 3 no 146 article pe392010

[69] F Vazquez S R Grossman Y Takahashi M V Rokas NNakamura andWR Sellers ldquoPhosphorylation of the PTEN tailacts as an inhibitory switch by preventing its recruitment into aprotein complexrdquo The Journal of Biological Chemistry vol 276no 52 pp 48627ndash48630 2001

[70] X Wang L C Trotman T Koppie et al ldquoNEDD4-1 is a proto-oncogenic ubiquitin ligase for PTENrdquo Cell vol 128 no 1 pp129ndash139 2007

[71] N R Leslie and M Foti ldquoNon-genomic loss of PTEN functionin cancer not in my genesrdquo Trends in Pharmacological Sciencesvol 32 no 3 pp 131ndash140 2011

[72] Y Xing C Li L Hu et al ldquoMechanisms of TGF120573 inhibition ofLUNG endodermal morphogenesis the role of T120573RII SmadsNkx21 and Ptenrdquo Developmental Biology vol 320 no 2 pp340ndash350 2008

[73] J P Luyendyk G A Schabbauer M Tencati T Holscher RPawlinski and N Mackman ldquoGenetic analysis of the role ofthe PI3K-Akt pathway in lipopolysaccharide-induced cytokineand tissue factor gene expression in monocytesmacrophagesrdquoJournal of Immunology vol 180 no 6 pp 4218ndash4226 2008

12 Journal of Signal Transduction

[74] F Sun K K Park S Belin et al ldquoSustained axon regenerationinduced by co-deletion of PTEN and SOCS3rdquo Nature vol 480no 7377 pp 372ndash375 2011

[75] C B Knobbe V Lapin A Suzuki and T W Mak ldquoThe roles ofPTEN in development physiology and tumorigenesis in mousemodels a tissue-by-tissue surveyrdquo Oncogene vol 27 no 41 pp5398ndash5415 2008

[76] S J Assinder Q Dong Z Kovacevic and D R RichardsonldquoThe TGF-beta PI3KAkt and PTEN pathways establishedand proposed biochemical integration in prostate cancerrdquoBiochemical Journal vol 417 no 2 pp 411ndash421 2009

[77] K A Waite and C Eng ldquoFrom developmental disorder toheritable cancer itrsquos all in the BMPTGF-120573 familyrdquo NatureReviews Genetics vol 4 no 10 pp 763ndash773 2003

[78] H B Newton ldquoMolecular neuro-oncology and developmentof targeted therapeutic strategies for brain tumors Part2 PI3KAktPTEN mTOR SHHPTCH and angiogenesisrdquoExpert Review of Anticancer Therapy vol 4 no 1 pp 105ndash1282004

[79] R H KimM Peters Y Jang et al ldquoDJ-1 a novel regulator of thetumor suppressor PTENrdquo Cancer Cell vol 7 no 3 pp 263ndash2732005

[80] J Lu H W Jeong N Kong et al ldquoStem cell factor SALL4represses the transcriptions of PTEN and SALL1 through anepigenetic repressor complexrdquo PLoS ONE vol 4 no 5 ArticleID e5577 2009

[81] M M A Rizvi M S Alam A Ali S J Mehdi S Batra andA KMandal ldquoAberrant promotermethylation and inactivationof PTEN gene in cervical carcinoma from Indian populationrdquoJournal of Cancer Research and Clinical Oncology vol 137 no 8pp 1255ndash1262 2011

[82] J Liu ldquoControl of protein synthesis and mRNA degradation bymicroRNAsrdquo Current Opinion in Cell Biology vol 20 no 2 pp214ndash221 2008

[83] S W Shan L Fang T Shatseva et al ldquoMature miR-17-5pand passenger miR-17-3p induce hepatocellular carcinoma bytargeting PTEN GalNT7 and vimentin in different signalpathwaysrdquo Journal of Cell Science vol 126 part 6 pp 1517ndash15302013

[84] Z Liang Y Li K Huang N Wagar and H Shim ldquoRegulationof miR-19 to breast cancer chemoresistance through targetingPTENrdquo Pharmaceutical Research vol 28 no 12 pp 3091ndash31002011

[85] X Lu Q Fan L Xu et al ldquoUrsolic acid attenuates diabeticmesangial cell injury through the up-regulation of autophagyvia miRNA-21PTENAktmTOR suppressionrdquo PLoS ONE vol10 no 2 Article ID e0117400 2015

[86] L Poliseno L Salmena J Zhang B Carver W J Havemanand P P Pandolfi ldquoA coding-independent function of geneand pseudogenemRNAs regulates tumour biologyrdquoNature vol465 no 7301 pp 1033ndash1038 2010

[87] Y Tay L Kats L Salmena et al ldquoCoding-independent regula-tion of the tumor suppressor PTEN by competing endogenousmRNAsrdquo Cell vol 147 no 2 pp 344ndash357 2011

[88] L Odriozola G Singh T Hoang and A M Chan ldquoRegula-tion of PTEN activity by its carboxyl-terminal autoinhibitorydomainrdquo The Journal of Biological Chemistry vol 282 no 32pp 23306ndash23315 2007

[89] Z Li X Dong Z Wang et al ldquoRegulation of PTEN by Rhosmall GTPasesrdquo Nature Cell Biology vol 7 no 4 pp 399ndash4042005

[90] E-K Yim G Peng H Dai et al ldquoRak functions as a tumorsuppressor by regulating PTEN protein stability and functionrdquoCancer Cell vol 15 no 4 pp 304ndash314 2009

[91] AMAl-Khouri YMa SH Togo SWilliams andTMustelinldquoCooperative phosphorylation of the tumor suppressor phos-phatase and tensin homologue (PTEN) by casein kinasesand glycogen synthase kinase 3120573rdquo The Journal of BiologicalChemistry vol 280 no 42 pp 35195ndash35202 2005

[92] H Maccario N M Perera L Davidson C P Downes and NR Leslie ldquoPTEN is destabilized by phosphorylation onThr366rdquoBiochemical Journal vol 405 no 3 pp 439ndash444 2007

[93] K A Waite and C Eng ldquoBMP2 exposure results in decreasedPTEN protein degradation and increased PTEN levelsrdquoHumanMolecular Genetics vol 12 no 6 pp 679ndash684 2003

[94] T J Jerde Z Wu D Theodorescu and W Bushman ldquoRegu-lation of phosphatase homologue of tensin protein expressionby bone morphogenetic proteins in prostate epithelial cellsrdquoProstate vol 71 no 8 pp 791ndash800 2011

[95] G Singh and A M Chan ldquoPost-translational modificationsof PTEN and their potential therapeutic implicationsrdquo CurrentCancer Drug Targets vol 11 no 5 pp 536ndash547 2011

[96] T Ikenoue K Inoki B Zhao and K-L Guan ldquoPTEN acety-lation modulates its interaction with PDZ domainrdquo CancerResearch vol 68 no 17 pp 6908ndash6912 2008

[97] L C Trotman X Wang A Alimonti et al ldquoUbiquitinationregulates PTEN nuclear import and tumor suppressionrdquo Cellvol 128 no 1 pp 141ndash156 2007

[98] T Tolkacheva M Boddapati A Sanfiz K Tsuchida A CKimmelman and AM-L Chan ldquoRegulation of PTEN bindingto MAGI-2 by two putative phosphorylation sites at threonine382 and 383rdquo Cancer Research vol 61 no 13 pp 4985ndash49892001

[99] E Lima-Fernandes H Enslen E Camand et al ldquoDistinct func-tional outputs of PTEN signalling are controlled by dynamicassociation with 120573-arrestinsrdquoThe EMBO Journal vol 30 no 13pp 2557ndash2568 2011

[100] M T van Diepen M Parsons C P Downes N R Leslie RHindges and B J Eickholt ldquoMyosinV controls PTEN functionand neuronal cell sizerdquo Nature Cell Biology vol 11 no 10 pp1191ndash1196 2009

[101] R B Chagpar P H Links M C Pastor et al ldquoDirect positiveregulation of PTEN by the p85 subunit of phosphatidylinositol3-kinaserdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 107 no 12 pp 5471ndash5476 2010

[102] Y Takahashi F C Morales E L Kreimann and M-MGeorgescu ldquoPTEN tumor suppressor associates with NHERFproteins to attenuate PDGF receptor signalingrdquo The EMBOJournal vol 25 no 4 pp 910ndash920 2006

[103] M Valiente A Andres-Pons B Gomar et al ldquoBinding ofPTEN to specific PDZ domains contributes to PTEN proteinstability and phosphorylation by microtubule-associated ser-inethreonine kinasesrdquoThe Journal of Biological Chemistry vol280 no 32 pp 28936ndash28943 2005

[104] SQuintes SGoebbels G SaherMH Schwab andK-ANaveldquoNeuron-glia signaling and the protection of axon function bySchwann cellsrdquo Journal of the Peripheral Nervous System vol 15no 1 pp 10ndash16 2010

[105] B Fine C Hodakoski S Koujak et al ldquoActivation of the PI3Kpathway in cancer through inhibition of PTEN by exchangefactor P-REX2ardquo Science vol 325 no 5945 pp 1261ndash1265 2009

Journal of Signal Transduction 13

[106] L He A Ingram A P Rybak and D Tang ldquoShank-interactingprotein-like 1 promotes tumorigenesis via PTEN inhibition inhuman tumor cellsrdquo The Journal of Clinical Investigation vol120 no 6 pp 2094ndash2108 2010

[107] L He C Fan A Kapoor et al ldquo120572-Mannosidase 2C1 attenuatesPTEN function in prostate cancer cellsrdquo Nature Communica-tions vol 2 no 1 article 307 2011

[108] Z Radisavljevic ldquoAKT as locus of cancer positive feedbackloops and extreme robustnessrdquo Journal of Cellular Physiologyvol 228 no 3 pp 522ndash524 2013

[109] M Y Lee HW Lim S H Lee andH J Han ldquoSmad PI3KAktand wnt-dependent signaling pathways are involved in BMP-4-induced ESC self-renewalrdquo Stem Cells vol 27 no 8 pp 1858ndash1868 2009

[110] K Song S C Cornelius M Reiss and D Danielpour ldquoInsulin-like growth factor-I inhibits transcriptional responses of trans-forming growth factor-120573 by phosphatidylinositol 3-kinaseAkt-dependent suppression of the activation of Smad3 but notSmad2rdquoThe Journal of Biological Chemistry vol 278 no 40 pp38342ndash38351 2003

[111] D Fang D Hawke Y Zheng et al ldquoPhosphorylation of 120573-catenin by AKT promotes 120573-catenin transcriptional activityrdquoThe Journal of Biological Chemistry vol 282 no 15 pp 11221ndash11229 2007

[112] Q Lei J Jiao L Xin et al ldquoNKX31 stabilizes p53 inhibitsAKT activation and blocks prostate cancer initiation caused byPTEN lossrdquo Cancer Cell vol 9 no 5 pp 367ndash378 2006

[113] A Sengupta J D Molkentin J-H Paik R A DePinho and KE Yutzey ldquoFoxO transcription factors promote cardiomyocytesurvival upon induction of oxidative stressrdquo The Journal ofBiological Chemistry vol 286 no 9 pp 7468ndash7478 2011

[114] C H M Jamieson L E Ailles S J Dylla et al ldquoGranulocyte-macrophage progenitors as candidate leukemic stem cells inblast-crisis CMLrdquoTheNewEngland Journal ofMedicine vol 351no 7 pp 657ndash667 2004

[115] A Androutsellis-Theotokis R R Leker F Soldner et al ldquoNotchsignalling regulates stem cell numbers in vitro and in vivordquoNature vol 442 no 7104 pp 823ndash826 2006

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

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Page 4: Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling TravisJ.Jerde Department of Pharmacology

4 Journal of Signal Transduction

hyperplasia of squamous cells resulting in mounted skindermis and papillomas [33] Additionally mice with specificmelanocytic PTEN deletion exhibit increased melanocyteexpansion [34]

24 Hematopoietic Development PTEN is necessary forproper development lineage fate and cell function in T cellsB cells myeloid cells NKT cells and hematopoietic stem cells(HSCs) as demonstrated by several elegant studies involvingglobal heterozygous and cell-conditional null PTEN models[35ndash40] It has been known that PTEN (+minus) mice exhibitlymphoid hyperplasia progressing to T-cell lymphoma com-plete with large nodal masses [36] and it has now alsobeen reported that PTEN (+minus) mice develop autoimmunedisorders at an early age due to abrogated PTEN function[37] Cell-type T-cell conditional PTEN null mice exhibitlymphadenopathy splenomegaly and hyperplastic enlargedthymus Similar to the global PTEN heterozygous miceconditional nulls also exhibit autoreactivity evidenced byincreased levels of autoantibodies expanded T-cell prolifer-ation and increased cytokine synthesis and release [38]

Indirect studies show that PTEN-mediated signalingplays a role in natural killer (NK) cells Unfortunatelytrue cell-selective knockout of PTEN in natural killer (NK)cells has not been reported due to the lack of a cell-typespecific promoter However purified NK cells from PTENimmune-system null mice exhibit abrogated maturation andactivation [39] Studies have demonstrated that when thesecells were adoptively transferred intoNK null mice harboringmetastatic melanoma cells the null cells exhibit stronglydecreased protection from metastases relative to wild-typeNKT cells [39 40]These results demonstrate that one criticalrole of NK cells namely tumor targeting is attenuatedin PTEN null NK cells In addition B-cell lineage-specificPTEN null mice exhibit expanded splenocytes mesentericlymph node cells and peritoneal cells [41] B cells deficientin PTEN display enhanced proliferation upon epitope ormitogen stimulation and defective class-switch antibodyrecombination resulting in decreased production of IgA andIgG antibodies and elevated IgM production [41]

Neutrophils isolated from mice with PTEN-null myeloidlineage cells display increased actin polymerization withenhanced membrane ruffling pseudopodia formation che-motaxis and migratory speed [42] Inflammation in thesemice is associated with vastly increased neutrophil recruit-ment [42] Paradoxically these mice are more susceptible toinfection with Leishmania and exhibit a slower clearance ofinfection than wild-type littermates This disconnect appearsto be due to decreased secretion of tumor necrosis factor(TNF) by mutant macrophages in these mice [43] To datelittle else is known about the development of monocytes inmyeloid-specific PTEN null bearing animals

Deletion of PTEN in murine hematopoietic stem cells inmice results in a very rapid onset of myeloproliferative disor-ders and an eventual depletion of the stem cell pool whichdespite their proliferative nature results in the loss of theability of these stem cells to produce all lineages needed forproper immune functioning [44] These myeloproliferativedisorders progressed to acute myeloid leukemia or acute

lymphoblastic leukemia [44] In a demonstration that Akt-signaling is downstream of this phenotype increased HSCproliferation and even the development of myeloproliferativedisorders and leukemia are all rescued when the mice weretreated with rapamycin [44]

25 Visceral OrganDevelopment There are numerous studiesto date examining the developmental effects of organ-specificPTEN mutation in mouse models This review summarizesthe highlights of these studies hereMammary ducts in tissue-specific conditional PTEN null mice exhibit loss of differ-entiation enhanced growth excessive side branching andprecocious budding relative to wild-type controls [45] Thesephenotypes are reported during puberty but also manifesttheir effects during mammary expansion during pregnancyNotably mammary gland involution after pregnancywas alsodefective [45] PTEN is important for the normal physiologyof oocytes as PTEN deficiency in murine oocytes causesthe entire oocyte pool to become activated prematurely [46]This proves to be critical for fertility and reproduction aspremature oocyte activation resulted in females having amaximum of one normal-sized litter before they becameinfertile at 12-13 weeks of age [46]

FabpCre-(Ptenfloxflox) mice exhibit a number of inter-esting phenotypes in the genitourinary system PTEN dele-tion occurs in the bladder ureter kidney colon prostateseminal vesicles and vagina of these mutants [47] Epithelialhyperplasia was omnipresent in these animals As expecteddeletion of PTEN resulted in increased susceptibility tochemically induced carcinogenesis [48] Similarly epithelialhyperplasia is present in organ specific PTEN knockoutsfollowed by intraepithelial neoplasia and ultimately by inva-sion of the cancer cells as invasive adenocarcinoma [49ndash51]Embryonic deletion of PTEN in the lower urinary systemresults in a loss of proper differentiation within affected cells[52] ultimately resulting in loss of proper patterning andgrowth control Based on these data and the collection ofphenotypes observed in PTEN deleted cells and animals it islikely that a loss of differentiation of cells plays a master rolein PTENrsquos role in organ development

Recent reports have demonstrated a critical role for PTENin the branching morphogenesis and nephron patterning ofdeveloping kidneys PTEN has been shown to be indispens-able for developing bud outgrowth mesenchymal invasionand branching morphogenesis in developing kidneys bymediating the signaling downstream of GDNFRET receptortyrosine kinases [53] Again this involves differentiation andchemotaxis of epithelial cells More recently Lindstrom etal have shown that PTEN sits at the center of nephrondevelopment by integrating signaling from BMP and wnt-beta-catenin pathways [54] Disruption of PTEN results in aloss of coordinated signaling and a loss of proper patterningof epithelial cells along the axis of the nephron tubule

Numerous developmental effects of PTEN have beennoted in the gastrointestinal tract In the colon PTEN (+minus)mice develop hamartomatous polyps consistent with dis-rupted control of differentiation of cells [55] Further PTENis critical for colon homeostasis involving inflammatoryrepair and recovery processes that reactivate developmental

Journal of Signal Transduction 5

signalingmechanisms [56] In the liver loss of PTENnot onlyincreases tumor susceptibility but also altersmetabolism [57]In addition hepatomegaly is observed in mice with condi-tional hepatic PTEN knockout as the ratio of liver weightto body weight increased in the mutants when comparedwith wild-type controls [57] Livers harvested from mutantanimals are discolored and show accumulation of triglyc-erides consistent with steatohepatitis associated with severeinflammation Passive diffusion of fatty acids in hepatocyteswas enhanced in PTEN null mice and PTEN-deficienthepatocytes exhibit an increased rate of fatty acid synthesisvia induced fatty acid synthase [57] PTEN-deficient miceexhibit defects in glucose metabolism including decreasedfasting plasma glucose levels and reduced serum insulinlevels [58] Clearance of glucose was accelerated in theabsence of PTEN concurrent with increased liver glycogenstorage

Pancreatic islet beta-cell specific PTEN-deficient miceexhibit increases in islet cell numbers total islet massand an increase in 120573-cell progenitor proliferation duringembryonic development and early postnatal life [59] AdultPTEN mutant mice were hypoglycemic and were resistantto streptozotocin-induced diabetes These mice are signifi-cantly smaller than controls and have a shorter lifespan Insome studies severe hypoglycemia is associated with seizureactivity and premature death before 5 weeks of age [59]In addition PTEN (+minus) mice exhibit protection againstincreased insulin production during reactive oxygen species-dependent type two diabetes and insulin-resistance uponaging [60]

PTENrsquos role in maintaining glucose balance is not limitedto the liver and pancreas but also involves adipocytes andmyocytes Inactivation of PTEN specifically in adipocytesproduces no obvious gross morphological effects on theadipose tissue or adipose tissue mass However this mouseexhibits increased systemic glucose tolerance and insulin sen-sitivity complete with decreased fasting insulin and resistinlevels [61] By controlling serum insulin and resistin levelsPTEN regulates insulin sensitivity and AMP kinase activityin the liver Similarly skeletal and cardiac muscle cell-specificdeletion causes increased systemic glucose tolerance andinsulin sensitivity [62] Interestingly however PTEN loss inthese tissues seems to protect thesemice from streptozotocin-induced diabetes and hyperglycemia indicating that theinsulin hypersensitivity exhibited in tissue-selective PTEN-deficient mice allowed them to maintain proper glucoselevels

PTEN regulates proper lung development Specific lungdeletion of PTEN during embryogenesis results in impairedlungmorphogenesis and early postnatal death [61]The lungsof these neonates exhibit increased epithelial cell proliferationand decreased alveolar cell differentiation Adults exhibitbronchiolar and alveolar epithelial hyperplasia Mutant miceexhibit hypertrophy of alveolar cells derived from bron-chioalveolar stem cells [61] Predictably adenocarcinomawasevident in aged adults Further study of PTENrsquos role inlung development revealed that PTEN-regulated signalingmediates lung endodermal morphogenesis coordinate withthe overall developmental process in the lung and it is central

to the interaction of several signaling pathways including theTGF beta-SMAD and Nkx21 pathways [62]

Normal development of the vascular system is alsodependent on proper PTEN function PTEN knockout inendothelial and endocardial cells in mice results in embry-onic lethality due to increased capillaries and endothelial cellhypertrophy [63] These mutant embryos exhibit pericardialcavity enlargement leakage of blood into the pericardialcavity and enlarged trunk vessels secondary to pericyte andvascular smooth muscle cell recruitment to blood vessels[63] In addition cardiomyocyte-specific deletion of PTENleads to cardiac phenotypes via development of cardiachypertrophy and contractile defect [64] Future studies onPTEN will hopefully be targeted at assessing injury-relatedresponses in the cardiovascular system as deletion of PTENin cardiomyocytes has been shown to protect the heart frommaladaptive remodeling upon biomechanical stress

PTEN regulates developing bone and cartilage by pro-tecting against overgrowth of the skeletal system Mice withdeletion of PTEN in osteochondroprogenitor cells exhibitgrowth plate dysfunction and overgrowth of the vertebrae[65] The bodies of these mice are notably longer than wild-type controls demonstrating a critical defect that resultsin loss of proper skeletal development Interestingly thisincrease in length was not due to bone cell proliferationincreases as might have been expected but rather is due toincreased matrix deposition and cellular hypertrophy [65]In a second model osteoblast-specific knockdown of PTENexpression results in increased bone volume and density[66] Interestingly this mutation is associated with improvedintramembranous and late endochondral fracture healingThis is now an active area of research within the boneremodeling research field

While PTEN remains virtually synonymous with cancerbiology the studies presented here make the importanceof proper PTEN signaling for regulating a wide variety ofdevelopmental processes clearly evident From regulation ofgrowth differentiation glucose maintenance and repair andrecovery to gross effects on organ and systems developmentPTEN is a protein with vast consequence in the field ofdevelopmental biology and the signaling affected by itsexpression is expansiveThe role PTEN plays in developmenthas clear correlates to human disease Further PTENrsquos effectson development acquire greater importance when the rolethat developmental signaling plays in cancer growth andprogression is consideredTherefore an extensive knowledgeof how PTEN is regulated by developmental signaling apartfrom somatic or genetic mutation is required for completeunderstanding of PTENrsquos role in these important physiologi-cal processes

3 PTEN Regulation as Part ofDevelopmental Signaling

31 Intrinsic and Extrinsic PTEN Regulation Most studiesevaluating the role of PTEN in human diseases have beencentered uponmutation in PTEN itself andmost of this workis done in its relationship to cancer initiation and progression

6 Journal of Signal Transduction

BMP Hh JagdeltaNOTCH

NICD

miRNA(17 19 21)

GF

PTEN mRNA

PTEN mRNA

PTENNICD

SMAD2 3

SMAD1 5 8 Gli2

AP -1

NICDAP -1

SMO

SMAD2 3

SMAD1 5 8 Gli2

SALL4

Cyt

p65p50

p65p50

ceRNAAkt

GSK3CK2

PCAF

SIRT1

PIP3 PIP2

PI3 kinase

TGF120573

Figure 3 Summary of regulation mechanisms for PTEN critical for its action in developmental biology PTEN transcription is regulatedby TGF120573 BMP Hh NOTCH and cytokine signaling in cells during development miRNAs and ceRNAs regulate PTEN message stabilityPhosphorylation or acetylation by then can regulate PTENrsquos protein stability enzymatic activity and cellular localization in a positive ornegative manner All told the regulation of PTEN is complex and precise during development and perturbations in this paradigm haveprofound effects

There is no question that mutations of PTEN play a criticalrole in this regard Studies over the last decade howeverhave discovered a tremendous diversity in the regulationof PTEN expression and found that PTEN is tightly con-trolled both transcriptionally and posttranscriptionally [67]Recent studies to date have implicated microRNAs in PTENsuppression [68] and the enzymatic phosphatase activityof PTEN is also regulated posttranslationally via phospho-rylation ubiquitination or oxidation [69 70] This sectionhighlights the multifaceted mechanisms of PTEN regulationsupported by the rapidly expanding literature on PTENrsquos rolein growth and patterning of tissues during development Inaddition special emphasis is given tomediators and pathwaysinvolved in development including insulin-like growth factortransforming growth factor bone morphogenetic proteinsNOTCH forkhead transcription factors (Fox) and othersPTENrsquos complex regulation at the levels of transcriptionmRNA stability posttranslational modifications andmiRNAlevels has become a critical series of mechanisms deserving acomprehensive review (for an overview see Figure 3)

32 Developmental Signaling Regulating PTEN Expressionand Action The regulation of PTEN expression occurs attranscriptional posttranscriptional posttranslational andprotein-protein interaction levels [71] PTENrsquos function isfurther controlled by its cellular location In this sectionwe highlight developmental pathways involved in regulating

PTEN expression at all these regulation points and makespecial reference to connections between signal transductionand development

321 Developmental Pathways in PTEN Gene ExpressionOne critical aspect of PTENrsquos regulation during developmentbegins at the transcriptional level To date PTEN expres-sion has been found to be regulated at the transcriptionallevel by pathways involving p53 PPAR120574 Egr-1 NF-120581Band SMADs and this regulation affects the developmentof proper immune function the vasculature the nervoussystem the gastrointestinal system and the airways [6372 73] While PTEN is constitutively expressed in manynormal adult tissues PTEN expression is altered dramat-ically through the course of development and in patho-logical settings and a primary source of this regulationcomes from bona fide developmental regulators In additionsuppressors of cytokine signaling (SOCS) and SNAIL alsoinduce PTEN and act by countering the growth-promotingactions of cytokines and growth factors in developmentand repair and recovery [74] This mechanism has beenclearly demonstrated in axonal outgrowth during neurondevelopment and regeneration [74] While the physiologicalramifications of this regulation remain unsolved mediatorsthat slow or inhibit cell proliferation are often involved ininducing this protein Developmental mediators includingNOTCH transforming growth factor beta (TGF120573) bone

Journal of Signal Transduction 7

morphogenetic proteins (BMPs) and hedgehogs (Hhs) allparticipate as players in external PTEN regulation [75ndash78] regulating such processes as proliferation and targetedepithelial budding and outgrowth of visceral organs [76 77]and outgrowth in neurons [75] As the direction of cell growthand differentiation balances on the fulcrum between theproliferative and differentiating actions of these mediatorstheir regulation to induce or repress PTEN expression isa critical aspect of their actions during development Thecritical developmental mediator TGF120573 contains both growthpromoting and inhibiting differentiation qualities and TGF120573induces PTEN during differentiation when growth is slowedand inhibits its expression during proliferation In additionthe developmental regulator DJ-1 was recently identified asa novel negative regulator of PTEN by a genetic screen inDrosophila [79] PTEN is also regulated through epigeneticsilencing by methylation of the PTEN promoter [80 81] Aninteresting zinc-finger transcription factor sal-like protein 4(SALL4) has been discovered as a critical negative regulatorof PTEN transcription by recruiting an epigenetic repressorcomplex involving anATPase and a histone deacetylase to thePTENpromoter [80] SALL4 plays a critical role in regulatingdevelopment by modulating self-renewal in stem cells andits function appears to at least partly involve methylation ofthe PTENpromoter andmodulation of its transcriptionDataon this mechanism are still limited but to date this processhas been shown to regulate kidney patterning during devel-opment as well as leukemogenesis [80] Current research inthe area of PTEN transcriptional regulation continues to bedynamic and more novel regulation patterns are likely to bediscovered in the near future

322 PTEN Regulation by Posttranscriptional RegulationRecent studies have identified several interesting develop-mentally expressed miRNAs that regulate PTEN mRNAmessage stability and translatability [82] These miRNAstypically downregulate PTEN mRNA levels by targeting itfor degradation and include miR-17 miR-19 and miR-21 [83ndash85] While several examples of miR-17 and miR-19-mediatedPTENRNA levels have been reported in the cancer literaturemiR-21 has been described to play a critical role in repairand recovery a developmental signaling-related processmiRNAs regulate this mechanism by modulating PTENRNA stability and ultimately downstream Akt signaling Forexample in the pancreas miR-21 regulates injury repair indiabetic models by targeting PTEN RNA for degradationInhibition of miR-21 results in autophagy in this model ina manner dependent on PTEN degradation [85] In anotherexample of novel miR-related PTEN regulation the PTENpseudogene 1 (PTENP1) acts as a decoy for PTEN-targetingmiRNAs and thereby regulates PTEN expression by coding-independent activity through sequestering these miRNAsand effectively inhibiting their effects on PTEN expression[86] Additionally combined bioinformatic and experimentalapproaches have identified ceRNA transcripts that controlPTEN expression by sequestering PTEN-targeting miRNAsduring development of both prostate and skin [87] Becausethis type of PTEN regulation and indeed this field of generegulation in general is in its infancy we are only beginning

to understand the PTEN regulation by coding and noncodingceRNAs Still this novel work provides a platform for furtherstudies investigating posttranscriptional regulation patternsof PTEN expression in both developmental biology anddisease conditions

323 PTENRegulation by PosttranslationalMechanisms Theprotein stability and enzyme activity of PTEN are regulatedin a number of ways at the posttranslational level FirstPTEN is phosphorylated in its C-terminal tail at Ser380Thr382 Thr383 and Ser385 and this functions to inhibitthe critical PTEN phosphatase activity thereby promotinggrowth in prostate and kidney cells [88] However thesephosphorylations also stabilize the PTEN protein by dis-suading ubiquitination While this may seem like a cellulardisconnect this paradoxical phenomenon is explained by thefinding that this closed more stable PTEN conformation isprevented from associating with membranes and thereforeis geographically separated from its substrates [88] PTENcan also be activated by phosphorylation in particular theC2 domain of PTEN is phosphorylated at Ser229 andThr321by RHOA-associated protein kinase (ROCK) [89] a phos-phorylation that results in its association with membranesand phosphoinositide substrates affecting differentiation inleukocytes PTEN is further phosphorylated at Tyr336 by theTyr protein kinase RAK and this phosphorylation resultsin its stabilization [90] Loss of this activity has the effectof promoting breast cell proliferation and migration FinallyPTEN is also phosphorylated at Ser370 and Thr366 by CK2and GSK3120573 [91 92] respectively however the consequencesof this phosphorylation are unclear The likely extensivesignaling networks that regulate these widespread phospho-rylations in PTEN are not fully studied but the TGFBMP-SMADdevelopmental pathways are known to regulate PTENphosphorylation [93 94] Given the widespread applicationof SMAD signaling to developmental biology the presence ofSMAD-regulated PTEN phosphorylation is a critical aspectof developmental regulation in cells

PTEN enzymatic activity is also regulated posttrans-lationally by acetylation [70 95ndash97] PTEN is acetylatedat Lys125ndashLys128 by p300CREB-binding protein- (CBP-)associated factor (PCAF) and at Lys402 by CBP itself [95]Acetylation at these residues inhibits PTENrsquos function as aphosphatase and has been shown to promote the growthof prostate epithelial cells and glial cells [95] In additionthe deacetylase Sirtuin 1 (SIRT1) is involved in excludingPTEN from the nucleus and therefore preventing its newlycharacterized nuclear functions [96]

324 PTEN Regulation by Protein-Protein Interactions Theconformation stability and subcellular distribution of PTENis regulated by critical interactions with other proteins withincells and these proteins are known to be critical for properdevelopment of a number of organ systems The guanylatekinase inverted 2 (MAGI2) and 120573-arrestins cooperate toenhance PTEN activity [98 99] MAGI2 phosphorylatesPTEN on threonine residues at positions 382 and 383 ofPTENrsquos carboxy terminus allowing recruitment to cell-cell

8 Journal of Signal Transduction

junctions [98] Mutations to these residues prevent PTENrecruitment Upon recruitment 120573-arrestins modulate PTENactivity by direct binding to the C2 domain and modulatingits protein phosphatase activity including that at the levelof small GTPases including RhoAROCK [99] In addi-tion Myosin V regulates PTENrsquos movement to and fromthe plasma membrane and this function is required forPTEN to access its phosphoinositide substrates [100] andfor disrupting the proper regulation of neuronal cell sizeThe p85 regulatory subunit of the PI

3kinase enzyme itself

interacts with PTEN in a novel mechanism of repressing thePI3KndashAKT pathway [101] independent of PTENrsquos action as a

phosphatase It is therefore proposed that p85 regulates thePI3KndashAKT pathway bidirectionally both through its binding

to catalytic p110 subunit resulting in the generation of phos-phoinositides and by binding PTEN leading to repressionThis work proposes a novel signaling model for PTEN-p85association in which p85120572 preferentially binds and stabilizesp110 preferentially when p85120572 levels are low but excess p85120572binds to and positively regulates PTEN phosphatase activitywhen p110 is saturated Therefore sustained activation ofPI3K signaling and activated p110-p85 complexing is modu-lated homeostatically by this mechanism

A fascinating group of recent studies have utilizedproteomic library screens to identify further novel PTENinteracting proteins First the Na+H+ exchanger regulatoryfactor (NHERF) binds to and recruits PTEN to the platelet-derived growth factor receptor (PDGFR) This representsanother action that restricts PI

3KndashAKT pathway activation

independent of phosphatase activity [102] This has the effectof inhibiting PDGF-induced cytoskeletal rearrangements andchemotactic migration of developing neurons In additionthe mammalian disks large homologue 1 (DLG1) MAGI-2 and MAST205 proteins directly interact with PTENand enhance PTEN stability and activity [103] Furtherneuregulin 1 (NRG1) has been shown to interact with bothDLG1 and PTEN in a stable complex that has the effect ofregulating myelin sheath thickness in developing mouse sci-atic nerves [104] Additional but less-characterized protein-protein interactions that modulate PTEN function includethe PIP

3-dependent RAC exchanger factor 2a (PREX2a)

[105] shank-interacting protein-like 1 (SIPL1) [106] and 120572-mannosidase 2C1 (MAN2C1) [107]

325 PTEN-Controlled Signal Transduction during Develop-ment PTEN is critically important in regulating signalingpathways involved in cell growth and animal developmentThrough its well-characterized function as a phosphataseof PIP

3 PTEN modulates a network of mitogen-activated

signals transduced through PI3KndashAkt signaling This pri-

mary action of PTEN has tremendous impact on cell growthcell migration cell death and cell differentiationmdashcellularprocesses that are all hallmarks of proper growth andpatterning during development The active phosphorylatedPIP3activates several signaling molecules including the

phosphatidylinositol-dependent kinases (PDKs) followed byAkt S6 kinase and mTOR Beyond this AKTrsquos targetsinclude the apoptotic factor BAD activator and executioner

caspases glycogen synthase kinase-3 (GSK-3) MDM2 p21and p27 forkhead transcription factors (FOXOs) and nuclearreceptors including the androgen and estrogen receptors[108] Akt-mediated phosphorylation of these moleculescauses activation translocation and increased stability

The PTENPI3kinaseAKT signaling cascade crosstalks

to several key signal transduction pathways that are criticalto developmental biology This includes the abovementionedTGF-120573SMAD pathway and the Wnt120573-catenin pathway[109] The TGF-120573SMAD pathway is one of the most seminalpathways in developmental biology and PTEN modulatesTGF120573SMAD signaling by reversing Akt-mediated phospho-rylation of SMAD3 the critical signaling intermediate ofTGF120573SMAD signaling [110] Similarly the Wnt signalingpathway is indispensable for properly regulated developmentcellular proliferation and differentiation [111] PTEN regu-lates this pathway by reversing AKT kinase phosphorylationand inhibition of GSK-3120573 resulting in 120573-catenin nucleartranslocation and activation Finally recent studies demon-strate that PTEN regulates the expression and action of thehomeobox genes NKX31 and hepatic nuclear factor [112]proteins that are critical to organ development

326 PTEN-Regulated Stem Cell Activities The scientificliterature in the field of tissue stem or stem-like ldquoprogen-itorrdquo cells and their role in tissue development growthrecovery and repair has become beyond extensive in recentyears Expansion of stemprogenitor cells is a hallmark ofgrowth and patterning during development and regulationof these cells including their proliferation maintenanceand differentiation is a critical factor of developmentalregulation Because of this a review of the current liter-ature on PTENrsquos role in stem and tissue progenitor cellsis warranted in this review PTEN plays an important rolein regulating the homeostasis of stemprogenitor cells inmultiple tissues Interestingly PTEN regulates both self-renewal and proliferation but paradoxically it also playsa role in stem cell exhaustion For example the FOXOfamily of transcription factors controls stem cell proliferationand survival in hematopoietic stem cells [113] and PTENsignaling is a critical modulator of FOXO activity FOXO3A-deficient HSCs exhibit increased proliferation rate decreasedquiescence and a reduced ability to repopulate bone marrowafter transplantation into recipient mice Additionally thepreviously mentioned Wnt120573-catenin signaling pathway iscritical for HSC self-renewal and its activation is well knownto be modulated by PTEN Interestingly PTEN loss and AKTactivation in HSCs lead to a moderate increase in the levelof unphosphorylated 120573-catenin but this is not sufficient tomaintain Pten-null HSC self-renewal [114] Finally NOTCHsignaling plays a key role in regulating neural stem cellexpansion [115] and as stated previously NOTCH pathwayactivation leads to reduced PTEN expression in neural andhematopoietic stem cells

4 Conclusions

PTEN acts as the key endogenous negative modulatorof phosphoinositide signaling in mammalian cells and

Journal of Signal Transduction 9

therefore its role in normal cell homeostasis proliferationapoptosis and many additional components of cell biologyis extensive Because PTEN regulates cancer progressionmuch of what has been studied regarding PTEN relates totumorigenesis and tumor growth While this is warrantedbecause of the relevance of cancer to humanhealth PTENhassubstantial but underappreciated effects in normal tissue andorgan development immune system development and reg-ulation axonal regeneration glucose regulation and benigngrowth disorders PTEN is often dogmatically thought ofas a constitutive protein that exhibits lost activity duringdiseases butwhat is underappreciated is that PTENhas a verycomplex regulation network that involves signaling path-ways that regulate PTEN transcription transcript stabilityposttranslationalmodifications protein-protein interactionsand cellular location PTEN then in turn regulates numerousdevelopmental signaling networks that are critical to devel-opment and adult tissue maintenance

Abbreviations

Bcl2 B-cell lymphoma 2Bim BCL-2-interacting mediatorCK2 Casein Kinase 2CREB Cyclic AMP response element binding

proteinDLG Disks large homolog 1Egr-1 Early growth response protein 1Erk Extracellular regulated kinaseFOX Forkhead transcription factorsGSK3120573 Glycogen synthase kinase 3JNK Jun-terminal kinaseMAGI2 Membrane-associated guanylate kinase

inverted 2MAN2C1 Mannosidase alpha class 2C member 1MDM2 Mouse double minute 2 homologmTOR Mechanistic target of rapamycinNHERF Sodium-hydrogen antiporter 3

regulator 1NRG1 Neuregulin 1PCAF P300CBP-associated factorPDZ Postsynaptic density proteinmdashDisc

large tumor suppressormdashZonulaoccludens-1 protein

PIP3 Phosphoinositide triphosphatePPAR120574 Peroxisome proliferating antigen

receptorPREX2a Phosphatidylinositol-345-

trisphosphate-dependent Rac exchangefactor A

PTEN Phosphatase and Tensin homologueROCK Rho-associated coiled-coil-containing

protein kinaseSALL Spalt-like transcription factor-1SIPL1 Shank-interacting protein-like 1SIRT1 Sirtuin 1SMAD Small mothers against decapentaplegicSOCS Suppressor of cytokine signalingTGF120573 Transforming growth factor-beta

Disclosure

Travis J Jerde carried out the extensive literature reviewrequired to write this paper and have written the entirepaper The author has therefore read and approved the papersubmitted

Conflict of Interests

The author has no financial or nonfinancial conflict ofinterests with the submission of this paper

Acknowledgments

The author gratefully acknowledges the financial supportof the Indiana University School of Medicine Departmentof Pharmacology and Toxicology and the Melvin and BrynSimon Cancer Center The author also gratefully acknowl-edges this paper as part of his training made possible byNational Institutes of Health-NIDDK (DK092366-01A1)

References

[1] M Milella I Falcone F Conciatori et al ldquoPTEN multiplefunctions in human malignant tumorsrdquo Frontiers in Oncologyvol 5 article 24 2015

[2] J-O Lee H Yang M-M Georgescu et al ldquoCrystal structure ofthe PTEN tumor suppressor implications for its phosphoinosi-tide phosphatase activity and membrane associationrdquo Cell vol99 no 3 pp 323ndash334 1999

[3] W-L Yang G Jin C-F Li et al ldquoCycles of ubiquitinationand deubiquitination critically regulate growth factor-mediatedactivation of Akt signalingrdquo Science Signaling vol 6 no 257article ra3 2013

[4] J Gu S Nada M Okada and K Sekiguchi ldquoCsk regulatesintegrin-mediated signals involvement of differential activa-tion of ERK and Aktrdquo Biochemical and Biophysical ResearchCommunications vol 303 no 3 pp 973ndash977 2003

[5] A Clerk and P H Sugden ldquoActivation of protein kinase cas-cades in the heart by hypertrophic G protein-coupled receptoragonistsrdquoTheAmerican Journal of Cardiology vol 83 no 12 pp64Hndash69H 1999

[6] I Tonic W-N Yu Y Park C-C Chen and N Hay ldquoAktactivation emulates Chk1 inhibition and Bcl2 overexpressionand abrogates G2 cell cycle checkpoint by inhibiting BRCA1focirdquo The Journal of Biological Chemistry vol 285 no 31 pp23790ndash23798 2010

[7] S Fatrai L Elghazi N Balcazar et al ldquoAkt induces 120573-cellproliferation by regulating cyclin D1 cyclin D2 and p21 levelsand cyclin-dependent kinase-4 activityrdquo Diabetes vol 55 no 2pp 318ndash325 2006

[8] M Aoki E Blazek and P K Vogt ldquoA role of the kinase mTORin cellular transformation induced by the oncoproteins P3k andAktrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 98 no 1 pp 136ndash141 2001

[9] H Guan L Song J Cai et al ldquoSphingosine kinase 1 regulatesthe AktFOXO3aBim pathway and contributes to apoptosisresistance in glioma cellsrdquo PLoS ONE vol 6 no 5 Article IDe19946 2011

[10] T D Dung C H Day T V Binh et al ldquoPP2Amediates diosminp53 activation to block HA22T cell proliferation and tumor

10 Journal of Signal Transduction

growth in xenografted nude mice through PI3K-Akt-MDM2signaling suppressionrdquo Food and Chemical Toxicology vol 50no 5 pp 1802ndash1810 2012

[11] K Shanmugasundaram K Block B K Nayak C B Livi MA Venkatachalam and S Sudarshan ldquoPI3K regulation of theSKP-2p27 axis through mTORC2rdquo Oncogene vol 32 no 16pp 2027ndash2036 2013

[12] J-C Chang H-H Chang C-T Lin and S J Lo ldquoThe integrin12057261205731modulation of PI3K andCdc42 activities induces dynamicfilopodium formation in humanplateletsrdquo Journal of BiomedicalScience vol 12 no 6 pp 881ndash898 2005

[13] E Hajduch G J Litherland and H S Hundal ldquoProtein kinaseB (PKBAkt)mdasha key regulator of glucose transportrdquo FEBSLetters vol 492 no 3 pp 199ndash203 2001

[14] M M Martin J A Buckenberger J Jiang et al ldquoTGF-beta1stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[15] M M Martin J A Buckenberger J Jiang et al ldquoTGF-1205731stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[16] K Abell and C J Watson ldquoThe JakStat pathway a novel wayto regulate PI3K activityrdquo Cell Cycle vol 4 no 7 pp 897ndash9002005

[17] J-Y Hwang R S Duncan C Madry M Singh and P KoulenldquoProgesterone potentiates calcium release through IP3 recep-tors by an Akt-mediated mechanism in hippocampal neuronsrdquoCell Calcium vol 45 no 3 pp 233ndash242 2009

[18] G Pappas L A Zumstein A Munshi M Hobbs and R EMeyn ldquoAdenoviral-mediated PTEN expression radiosensitizesnon-small cell lung cancer cells by suppressing DNA repaircapacityrdquoCancer GeneTherapy vol 14 no 6 pp 543ndash549 2007

[19] A Di Cristofano B Pesce C Cordon-Cardo and P P PandolfildquoPten is essential for embryonic development and tumoursuppressionrdquo Nature Genetics vol 19 no 4 pp 348ndash355 1998

[20] J Bloomekatz J Grego-Bessa I Migeotte and K V AndersonldquoPten regulates collective cell migration during specification ofthe anterior-posterior axis of the mouse embryordquo Developmen-tal Biology vol 364 no 2 pp 192ndash201 2012

[21] S Ueno R Kono andY Iwao ldquoPTEN is required for the normalprogression of gastrulation by repressing cell proliferation afterMBT in Xenopus embryosrdquoDevelopmental Biology vol 297 no1 pp 274ndash283 2006

[22] C B Knobbe A Merlo and G Reifenberger ldquoPten signaling ingliomasrdquo Neuro Oncology vol 4 pp 196ndash211 2002

[23] E Kirches J Steiner T Schneider et al ldquoLhermitte-Duclosdisease caused by a novel germline PTEN mutation R173P in apatient presenting with psychosisrdquoNeuropathology and AppliedNeurobiology vol 36 no 1 pp 86ndash89 2010

[24] J-I Murata M Tada Y Sawamura K Mitsumori H Abe andK Nagashima ldquoDysplastic gangliocytoma (Lhermitte-Duclosdisease) associated with Cowden disease report of a case andreview of the literature for the genetic relationship between thetwo diseasesrdquo Journal of Neuro-Oncology vol 41 no 2 pp 129ndash136 1999

[25] G Zhu L M L Chow I T Bayazitov et al ldquoPten deletioncauses mTorc1-dependent ectopic neuroblast differentiation

without causing uniform migration defectsrdquo Development vol139 no 18 pp 3422ndash3431 2012

[26] K L McBride E A Varga M T Pastore et al ldquoConfirmationstudy of PTEN mutations among individuals with autism ordevelopmental delaysmental retardation and macrocephalyrdquoAutism Research vol 3 no 3 pp 137ndash141 2010

[27] J Zhou and L F Parada ldquoPTEN signaling in autism spectrumdisordersrdquo Current Opinion in Neurobiology vol 22 no 5 pp873ndash879 2012

[28] S A Backman V Stambolic A Suzuki et al ldquoDeletion of Ptenin mouse brain causes seizures ataxia and defects in soma sizeresembling Lhermitte-Duclos diseaserdquo Nature Genetics vol 29no 4 pp 396ndash403 2001

[29] L Cotter M Ozcelik C Jacob et al ldquoDlg1-PTEN interactionregulates myelin thickness to prevent damaging peripheralnerve overmyelinationrdquo Science vol 328 no 5984 pp 1415ndash1418 2010

[30] S Ogawa C-H Kwon J Zhou D Koovakkattu L F Paradaand C M Sinton ldquoA seizure-prone phenotype is associatedwith altered free-running rhythm in Pten mutant micerdquo BrainResearch vol 1168 no 1 pp 112ndash123 2007

[31] C-H Kwon X Zhu J Zhang and S J Baker ldquomTor isrequired for hypertrophy of Pten-deficient neuronal soma invivordquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 22 pp 12923ndash12928 2003

[32] C-H Kwon B W Luikart C M Powell et al ldquoPten regulatesneuronal arborization and social interaction in micerdquo Neuronvol 50 no 3 pp 377ndash388 2006

[33] A Suzuki S Itami M Ohishi et al ldquoKeratinocyte-specific Ptendeficiency results in epidermal hyperplasia accelerated hairfollicle morphogenesis and tumor formationrdquo Cancer Researchvol 63 no 3 pp 674ndash681 2003

[34] T Inoue-Narita K Hamada T Sasaki et al ldquoPten deficiency inmelanocytes results in resistance to hair graying and susceptibil-ity to carcinogen-induced melanomagenesisrdquo Cancer Researchvol 68 no 14 pp 5760ndash5768 2008

[35] R K Patel and C Mohan ldquoPI3KAKT signaling and systemicautoimmunityrdquo Immunologic Research vol 31 no 1 pp 47ndash552005

[36] K Podsypanina L H Ellenson A Nemes et al ldquoMutationof PtenMmac1 in mice causes neoplasia in multiple organsystemsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 4 pp 1563ndash1568 1999

[37] M Kashiwada P Lu and P B Rothman ldquoPIP3 pathway inregulatory T cells and autoimmunityrdquo Immunologic Researchvol 39 no 1ndash3 pp 194ndash224 2007

[38] A Suzuki M T Yamaguchi T Ohteki et al ldquoT cell-specificloss of Pten leads to defects in central and peripheral tolerancerdquoImmunity vol 14 no 5 pp 523ndash534 2001

[39] Y Yamanaka H Tagawa N Takahashi et al ldquoAberrant over-expression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lym-phomaleukemiardquo Blood vol 114 no 15 pp 3265ndash3275 2009

[40] H Kishimoto T Ohteki N Yajima et al ldquoThe PtenPI3Kpathway governs the homeostasis of V12057214iNKT cellsrdquo Bloodvol 109 no 8 pp 3316ndash3324 2007

[41] A Suzuki T Kaisho M Ohishi et al ldquoCritical roles ofPten in B cell homeostasis and immunoglobulin class switchrecombinationrdquo Journal of Experimental Medicine vol 197 no5 pp 657ndash667 2003

Journal of Signal Transduction 11

[42] M Nishio K-IWatanabe J Sasaki et al ldquoControl of cell polar-ity and motility by the PtdIns(345)P

3phosphatase SHIP1rdquo

Nature Cell Biology vol 9 no 1 pp 36ndash44 2007[43] S Kuroda M Nishio T Sasaki et al ldquoEffective clearance

of intracellular Leishmania major in vivo requires Pten inmacrophagesrdquo European Journal of Immunology vol 38 no 5pp 1331ndash1340 2008

[44] O H Yilmaz R Valdez B K Theisen et al ldquoPten depen-dence distinguishes haematopoietic stem cells from leukaemia-initiating cellsrdquo Nature vol 441 no 7092 pp 475ndash482 2006

[45] Y Li K Podsypanina X Liu et al ldquoDeficiency of Ptenaccelerates mammary oncogenesis in MMTV-Wnt-1 transgenicmicerdquo BMCMolecular Biology vol 2 article 2 2001

[46] P Reddy L Liu D Adhikari et al ldquoOocyte-specific deletion ofpten causes premature activation of the primordial follicle poolrdquoScience vol 319 no 5863 pp 611ndash613 2008

[47] H Tsuruta H Kishimoto T Sasaki et al ldquoHyperplasia andcarcinomas in Pten-deficient mice and reduced PTEN proteinin human bladder cancer patientsrdquoCancer Research vol 66 no17 pp 8389ndash8396 2006

[48] L I Yoo D W Liu S Le Vu R T Bronson H Wu and JYuan ldquoPten deficiency activates distinct downstream signalingpathways in a tissue-specific mannerrdquo Cancer Research vol 66no 4 pp 1929ndash1939 2006

[49] J Li C Yen D Liaw et al ldquoPTEN a putative protein tyrosinephosphatase gene mutated in human brain breast and prostatecancerrdquo Science vol 275 no 5308 pp 1943ndash1947 1997

[50] N D Deocampo H Huang and D J Tindall ldquoThe role ofPTEN in the progression and survival of prostate cancerrdquoMinerva Endocrinologica vol 28 no 2 pp 145ndash153 2003

[51] S A Backman D Ghazarian K So et al ldquoEarly onset ofneoplasia in the prostate and skin of mice with tissue-specificdeletion of Ptenrdquo Proceedings of the National Academy ofSciences of the United States of America vol 101 no 6 pp 1725ndash1730 2004

[52] X Wu K Xu L Zhang et al ldquoDifferentiation of the ductalepithelium and smooth muscle in the prostate gland areregulated by the NotchPTEN-dependent mechanismrdquo Devel-opmental Biology vol 356 no 2 pp 337ndash349 2011

[53] D Kim and G R Dressler ldquoPTEN modulates GDNFRETmediated chemotaxis and branching morphogenesis in thedeveloping kidneyrdquo Developmental Biology vol 307 no 2 pp290ndash299 2007

[54] N O Lindstrom M L Lawrence S F Burn et al ldquoIntegrated120573-catenin BMP PTEN and notch signalling patterns thenephronrdquo eLife no 4 Article ID e04000 2015

[55] V Marsh D J Winton G T Williams et al ldquoEpithelialPten is dispensable for intestinal homeostasis but suppressesadenoma development and progression after Apc mutationrdquoNature Genetics vol 40 no 12 pp 1436ndash1444 2008

[56] S Matsuda M Kobayashi and Y Kitagishi ldquoRoles forPI3KAKTPTEN pathway in cell signaling of nonalcoholicfatty liver diseaserdquo ISRN Endocrinology vol 2013 Article ID472432 7 pages 2013

[57] X Qi J Xu P Gu X Yang and X Gao ldquoPTEN in smoothmuscle cells is essential for colonic immune homeostasisrdquoInternational Journal of Biochemistry and Cell Biology vol 53pp 108ndash114 2014

[58] A Pal T M Barber M Van de Bunt et al ldquoPTENmutations asa cause of constitutive insulin sensitivity and obesityrdquoThe NewEngland Journal of Medicine vol 367 no 11 pp 1002ndash1011 2012

[59] B L Stiles C Kuralwalla-Martinez W Guo et al ldquoSelectivedeletion of Pten in pancreatic 120573 cells leads to increased isletmass and resistance to STZ-induced diabetesrdquo Molecular andCellular Biology vol 26 no 7 pp 2772ndash2781 2006

[60] LWang C T Luk E P Cai et al ldquoPTEN deletion in pancreatic120572-cells protects against high-fat diet-induced hyperglucagone-mia and insulin resistancerdquo Diabetes vol 64 no 1 pp 147ndash1572015

[61] C Kurlawalla-Martinez B Stiles Y Wang S U Devaskar BB Kahn and H Wu ldquoInsulin hypersensitivity and resistanceto streptozotocin-induced diabetes in mice lacking PTEN inadipose tissuerdquo Molecular and Cellular Biology vol 25 no 6pp 2498ndash2510 2005

[62] N Wijesekara D Konrad M Eweida et al ldquoMuscle-specificPten deletion protects against insulin resistance and diabetesrdquoMolecular and Cellular Biology vol 25 no 3 pp 1135ndash11452005

[63] K Hamada T Sasaki P A Koni et al ldquoThe PTENPI3Kpathway governs normal vascular development and tumorangiogenesisrdquo Genes and Development vol 19 no 17 pp 2054ndash2065 2005

[64] N D Roe X Xu M R Kandadi et al ldquoTargeted deletionof PTEN in cardiomyocytes renders cardiac contractile dys-function through interruption of Pink1-AMPK signaling andautophagyrdquo Biochimica et Biophysica Acta Molecular Basis ofDisease vol 1852 no 2 pp 290ndash298 2015

[65] A F Ford-Hutchinson Z Ali S E Lines B HallgrımssonS K Boyd and F R Jirik ldquoInactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnor-malities and skeletal overgrowthrdquo Journal of Bone and MineralResearch vol 22 no 8 pp 1245ndash1259 2007

[66] T A Burgers M F Hoffmann C J Collins et al ldquoMice lackingpten in osteoblasts have improved intramembranous and lateendochondral fracture healingrdquo PLoS ONE vol 8 no 5 ArticleID e63857 2013

[67] N R Leslie L Spinelli P Tibarewal et al ldquoIndirect mecha-nisms of carcinogenesis via downregulation of PTEN functionrdquoAdvances in Enzyme Regulation vol 50 no 1 pp 112ndash118 2010

[68] L He ldquoPosttranscriptional regulation of PTEN dosage bynoncoding RNAsrdquo Science Signaling vol 3 no 146 article pe392010

[69] F Vazquez S R Grossman Y Takahashi M V Rokas NNakamura andWR Sellers ldquoPhosphorylation of the PTEN tailacts as an inhibitory switch by preventing its recruitment into aprotein complexrdquo The Journal of Biological Chemistry vol 276no 52 pp 48627ndash48630 2001

[70] X Wang L C Trotman T Koppie et al ldquoNEDD4-1 is a proto-oncogenic ubiquitin ligase for PTENrdquo Cell vol 128 no 1 pp129ndash139 2007

[71] N R Leslie and M Foti ldquoNon-genomic loss of PTEN functionin cancer not in my genesrdquo Trends in Pharmacological Sciencesvol 32 no 3 pp 131ndash140 2011

[72] Y Xing C Li L Hu et al ldquoMechanisms of TGF120573 inhibition ofLUNG endodermal morphogenesis the role of T120573RII SmadsNkx21 and Ptenrdquo Developmental Biology vol 320 no 2 pp340ndash350 2008

[73] J P Luyendyk G A Schabbauer M Tencati T Holscher RPawlinski and N Mackman ldquoGenetic analysis of the role ofthe PI3K-Akt pathway in lipopolysaccharide-induced cytokineand tissue factor gene expression in monocytesmacrophagesrdquoJournal of Immunology vol 180 no 6 pp 4218ndash4226 2008

12 Journal of Signal Transduction

[74] F Sun K K Park S Belin et al ldquoSustained axon regenerationinduced by co-deletion of PTEN and SOCS3rdquo Nature vol 480no 7377 pp 372ndash375 2011

[75] C B Knobbe V Lapin A Suzuki and T W Mak ldquoThe roles ofPTEN in development physiology and tumorigenesis in mousemodels a tissue-by-tissue surveyrdquo Oncogene vol 27 no 41 pp5398ndash5415 2008

[76] S J Assinder Q Dong Z Kovacevic and D R RichardsonldquoThe TGF-beta PI3KAkt and PTEN pathways establishedand proposed biochemical integration in prostate cancerrdquoBiochemical Journal vol 417 no 2 pp 411ndash421 2009

[77] K A Waite and C Eng ldquoFrom developmental disorder toheritable cancer itrsquos all in the BMPTGF-120573 familyrdquo NatureReviews Genetics vol 4 no 10 pp 763ndash773 2003

[78] H B Newton ldquoMolecular neuro-oncology and developmentof targeted therapeutic strategies for brain tumors Part2 PI3KAktPTEN mTOR SHHPTCH and angiogenesisrdquoExpert Review of Anticancer Therapy vol 4 no 1 pp 105ndash1282004

[79] R H KimM Peters Y Jang et al ldquoDJ-1 a novel regulator of thetumor suppressor PTENrdquo Cancer Cell vol 7 no 3 pp 263ndash2732005

[80] J Lu H W Jeong N Kong et al ldquoStem cell factor SALL4represses the transcriptions of PTEN and SALL1 through anepigenetic repressor complexrdquo PLoS ONE vol 4 no 5 ArticleID e5577 2009

[81] M M A Rizvi M S Alam A Ali S J Mehdi S Batra andA KMandal ldquoAberrant promotermethylation and inactivationof PTEN gene in cervical carcinoma from Indian populationrdquoJournal of Cancer Research and Clinical Oncology vol 137 no 8pp 1255ndash1262 2011

[82] J Liu ldquoControl of protein synthesis and mRNA degradation bymicroRNAsrdquo Current Opinion in Cell Biology vol 20 no 2 pp214ndash221 2008

[83] S W Shan L Fang T Shatseva et al ldquoMature miR-17-5pand passenger miR-17-3p induce hepatocellular carcinoma bytargeting PTEN GalNT7 and vimentin in different signalpathwaysrdquo Journal of Cell Science vol 126 part 6 pp 1517ndash15302013

[84] Z Liang Y Li K Huang N Wagar and H Shim ldquoRegulationof miR-19 to breast cancer chemoresistance through targetingPTENrdquo Pharmaceutical Research vol 28 no 12 pp 3091ndash31002011

[85] X Lu Q Fan L Xu et al ldquoUrsolic acid attenuates diabeticmesangial cell injury through the up-regulation of autophagyvia miRNA-21PTENAktmTOR suppressionrdquo PLoS ONE vol10 no 2 Article ID e0117400 2015

[86] L Poliseno L Salmena J Zhang B Carver W J Havemanand P P Pandolfi ldquoA coding-independent function of geneand pseudogenemRNAs regulates tumour biologyrdquoNature vol465 no 7301 pp 1033ndash1038 2010

[87] Y Tay L Kats L Salmena et al ldquoCoding-independent regula-tion of the tumor suppressor PTEN by competing endogenousmRNAsrdquo Cell vol 147 no 2 pp 344ndash357 2011

[88] L Odriozola G Singh T Hoang and A M Chan ldquoRegula-tion of PTEN activity by its carboxyl-terminal autoinhibitorydomainrdquo The Journal of Biological Chemistry vol 282 no 32pp 23306ndash23315 2007

[89] Z Li X Dong Z Wang et al ldquoRegulation of PTEN by Rhosmall GTPasesrdquo Nature Cell Biology vol 7 no 4 pp 399ndash4042005

[90] E-K Yim G Peng H Dai et al ldquoRak functions as a tumorsuppressor by regulating PTEN protein stability and functionrdquoCancer Cell vol 15 no 4 pp 304ndash314 2009

[91] AMAl-Khouri YMa SH Togo SWilliams andTMustelinldquoCooperative phosphorylation of the tumor suppressor phos-phatase and tensin homologue (PTEN) by casein kinasesand glycogen synthase kinase 3120573rdquo The Journal of BiologicalChemistry vol 280 no 42 pp 35195ndash35202 2005

[92] H Maccario N M Perera L Davidson C P Downes and NR Leslie ldquoPTEN is destabilized by phosphorylation onThr366rdquoBiochemical Journal vol 405 no 3 pp 439ndash444 2007

[93] K A Waite and C Eng ldquoBMP2 exposure results in decreasedPTEN protein degradation and increased PTEN levelsrdquoHumanMolecular Genetics vol 12 no 6 pp 679ndash684 2003

[94] T J Jerde Z Wu D Theodorescu and W Bushman ldquoRegu-lation of phosphatase homologue of tensin protein expressionby bone morphogenetic proteins in prostate epithelial cellsrdquoProstate vol 71 no 8 pp 791ndash800 2011

[95] G Singh and A M Chan ldquoPost-translational modificationsof PTEN and their potential therapeutic implicationsrdquo CurrentCancer Drug Targets vol 11 no 5 pp 536ndash547 2011

[96] T Ikenoue K Inoki B Zhao and K-L Guan ldquoPTEN acety-lation modulates its interaction with PDZ domainrdquo CancerResearch vol 68 no 17 pp 6908ndash6912 2008

[97] L C Trotman X Wang A Alimonti et al ldquoUbiquitinationregulates PTEN nuclear import and tumor suppressionrdquo Cellvol 128 no 1 pp 141ndash156 2007

[98] T Tolkacheva M Boddapati A Sanfiz K Tsuchida A CKimmelman and AM-L Chan ldquoRegulation of PTEN bindingto MAGI-2 by two putative phosphorylation sites at threonine382 and 383rdquo Cancer Research vol 61 no 13 pp 4985ndash49892001

[99] E Lima-Fernandes H Enslen E Camand et al ldquoDistinct func-tional outputs of PTEN signalling are controlled by dynamicassociation with 120573-arrestinsrdquoThe EMBO Journal vol 30 no 13pp 2557ndash2568 2011

[100] M T van Diepen M Parsons C P Downes N R Leslie RHindges and B J Eickholt ldquoMyosinV controls PTEN functionand neuronal cell sizerdquo Nature Cell Biology vol 11 no 10 pp1191ndash1196 2009

[101] R B Chagpar P H Links M C Pastor et al ldquoDirect positiveregulation of PTEN by the p85 subunit of phosphatidylinositol3-kinaserdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 107 no 12 pp 5471ndash5476 2010

[102] Y Takahashi F C Morales E L Kreimann and M-MGeorgescu ldquoPTEN tumor suppressor associates with NHERFproteins to attenuate PDGF receptor signalingrdquo The EMBOJournal vol 25 no 4 pp 910ndash920 2006

[103] M Valiente A Andres-Pons B Gomar et al ldquoBinding ofPTEN to specific PDZ domains contributes to PTEN proteinstability and phosphorylation by microtubule-associated ser-inethreonine kinasesrdquoThe Journal of Biological Chemistry vol280 no 32 pp 28936ndash28943 2005

[104] SQuintes SGoebbels G SaherMH Schwab andK-ANaveldquoNeuron-glia signaling and the protection of axon function bySchwann cellsrdquo Journal of the Peripheral Nervous System vol 15no 1 pp 10ndash16 2010

[105] B Fine C Hodakoski S Koujak et al ldquoActivation of the PI3Kpathway in cancer through inhibition of PTEN by exchangefactor P-REX2ardquo Science vol 325 no 5945 pp 1261ndash1265 2009

Journal of Signal Transduction 13

[106] L He A Ingram A P Rybak and D Tang ldquoShank-interactingprotein-like 1 promotes tumorigenesis via PTEN inhibition inhuman tumor cellsrdquo The Journal of Clinical Investigation vol120 no 6 pp 2094ndash2108 2010

[107] L He C Fan A Kapoor et al ldquo120572-Mannosidase 2C1 attenuatesPTEN function in prostate cancer cellsrdquo Nature Communica-tions vol 2 no 1 article 307 2011

[108] Z Radisavljevic ldquoAKT as locus of cancer positive feedbackloops and extreme robustnessrdquo Journal of Cellular Physiologyvol 228 no 3 pp 522ndash524 2013

[109] M Y Lee HW Lim S H Lee andH J Han ldquoSmad PI3KAktand wnt-dependent signaling pathways are involved in BMP-4-induced ESC self-renewalrdquo Stem Cells vol 27 no 8 pp 1858ndash1868 2009

[110] K Song S C Cornelius M Reiss and D Danielpour ldquoInsulin-like growth factor-I inhibits transcriptional responses of trans-forming growth factor-120573 by phosphatidylinositol 3-kinaseAkt-dependent suppression of the activation of Smad3 but notSmad2rdquoThe Journal of Biological Chemistry vol 278 no 40 pp38342ndash38351 2003

[111] D Fang D Hawke Y Zheng et al ldquoPhosphorylation of 120573-catenin by AKT promotes 120573-catenin transcriptional activityrdquoThe Journal of Biological Chemistry vol 282 no 15 pp 11221ndash11229 2007

[112] Q Lei J Jiao L Xin et al ldquoNKX31 stabilizes p53 inhibitsAKT activation and blocks prostate cancer initiation caused byPTEN lossrdquo Cancer Cell vol 9 no 5 pp 367ndash378 2006

[113] A Sengupta J D Molkentin J-H Paik R A DePinho and KE Yutzey ldquoFoxO transcription factors promote cardiomyocytesurvival upon induction of oxidative stressrdquo The Journal ofBiological Chemistry vol 286 no 9 pp 7468ndash7478 2011

[114] C H M Jamieson L E Ailles S J Dylla et al ldquoGranulocyte-macrophage progenitors as candidate leukemic stem cells inblast-crisis CMLrdquoTheNewEngland Journal ofMedicine vol 351no 7 pp 657ndash667 2004

[115] A Androutsellis-Theotokis R R Leker F Soldner et al ldquoNotchsignalling regulates stem cell numbers in vitro and in vivordquoNature vol 442 no 7104 pp 823ndash826 2006

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

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Stem CellsInternational

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Enzyme Research

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International Journal of

Microbiology

Page 5: Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling TravisJ.Jerde Department of Pharmacology

Journal of Signal Transduction 5

signalingmechanisms [56] In the liver loss of PTENnot onlyincreases tumor susceptibility but also altersmetabolism [57]In addition hepatomegaly is observed in mice with condi-tional hepatic PTEN knockout as the ratio of liver weightto body weight increased in the mutants when comparedwith wild-type controls [57] Livers harvested from mutantanimals are discolored and show accumulation of triglyc-erides consistent with steatohepatitis associated with severeinflammation Passive diffusion of fatty acids in hepatocyteswas enhanced in PTEN null mice and PTEN-deficienthepatocytes exhibit an increased rate of fatty acid synthesisvia induced fatty acid synthase [57] PTEN-deficient miceexhibit defects in glucose metabolism including decreasedfasting plasma glucose levels and reduced serum insulinlevels [58] Clearance of glucose was accelerated in theabsence of PTEN concurrent with increased liver glycogenstorage

Pancreatic islet beta-cell specific PTEN-deficient miceexhibit increases in islet cell numbers total islet massand an increase in 120573-cell progenitor proliferation duringembryonic development and early postnatal life [59] AdultPTEN mutant mice were hypoglycemic and were resistantto streptozotocin-induced diabetes These mice are signifi-cantly smaller than controls and have a shorter lifespan Insome studies severe hypoglycemia is associated with seizureactivity and premature death before 5 weeks of age [59]In addition PTEN (+minus) mice exhibit protection againstincreased insulin production during reactive oxygen species-dependent type two diabetes and insulin-resistance uponaging [60]

PTENrsquos role in maintaining glucose balance is not limitedto the liver and pancreas but also involves adipocytes andmyocytes Inactivation of PTEN specifically in adipocytesproduces no obvious gross morphological effects on theadipose tissue or adipose tissue mass However this mouseexhibits increased systemic glucose tolerance and insulin sen-sitivity complete with decreased fasting insulin and resistinlevels [61] By controlling serum insulin and resistin levelsPTEN regulates insulin sensitivity and AMP kinase activityin the liver Similarly skeletal and cardiac muscle cell-specificdeletion causes increased systemic glucose tolerance andinsulin sensitivity [62] Interestingly however PTEN loss inthese tissues seems to protect thesemice from streptozotocin-induced diabetes and hyperglycemia indicating that theinsulin hypersensitivity exhibited in tissue-selective PTEN-deficient mice allowed them to maintain proper glucoselevels

PTEN regulates proper lung development Specific lungdeletion of PTEN during embryogenesis results in impairedlungmorphogenesis and early postnatal death [61]The lungsof these neonates exhibit increased epithelial cell proliferationand decreased alveolar cell differentiation Adults exhibitbronchiolar and alveolar epithelial hyperplasia Mutant miceexhibit hypertrophy of alveolar cells derived from bron-chioalveolar stem cells [61] Predictably adenocarcinomawasevident in aged adults Further study of PTENrsquos role inlung development revealed that PTEN-regulated signalingmediates lung endodermal morphogenesis coordinate withthe overall developmental process in the lung and it is central

to the interaction of several signaling pathways including theTGF beta-SMAD and Nkx21 pathways [62]

Normal development of the vascular system is alsodependent on proper PTEN function PTEN knockout inendothelial and endocardial cells in mice results in embry-onic lethality due to increased capillaries and endothelial cellhypertrophy [63] These mutant embryos exhibit pericardialcavity enlargement leakage of blood into the pericardialcavity and enlarged trunk vessels secondary to pericyte andvascular smooth muscle cell recruitment to blood vessels[63] In addition cardiomyocyte-specific deletion of PTENleads to cardiac phenotypes via development of cardiachypertrophy and contractile defect [64] Future studies onPTEN will hopefully be targeted at assessing injury-relatedresponses in the cardiovascular system as deletion of PTENin cardiomyocytes has been shown to protect the heart frommaladaptive remodeling upon biomechanical stress

PTEN regulates developing bone and cartilage by pro-tecting against overgrowth of the skeletal system Mice withdeletion of PTEN in osteochondroprogenitor cells exhibitgrowth plate dysfunction and overgrowth of the vertebrae[65] The bodies of these mice are notably longer than wild-type controls demonstrating a critical defect that resultsin loss of proper skeletal development Interestingly thisincrease in length was not due to bone cell proliferationincreases as might have been expected but rather is due toincreased matrix deposition and cellular hypertrophy [65]In a second model osteoblast-specific knockdown of PTENexpression results in increased bone volume and density[66] Interestingly this mutation is associated with improvedintramembranous and late endochondral fracture healingThis is now an active area of research within the boneremodeling research field

While PTEN remains virtually synonymous with cancerbiology the studies presented here make the importanceof proper PTEN signaling for regulating a wide variety ofdevelopmental processes clearly evident From regulation ofgrowth differentiation glucose maintenance and repair andrecovery to gross effects on organ and systems developmentPTEN is a protein with vast consequence in the field ofdevelopmental biology and the signaling affected by itsexpression is expansiveThe role PTEN plays in developmenthas clear correlates to human disease Further PTENrsquos effectson development acquire greater importance when the rolethat developmental signaling plays in cancer growth andprogression is consideredTherefore an extensive knowledgeof how PTEN is regulated by developmental signaling apartfrom somatic or genetic mutation is required for completeunderstanding of PTENrsquos role in these important physiologi-cal processes

3 PTEN Regulation as Part ofDevelopmental Signaling

31 Intrinsic and Extrinsic PTEN Regulation Most studiesevaluating the role of PTEN in human diseases have beencentered uponmutation in PTEN itself andmost of this workis done in its relationship to cancer initiation and progression

6 Journal of Signal Transduction

BMP Hh JagdeltaNOTCH

NICD

miRNA(17 19 21)

GF

PTEN mRNA

PTEN mRNA

PTENNICD

SMAD2 3

SMAD1 5 8 Gli2

AP -1

NICDAP -1

SMO

SMAD2 3

SMAD1 5 8 Gli2

SALL4

Cyt

p65p50

p65p50

ceRNAAkt

GSK3CK2

PCAF

SIRT1

PIP3 PIP2

PI3 kinase

TGF120573

Figure 3 Summary of regulation mechanisms for PTEN critical for its action in developmental biology PTEN transcription is regulatedby TGF120573 BMP Hh NOTCH and cytokine signaling in cells during development miRNAs and ceRNAs regulate PTEN message stabilityPhosphorylation or acetylation by then can regulate PTENrsquos protein stability enzymatic activity and cellular localization in a positive ornegative manner All told the regulation of PTEN is complex and precise during development and perturbations in this paradigm haveprofound effects

There is no question that mutations of PTEN play a criticalrole in this regard Studies over the last decade howeverhave discovered a tremendous diversity in the regulationof PTEN expression and found that PTEN is tightly con-trolled both transcriptionally and posttranscriptionally [67]Recent studies to date have implicated microRNAs in PTENsuppression [68] and the enzymatic phosphatase activityof PTEN is also regulated posttranslationally via phospho-rylation ubiquitination or oxidation [69 70] This sectionhighlights the multifaceted mechanisms of PTEN regulationsupported by the rapidly expanding literature on PTENrsquos rolein growth and patterning of tissues during development Inaddition special emphasis is given tomediators and pathwaysinvolved in development including insulin-like growth factortransforming growth factor bone morphogenetic proteinsNOTCH forkhead transcription factors (Fox) and othersPTENrsquos complex regulation at the levels of transcriptionmRNA stability posttranslational modifications andmiRNAlevels has become a critical series of mechanisms deserving acomprehensive review (for an overview see Figure 3)

32 Developmental Signaling Regulating PTEN Expressionand Action The regulation of PTEN expression occurs attranscriptional posttranscriptional posttranslational andprotein-protein interaction levels [71] PTENrsquos function isfurther controlled by its cellular location In this sectionwe highlight developmental pathways involved in regulating

PTEN expression at all these regulation points and makespecial reference to connections between signal transductionand development

321 Developmental Pathways in PTEN Gene ExpressionOne critical aspect of PTENrsquos regulation during developmentbegins at the transcriptional level To date PTEN expres-sion has been found to be regulated at the transcriptionallevel by pathways involving p53 PPAR120574 Egr-1 NF-120581Band SMADs and this regulation affects the developmentof proper immune function the vasculature the nervoussystem the gastrointestinal system and the airways [6372 73] While PTEN is constitutively expressed in manynormal adult tissues PTEN expression is altered dramat-ically through the course of development and in patho-logical settings and a primary source of this regulationcomes from bona fide developmental regulators In additionsuppressors of cytokine signaling (SOCS) and SNAIL alsoinduce PTEN and act by countering the growth-promotingactions of cytokines and growth factors in developmentand repair and recovery [74] This mechanism has beenclearly demonstrated in axonal outgrowth during neurondevelopment and regeneration [74] While the physiologicalramifications of this regulation remain unsolved mediatorsthat slow or inhibit cell proliferation are often involved ininducing this protein Developmental mediators includingNOTCH transforming growth factor beta (TGF120573) bone

Journal of Signal Transduction 7

morphogenetic proteins (BMPs) and hedgehogs (Hhs) allparticipate as players in external PTEN regulation [75ndash78] regulating such processes as proliferation and targetedepithelial budding and outgrowth of visceral organs [76 77]and outgrowth in neurons [75] As the direction of cell growthand differentiation balances on the fulcrum between theproliferative and differentiating actions of these mediatorstheir regulation to induce or repress PTEN expression isa critical aspect of their actions during development Thecritical developmental mediator TGF120573 contains both growthpromoting and inhibiting differentiation qualities and TGF120573induces PTEN during differentiation when growth is slowedand inhibits its expression during proliferation In additionthe developmental regulator DJ-1 was recently identified asa novel negative regulator of PTEN by a genetic screen inDrosophila [79] PTEN is also regulated through epigeneticsilencing by methylation of the PTEN promoter [80 81] Aninteresting zinc-finger transcription factor sal-like protein 4(SALL4) has been discovered as a critical negative regulatorof PTEN transcription by recruiting an epigenetic repressorcomplex involving anATPase and a histone deacetylase to thePTENpromoter [80] SALL4 plays a critical role in regulatingdevelopment by modulating self-renewal in stem cells andits function appears to at least partly involve methylation ofthe PTENpromoter andmodulation of its transcriptionDataon this mechanism are still limited but to date this processhas been shown to regulate kidney patterning during devel-opment as well as leukemogenesis [80] Current research inthe area of PTEN transcriptional regulation continues to bedynamic and more novel regulation patterns are likely to bediscovered in the near future

322 PTEN Regulation by Posttranscriptional RegulationRecent studies have identified several interesting develop-mentally expressed miRNAs that regulate PTEN mRNAmessage stability and translatability [82] These miRNAstypically downregulate PTEN mRNA levels by targeting itfor degradation and include miR-17 miR-19 and miR-21 [83ndash85] While several examples of miR-17 and miR-19-mediatedPTENRNA levels have been reported in the cancer literaturemiR-21 has been described to play a critical role in repairand recovery a developmental signaling-related processmiRNAs regulate this mechanism by modulating PTENRNA stability and ultimately downstream Akt signaling Forexample in the pancreas miR-21 regulates injury repair indiabetic models by targeting PTEN RNA for degradationInhibition of miR-21 results in autophagy in this model ina manner dependent on PTEN degradation [85] In anotherexample of novel miR-related PTEN regulation the PTENpseudogene 1 (PTENP1) acts as a decoy for PTEN-targetingmiRNAs and thereby regulates PTEN expression by coding-independent activity through sequestering these miRNAsand effectively inhibiting their effects on PTEN expression[86] Additionally combined bioinformatic and experimentalapproaches have identified ceRNA transcripts that controlPTEN expression by sequestering PTEN-targeting miRNAsduring development of both prostate and skin [87] Becausethis type of PTEN regulation and indeed this field of generegulation in general is in its infancy we are only beginning

to understand the PTEN regulation by coding and noncodingceRNAs Still this novel work provides a platform for furtherstudies investigating posttranscriptional regulation patternsof PTEN expression in both developmental biology anddisease conditions

323 PTENRegulation by PosttranslationalMechanisms Theprotein stability and enzyme activity of PTEN are regulatedin a number of ways at the posttranslational level FirstPTEN is phosphorylated in its C-terminal tail at Ser380Thr382 Thr383 and Ser385 and this functions to inhibitthe critical PTEN phosphatase activity thereby promotinggrowth in prostate and kidney cells [88] However thesephosphorylations also stabilize the PTEN protein by dis-suading ubiquitination While this may seem like a cellulardisconnect this paradoxical phenomenon is explained by thefinding that this closed more stable PTEN conformation isprevented from associating with membranes and thereforeis geographically separated from its substrates [88] PTENcan also be activated by phosphorylation in particular theC2 domain of PTEN is phosphorylated at Ser229 andThr321by RHOA-associated protein kinase (ROCK) [89] a phos-phorylation that results in its association with membranesand phosphoinositide substrates affecting differentiation inleukocytes PTEN is further phosphorylated at Tyr336 by theTyr protein kinase RAK and this phosphorylation resultsin its stabilization [90] Loss of this activity has the effectof promoting breast cell proliferation and migration FinallyPTEN is also phosphorylated at Ser370 and Thr366 by CK2and GSK3120573 [91 92] respectively however the consequencesof this phosphorylation are unclear The likely extensivesignaling networks that regulate these widespread phospho-rylations in PTEN are not fully studied but the TGFBMP-SMADdevelopmental pathways are known to regulate PTENphosphorylation [93 94] Given the widespread applicationof SMAD signaling to developmental biology the presence ofSMAD-regulated PTEN phosphorylation is a critical aspectof developmental regulation in cells

PTEN enzymatic activity is also regulated posttrans-lationally by acetylation [70 95ndash97] PTEN is acetylatedat Lys125ndashLys128 by p300CREB-binding protein- (CBP-)associated factor (PCAF) and at Lys402 by CBP itself [95]Acetylation at these residues inhibits PTENrsquos function as aphosphatase and has been shown to promote the growthof prostate epithelial cells and glial cells [95] In additionthe deacetylase Sirtuin 1 (SIRT1) is involved in excludingPTEN from the nucleus and therefore preventing its newlycharacterized nuclear functions [96]

324 PTEN Regulation by Protein-Protein Interactions Theconformation stability and subcellular distribution of PTENis regulated by critical interactions with other proteins withincells and these proteins are known to be critical for properdevelopment of a number of organ systems The guanylatekinase inverted 2 (MAGI2) and 120573-arrestins cooperate toenhance PTEN activity [98 99] MAGI2 phosphorylatesPTEN on threonine residues at positions 382 and 383 ofPTENrsquos carboxy terminus allowing recruitment to cell-cell

8 Journal of Signal Transduction

junctions [98] Mutations to these residues prevent PTENrecruitment Upon recruitment 120573-arrestins modulate PTENactivity by direct binding to the C2 domain and modulatingits protein phosphatase activity including that at the levelof small GTPases including RhoAROCK [99] In addi-tion Myosin V regulates PTENrsquos movement to and fromthe plasma membrane and this function is required forPTEN to access its phosphoinositide substrates [100] andfor disrupting the proper regulation of neuronal cell sizeThe p85 regulatory subunit of the PI

3kinase enzyme itself

interacts with PTEN in a novel mechanism of repressing thePI3KndashAKT pathway [101] independent of PTENrsquos action as a

phosphatase It is therefore proposed that p85 regulates thePI3KndashAKT pathway bidirectionally both through its binding

to catalytic p110 subunit resulting in the generation of phos-phoinositides and by binding PTEN leading to repressionThis work proposes a novel signaling model for PTEN-p85association in which p85120572 preferentially binds and stabilizesp110 preferentially when p85120572 levels are low but excess p85120572binds to and positively regulates PTEN phosphatase activitywhen p110 is saturated Therefore sustained activation ofPI3K signaling and activated p110-p85 complexing is modu-lated homeostatically by this mechanism

A fascinating group of recent studies have utilizedproteomic library screens to identify further novel PTENinteracting proteins First the Na+H+ exchanger regulatoryfactor (NHERF) binds to and recruits PTEN to the platelet-derived growth factor receptor (PDGFR) This representsanother action that restricts PI

3KndashAKT pathway activation

independent of phosphatase activity [102] This has the effectof inhibiting PDGF-induced cytoskeletal rearrangements andchemotactic migration of developing neurons In additionthe mammalian disks large homologue 1 (DLG1) MAGI-2 and MAST205 proteins directly interact with PTENand enhance PTEN stability and activity [103] Furtherneuregulin 1 (NRG1) has been shown to interact with bothDLG1 and PTEN in a stable complex that has the effect ofregulating myelin sheath thickness in developing mouse sci-atic nerves [104] Additional but less-characterized protein-protein interactions that modulate PTEN function includethe PIP

3-dependent RAC exchanger factor 2a (PREX2a)

[105] shank-interacting protein-like 1 (SIPL1) [106] and 120572-mannosidase 2C1 (MAN2C1) [107]

325 PTEN-Controlled Signal Transduction during Develop-ment PTEN is critically important in regulating signalingpathways involved in cell growth and animal developmentThrough its well-characterized function as a phosphataseof PIP

3 PTEN modulates a network of mitogen-activated

signals transduced through PI3KndashAkt signaling This pri-

mary action of PTEN has tremendous impact on cell growthcell migration cell death and cell differentiationmdashcellularprocesses that are all hallmarks of proper growth andpatterning during development The active phosphorylatedPIP3activates several signaling molecules including the

phosphatidylinositol-dependent kinases (PDKs) followed byAkt S6 kinase and mTOR Beyond this AKTrsquos targetsinclude the apoptotic factor BAD activator and executioner

caspases glycogen synthase kinase-3 (GSK-3) MDM2 p21and p27 forkhead transcription factors (FOXOs) and nuclearreceptors including the androgen and estrogen receptors[108] Akt-mediated phosphorylation of these moleculescauses activation translocation and increased stability

The PTENPI3kinaseAKT signaling cascade crosstalks

to several key signal transduction pathways that are criticalto developmental biology This includes the abovementionedTGF-120573SMAD pathway and the Wnt120573-catenin pathway[109] The TGF-120573SMAD pathway is one of the most seminalpathways in developmental biology and PTEN modulatesTGF120573SMAD signaling by reversing Akt-mediated phospho-rylation of SMAD3 the critical signaling intermediate ofTGF120573SMAD signaling [110] Similarly the Wnt signalingpathway is indispensable for properly regulated developmentcellular proliferation and differentiation [111] PTEN regu-lates this pathway by reversing AKT kinase phosphorylationand inhibition of GSK-3120573 resulting in 120573-catenin nucleartranslocation and activation Finally recent studies demon-strate that PTEN regulates the expression and action of thehomeobox genes NKX31 and hepatic nuclear factor [112]proteins that are critical to organ development

326 PTEN-Regulated Stem Cell Activities The scientificliterature in the field of tissue stem or stem-like ldquoprogen-itorrdquo cells and their role in tissue development growthrecovery and repair has become beyond extensive in recentyears Expansion of stemprogenitor cells is a hallmark ofgrowth and patterning during development and regulationof these cells including their proliferation maintenanceand differentiation is a critical factor of developmentalregulation Because of this a review of the current liter-ature on PTENrsquos role in stem and tissue progenitor cellsis warranted in this review PTEN plays an important rolein regulating the homeostasis of stemprogenitor cells inmultiple tissues Interestingly PTEN regulates both self-renewal and proliferation but paradoxically it also playsa role in stem cell exhaustion For example the FOXOfamily of transcription factors controls stem cell proliferationand survival in hematopoietic stem cells [113] and PTENsignaling is a critical modulator of FOXO activity FOXO3A-deficient HSCs exhibit increased proliferation rate decreasedquiescence and a reduced ability to repopulate bone marrowafter transplantation into recipient mice Additionally thepreviously mentioned Wnt120573-catenin signaling pathway iscritical for HSC self-renewal and its activation is well knownto be modulated by PTEN Interestingly PTEN loss and AKTactivation in HSCs lead to a moderate increase in the levelof unphosphorylated 120573-catenin but this is not sufficient tomaintain Pten-null HSC self-renewal [114] Finally NOTCHsignaling plays a key role in regulating neural stem cellexpansion [115] and as stated previously NOTCH pathwayactivation leads to reduced PTEN expression in neural andhematopoietic stem cells

4 Conclusions

PTEN acts as the key endogenous negative modulatorof phosphoinositide signaling in mammalian cells and

Journal of Signal Transduction 9

therefore its role in normal cell homeostasis proliferationapoptosis and many additional components of cell biologyis extensive Because PTEN regulates cancer progressionmuch of what has been studied regarding PTEN relates totumorigenesis and tumor growth While this is warrantedbecause of the relevance of cancer to humanhealth PTENhassubstantial but underappreciated effects in normal tissue andorgan development immune system development and reg-ulation axonal regeneration glucose regulation and benigngrowth disorders PTEN is often dogmatically thought ofas a constitutive protein that exhibits lost activity duringdiseases butwhat is underappreciated is that PTENhas a verycomplex regulation network that involves signaling path-ways that regulate PTEN transcription transcript stabilityposttranslationalmodifications protein-protein interactionsand cellular location PTEN then in turn regulates numerousdevelopmental signaling networks that are critical to devel-opment and adult tissue maintenance

Abbreviations

Bcl2 B-cell lymphoma 2Bim BCL-2-interacting mediatorCK2 Casein Kinase 2CREB Cyclic AMP response element binding

proteinDLG Disks large homolog 1Egr-1 Early growth response protein 1Erk Extracellular regulated kinaseFOX Forkhead transcription factorsGSK3120573 Glycogen synthase kinase 3JNK Jun-terminal kinaseMAGI2 Membrane-associated guanylate kinase

inverted 2MAN2C1 Mannosidase alpha class 2C member 1MDM2 Mouse double minute 2 homologmTOR Mechanistic target of rapamycinNHERF Sodium-hydrogen antiporter 3

regulator 1NRG1 Neuregulin 1PCAF P300CBP-associated factorPDZ Postsynaptic density proteinmdashDisc

large tumor suppressormdashZonulaoccludens-1 protein

PIP3 Phosphoinositide triphosphatePPAR120574 Peroxisome proliferating antigen

receptorPREX2a Phosphatidylinositol-345-

trisphosphate-dependent Rac exchangefactor A

PTEN Phosphatase and Tensin homologueROCK Rho-associated coiled-coil-containing

protein kinaseSALL Spalt-like transcription factor-1SIPL1 Shank-interacting protein-like 1SIRT1 Sirtuin 1SMAD Small mothers against decapentaplegicSOCS Suppressor of cytokine signalingTGF120573 Transforming growth factor-beta

Disclosure

Travis J Jerde carried out the extensive literature reviewrequired to write this paper and have written the entirepaper The author has therefore read and approved the papersubmitted

Conflict of Interests

The author has no financial or nonfinancial conflict ofinterests with the submission of this paper

Acknowledgments

The author gratefully acknowledges the financial supportof the Indiana University School of Medicine Departmentof Pharmacology and Toxicology and the Melvin and BrynSimon Cancer Center The author also gratefully acknowl-edges this paper as part of his training made possible byNational Institutes of Health-NIDDK (DK092366-01A1)

References

[1] M Milella I Falcone F Conciatori et al ldquoPTEN multiplefunctions in human malignant tumorsrdquo Frontiers in Oncologyvol 5 article 24 2015

[2] J-O Lee H Yang M-M Georgescu et al ldquoCrystal structure ofthe PTEN tumor suppressor implications for its phosphoinosi-tide phosphatase activity and membrane associationrdquo Cell vol99 no 3 pp 323ndash334 1999

[3] W-L Yang G Jin C-F Li et al ldquoCycles of ubiquitinationand deubiquitination critically regulate growth factor-mediatedactivation of Akt signalingrdquo Science Signaling vol 6 no 257article ra3 2013

[4] J Gu S Nada M Okada and K Sekiguchi ldquoCsk regulatesintegrin-mediated signals involvement of differential activa-tion of ERK and Aktrdquo Biochemical and Biophysical ResearchCommunications vol 303 no 3 pp 973ndash977 2003

[5] A Clerk and P H Sugden ldquoActivation of protein kinase cas-cades in the heart by hypertrophic G protein-coupled receptoragonistsrdquoTheAmerican Journal of Cardiology vol 83 no 12 pp64Hndash69H 1999

[6] I Tonic W-N Yu Y Park C-C Chen and N Hay ldquoAktactivation emulates Chk1 inhibition and Bcl2 overexpressionand abrogates G2 cell cycle checkpoint by inhibiting BRCA1focirdquo The Journal of Biological Chemistry vol 285 no 31 pp23790ndash23798 2010

[7] S Fatrai L Elghazi N Balcazar et al ldquoAkt induces 120573-cellproliferation by regulating cyclin D1 cyclin D2 and p21 levelsand cyclin-dependent kinase-4 activityrdquo Diabetes vol 55 no 2pp 318ndash325 2006

[8] M Aoki E Blazek and P K Vogt ldquoA role of the kinase mTORin cellular transformation induced by the oncoproteins P3k andAktrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 98 no 1 pp 136ndash141 2001

[9] H Guan L Song J Cai et al ldquoSphingosine kinase 1 regulatesthe AktFOXO3aBim pathway and contributes to apoptosisresistance in glioma cellsrdquo PLoS ONE vol 6 no 5 Article IDe19946 2011

[10] T D Dung C H Day T V Binh et al ldquoPP2Amediates diosminp53 activation to block HA22T cell proliferation and tumor

10 Journal of Signal Transduction

growth in xenografted nude mice through PI3K-Akt-MDM2signaling suppressionrdquo Food and Chemical Toxicology vol 50no 5 pp 1802ndash1810 2012

[11] K Shanmugasundaram K Block B K Nayak C B Livi MA Venkatachalam and S Sudarshan ldquoPI3K regulation of theSKP-2p27 axis through mTORC2rdquo Oncogene vol 32 no 16pp 2027ndash2036 2013

[12] J-C Chang H-H Chang C-T Lin and S J Lo ldquoThe integrin12057261205731modulation of PI3K andCdc42 activities induces dynamicfilopodium formation in humanplateletsrdquo Journal of BiomedicalScience vol 12 no 6 pp 881ndash898 2005

[13] E Hajduch G J Litherland and H S Hundal ldquoProtein kinaseB (PKBAkt)mdasha key regulator of glucose transportrdquo FEBSLetters vol 492 no 3 pp 199ndash203 2001

[14] M M Martin J A Buckenberger J Jiang et al ldquoTGF-beta1stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[15] M M Martin J A Buckenberger J Jiang et al ldquoTGF-1205731stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[16] K Abell and C J Watson ldquoThe JakStat pathway a novel wayto regulate PI3K activityrdquo Cell Cycle vol 4 no 7 pp 897ndash9002005

[17] J-Y Hwang R S Duncan C Madry M Singh and P KoulenldquoProgesterone potentiates calcium release through IP3 recep-tors by an Akt-mediated mechanism in hippocampal neuronsrdquoCell Calcium vol 45 no 3 pp 233ndash242 2009

[18] G Pappas L A Zumstein A Munshi M Hobbs and R EMeyn ldquoAdenoviral-mediated PTEN expression radiosensitizesnon-small cell lung cancer cells by suppressing DNA repaircapacityrdquoCancer GeneTherapy vol 14 no 6 pp 543ndash549 2007

[19] A Di Cristofano B Pesce C Cordon-Cardo and P P PandolfildquoPten is essential for embryonic development and tumoursuppressionrdquo Nature Genetics vol 19 no 4 pp 348ndash355 1998

[20] J Bloomekatz J Grego-Bessa I Migeotte and K V AndersonldquoPten regulates collective cell migration during specification ofthe anterior-posterior axis of the mouse embryordquo Developmen-tal Biology vol 364 no 2 pp 192ndash201 2012

[21] S Ueno R Kono andY Iwao ldquoPTEN is required for the normalprogression of gastrulation by repressing cell proliferation afterMBT in Xenopus embryosrdquoDevelopmental Biology vol 297 no1 pp 274ndash283 2006

[22] C B Knobbe A Merlo and G Reifenberger ldquoPten signaling ingliomasrdquo Neuro Oncology vol 4 pp 196ndash211 2002

[23] E Kirches J Steiner T Schneider et al ldquoLhermitte-Duclosdisease caused by a novel germline PTEN mutation R173P in apatient presenting with psychosisrdquoNeuropathology and AppliedNeurobiology vol 36 no 1 pp 86ndash89 2010

[24] J-I Murata M Tada Y Sawamura K Mitsumori H Abe andK Nagashima ldquoDysplastic gangliocytoma (Lhermitte-Duclosdisease) associated with Cowden disease report of a case andreview of the literature for the genetic relationship between thetwo diseasesrdquo Journal of Neuro-Oncology vol 41 no 2 pp 129ndash136 1999

[25] G Zhu L M L Chow I T Bayazitov et al ldquoPten deletioncauses mTorc1-dependent ectopic neuroblast differentiation

without causing uniform migration defectsrdquo Development vol139 no 18 pp 3422ndash3431 2012

[26] K L McBride E A Varga M T Pastore et al ldquoConfirmationstudy of PTEN mutations among individuals with autism ordevelopmental delaysmental retardation and macrocephalyrdquoAutism Research vol 3 no 3 pp 137ndash141 2010

[27] J Zhou and L F Parada ldquoPTEN signaling in autism spectrumdisordersrdquo Current Opinion in Neurobiology vol 22 no 5 pp873ndash879 2012

[28] S A Backman V Stambolic A Suzuki et al ldquoDeletion of Ptenin mouse brain causes seizures ataxia and defects in soma sizeresembling Lhermitte-Duclos diseaserdquo Nature Genetics vol 29no 4 pp 396ndash403 2001

[29] L Cotter M Ozcelik C Jacob et al ldquoDlg1-PTEN interactionregulates myelin thickness to prevent damaging peripheralnerve overmyelinationrdquo Science vol 328 no 5984 pp 1415ndash1418 2010

[30] S Ogawa C-H Kwon J Zhou D Koovakkattu L F Paradaand C M Sinton ldquoA seizure-prone phenotype is associatedwith altered free-running rhythm in Pten mutant micerdquo BrainResearch vol 1168 no 1 pp 112ndash123 2007

[31] C-H Kwon X Zhu J Zhang and S J Baker ldquomTor isrequired for hypertrophy of Pten-deficient neuronal soma invivordquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 22 pp 12923ndash12928 2003

[32] C-H Kwon B W Luikart C M Powell et al ldquoPten regulatesneuronal arborization and social interaction in micerdquo Neuronvol 50 no 3 pp 377ndash388 2006

[33] A Suzuki S Itami M Ohishi et al ldquoKeratinocyte-specific Ptendeficiency results in epidermal hyperplasia accelerated hairfollicle morphogenesis and tumor formationrdquo Cancer Researchvol 63 no 3 pp 674ndash681 2003

[34] T Inoue-Narita K Hamada T Sasaki et al ldquoPten deficiency inmelanocytes results in resistance to hair graying and susceptibil-ity to carcinogen-induced melanomagenesisrdquo Cancer Researchvol 68 no 14 pp 5760ndash5768 2008

[35] R K Patel and C Mohan ldquoPI3KAKT signaling and systemicautoimmunityrdquo Immunologic Research vol 31 no 1 pp 47ndash552005

[36] K Podsypanina L H Ellenson A Nemes et al ldquoMutationof PtenMmac1 in mice causes neoplasia in multiple organsystemsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 4 pp 1563ndash1568 1999

[37] M Kashiwada P Lu and P B Rothman ldquoPIP3 pathway inregulatory T cells and autoimmunityrdquo Immunologic Researchvol 39 no 1ndash3 pp 194ndash224 2007

[38] A Suzuki M T Yamaguchi T Ohteki et al ldquoT cell-specificloss of Pten leads to defects in central and peripheral tolerancerdquoImmunity vol 14 no 5 pp 523ndash534 2001

[39] Y Yamanaka H Tagawa N Takahashi et al ldquoAberrant over-expression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lym-phomaleukemiardquo Blood vol 114 no 15 pp 3265ndash3275 2009

[40] H Kishimoto T Ohteki N Yajima et al ldquoThe PtenPI3Kpathway governs the homeostasis of V12057214iNKT cellsrdquo Bloodvol 109 no 8 pp 3316ndash3324 2007

[41] A Suzuki T Kaisho M Ohishi et al ldquoCritical roles ofPten in B cell homeostasis and immunoglobulin class switchrecombinationrdquo Journal of Experimental Medicine vol 197 no5 pp 657ndash667 2003

Journal of Signal Transduction 11

[42] M Nishio K-IWatanabe J Sasaki et al ldquoControl of cell polar-ity and motility by the PtdIns(345)P

3phosphatase SHIP1rdquo

Nature Cell Biology vol 9 no 1 pp 36ndash44 2007[43] S Kuroda M Nishio T Sasaki et al ldquoEffective clearance

of intracellular Leishmania major in vivo requires Pten inmacrophagesrdquo European Journal of Immunology vol 38 no 5pp 1331ndash1340 2008

[44] O H Yilmaz R Valdez B K Theisen et al ldquoPten depen-dence distinguishes haematopoietic stem cells from leukaemia-initiating cellsrdquo Nature vol 441 no 7092 pp 475ndash482 2006

[45] Y Li K Podsypanina X Liu et al ldquoDeficiency of Ptenaccelerates mammary oncogenesis in MMTV-Wnt-1 transgenicmicerdquo BMCMolecular Biology vol 2 article 2 2001

[46] P Reddy L Liu D Adhikari et al ldquoOocyte-specific deletion ofpten causes premature activation of the primordial follicle poolrdquoScience vol 319 no 5863 pp 611ndash613 2008

[47] H Tsuruta H Kishimoto T Sasaki et al ldquoHyperplasia andcarcinomas in Pten-deficient mice and reduced PTEN proteinin human bladder cancer patientsrdquoCancer Research vol 66 no17 pp 8389ndash8396 2006

[48] L I Yoo D W Liu S Le Vu R T Bronson H Wu and JYuan ldquoPten deficiency activates distinct downstream signalingpathways in a tissue-specific mannerrdquo Cancer Research vol 66no 4 pp 1929ndash1939 2006

[49] J Li C Yen D Liaw et al ldquoPTEN a putative protein tyrosinephosphatase gene mutated in human brain breast and prostatecancerrdquo Science vol 275 no 5308 pp 1943ndash1947 1997

[50] N D Deocampo H Huang and D J Tindall ldquoThe role ofPTEN in the progression and survival of prostate cancerrdquoMinerva Endocrinologica vol 28 no 2 pp 145ndash153 2003

[51] S A Backman D Ghazarian K So et al ldquoEarly onset ofneoplasia in the prostate and skin of mice with tissue-specificdeletion of Ptenrdquo Proceedings of the National Academy ofSciences of the United States of America vol 101 no 6 pp 1725ndash1730 2004

[52] X Wu K Xu L Zhang et al ldquoDifferentiation of the ductalepithelium and smooth muscle in the prostate gland areregulated by the NotchPTEN-dependent mechanismrdquo Devel-opmental Biology vol 356 no 2 pp 337ndash349 2011

[53] D Kim and G R Dressler ldquoPTEN modulates GDNFRETmediated chemotaxis and branching morphogenesis in thedeveloping kidneyrdquo Developmental Biology vol 307 no 2 pp290ndash299 2007

[54] N O Lindstrom M L Lawrence S F Burn et al ldquoIntegrated120573-catenin BMP PTEN and notch signalling patterns thenephronrdquo eLife no 4 Article ID e04000 2015

[55] V Marsh D J Winton G T Williams et al ldquoEpithelialPten is dispensable for intestinal homeostasis but suppressesadenoma development and progression after Apc mutationrdquoNature Genetics vol 40 no 12 pp 1436ndash1444 2008

[56] S Matsuda M Kobayashi and Y Kitagishi ldquoRoles forPI3KAKTPTEN pathway in cell signaling of nonalcoholicfatty liver diseaserdquo ISRN Endocrinology vol 2013 Article ID472432 7 pages 2013

[57] X Qi J Xu P Gu X Yang and X Gao ldquoPTEN in smoothmuscle cells is essential for colonic immune homeostasisrdquoInternational Journal of Biochemistry and Cell Biology vol 53pp 108ndash114 2014

[58] A Pal T M Barber M Van de Bunt et al ldquoPTENmutations asa cause of constitutive insulin sensitivity and obesityrdquoThe NewEngland Journal of Medicine vol 367 no 11 pp 1002ndash1011 2012

[59] B L Stiles C Kuralwalla-Martinez W Guo et al ldquoSelectivedeletion of Pten in pancreatic 120573 cells leads to increased isletmass and resistance to STZ-induced diabetesrdquo Molecular andCellular Biology vol 26 no 7 pp 2772ndash2781 2006

[60] LWang C T Luk E P Cai et al ldquoPTEN deletion in pancreatic120572-cells protects against high-fat diet-induced hyperglucagone-mia and insulin resistancerdquo Diabetes vol 64 no 1 pp 147ndash1572015

[61] C Kurlawalla-Martinez B Stiles Y Wang S U Devaskar BB Kahn and H Wu ldquoInsulin hypersensitivity and resistanceto streptozotocin-induced diabetes in mice lacking PTEN inadipose tissuerdquo Molecular and Cellular Biology vol 25 no 6pp 2498ndash2510 2005

[62] N Wijesekara D Konrad M Eweida et al ldquoMuscle-specificPten deletion protects against insulin resistance and diabetesrdquoMolecular and Cellular Biology vol 25 no 3 pp 1135ndash11452005

[63] K Hamada T Sasaki P A Koni et al ldquoThe PTENPI3Kpathway governs normal vascular development and tumorangiogenesisrdquo Genes and Development vol 19 no 17 pp 2054ndash2065 2005

[64] N D Roe X Xu M R Kandadi et al ldquoTargeted deletionof PTEN in cardiomyocytes renders cardiac contractile dys-function through interruption of Pink1-AMPK signaling andautophagyrdquo Biochimica et Biophysica Acta Molecular Basis ofDisease vol 1852 no 2 pp 290ndash298 2015

[65] A F Ford-Hutchinson Z Ali S E Lines B HallgrımssonS K Boyd and F R Jirik ldquoInactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnor-malities and skeletal overgrowthrdquo Journal of Bone and MineralResearch vol 22 no 8 pp 1245ndash1259 2007

[66] T A Burgers M F Hoffmann C J Collins et al ldquoMice lackingpten in osteoblasts have improved intramembranous and lateendochondral fracture healingrdquo PLoS ONE vol 8 no 5 ArticleID e63857 2013

[67] N R Leslie L Spinelli P Tibarewal et al ldquoIndirect mecha-nisms of carcinogenesis via downregulation of PTEN functionrdquoAdvances in Enzyme Regulation vol 50 no 1 pp 112ndash118 2010

[68] L He ldquoPosttranscriptional regulation of PTEN dosage bynoncoding RNAsrdquo Science Signaling vol 3 no 146 article pe392010

[69] F Vazquez S R Grossman Y Takahashi M V Rokas NNakamura andWR Sellers ldquoPhosphorylation of the PTEN tailacts as an inhibitory switch by preventing its recruitment into aprotein complexrdquo The Journal of Biological Chemistry vol 276no 52 pp 48627ndash48630 2001

[70] X Wang L C Trotman T Koppie et al ldquoNEDD4-1 is a proto-oncogenic ubiquitin ligase for PTENrdquo Cell vol 128 no 1 pp129ndash139 2007

[71] N R Leslie and M Foti ldquoNon-genomic loss of PTEN functionin cancer not in my genesrdquo Trends in Pharmacological Sciencesvol 32 no 3 pp 131ndash140 2011

[72] Y Xing C Li L Hu et al ldquoMechanisms of TGF120573 inhibition ofLUNG endodermal morphogenesis the role of T120573RII SmadsNkx21 and Ptenrdquo Developmental Biology vol 320 no 2 pp340ndash350 2008

[73] J P Luyendyk G A Schabbauer M Tencati T Holscher RPawlinski and N Mackman ldquoGenetic analysis of the role ofthe PI3K-Akt pathway in lipopolysaccharide-induced cytokineand tissue factor gene expression in monocytesmacrophagesrdquoJournal of Immunology vol 180 no 6 pp 4218ndash4226 2008

12 Journal of Signal Transduction

[74] F Sun K K Park S Belin et al ldquoSustained axon regenerationinduced by co-deletion of PTEN and SOCS3rdquo Nature vol 480no 7377 pp 372ndash375 2011

[75] C B Knobbe V Lapin A Suzuki and T W Mak ldquoThe roles ofPTEN in development physiology and tumorigenesis in mousemodels a tissue-by-tissue surveyrdquo Oncogene vol 27 no 41 pp5398ndash5415 2008

[76] S J Assinder Q Dong Z Kovacevic and D R RichardsonldquoThe TGF-beta PI3KAkt and PTEN pathways establishedand proposed biochemical integration in prostate cancerrdquoBiochemical Journal vol 417 no 2 pp 411ndash421 2009

[77] K A Waite and C Eng ldquoFrom developmental disorder toheritable cancer itrsquos all in the BMPTGF-120573 familyrdquo NatureReviews Genetics vol 4 no 10 pp 763ndash773 2003

[78] H B Newton ldquoMolecular neuro-oncology and developmentof targeted therapeutic strategies for brain tumors Part2 PI3KAktPTEN mTOR SHHPTCH and angiogenesisrdquoExpert Review of Anticancer Therapy vol 4 no 1 pp 105ndash1282004

[79] R H KimM Peters Y Jang et al ldquoDJ-1 a novel regulator of thetumor suppressor PTENrdquo Cancer Cell vol 7 no 3 pp 263ndash2732005

[80] J Lu H W Jeong N Kong et al ldquoStem cell factor SALL4represses the transcriptions of PTEN and SALL1 through anepigenetic repressor complexrdquo PLoS ONE vol 4 no 5 ArticleID e5577 2009

[81] M M A Rizvi M S Alam A Ali S J Mehdi S Batra andA KMandal ldquoAberrant promotermethylation and inactivationof PTEN gene in cervical carcinoma from Indian populationrdquoJournal of Cancer Research and Clinical Oncology vol 137 no 8pp 1255ndash1262 2011

[82] J Liu ldquoControl of protein synthesis and mRNA degradation bymicroRNAsrdquo Current Opinion in Cell Biology vol 20 no 2 pp214ndash221 2008

[83] S W Shan L Fang T Shatseva et al ldquoMature miR-17-5pand passenger miR-17-3p induce hepatocellular carcinoma bytargeting PTEN GalNT7 and vimentin in different signalpathwaysrdquo Journal of Cell Science vol 126 part 6 pp 1517ndash15302013

[84] Z Liang Y Li K Huang N Wagar and H Shim ldquoRegulationof miR-19 to breast cancer chemoresistance through targetingPTENrdquo Pharmaceutical Research vol 28 no 12 pp 3091ndash31002011

[85] X Lu Q Fan L Xu et al ldquoUrsolic acid attenuates diabeticmesangial cell injury through the up-regulation of autophagyvia miRNA-21PTENAktmTOR suppressionrdquo PLoS ONE vol10 no 2 Article ID e0117400 2015

[86] L Poliseno L Salmena J Zhang B Carver W J Havemanand P P Pandolfi ldquoA coding-independent function of geneand pseudogenemRNAs regulates tumour biologyrdquoNature vol465 no 7301 pp 1033ndash1038 2010

[87] Y Tay L Kats L Salmena et al ldquoCoding-independent regula-tion of the tumor suppressor PTEN by competing endogenousmRNAsrdquo Cell vol 147 no 2 pp 344ndash357 2011

[88] L Odriozola G Singh T Hoang and A M Chan ldquoRegula-tion of PTEN activity by its carboxyl-terminal autoinhibitorydomainrdquo The Journal of Biological Chemistry vol 282 no 32pp 23306ndash23315 2007

[89] Z Li X Dong Z Wang et al ldquoRegulation of PTEN by Rhosmall GTPasesrdquo Nature Cell Biology vol 7 no 4 pp 399ndash4042005

[90] E-K Yim G Peng H Dai et al ldquoRak functions as a tumorsuppressor by regulating PTEN protein stability and functionrdquoCancer Cell vol 15 no 4 pp 304ndash314 2009

[91] AMAl-Khouri YMa SH Togo SWilliams andTMustelinldquoCooperative phosphorylation of the tumor suppressor phos-phatase and tensin homologue (PTEN) by casein kinasesand glycogen synthase kinase 3120573rdquo The Journal of BiologicalChemistry vol 280 no 42 pp 35195ndash35202 2005

[92] H Maccario N M Perera L Davidson C P Downes and NR Leslie ldquoPTEN is destabilized by phosphorylation onThr366rdquoBiochemical Journal vol 405 no 3 pp 439ndash444 2007

[93] K A Waite and C Eng ldquoBMP2 exposure results in decreasedPTEN protein degradation and increased PTEN levelsrdquoHumanMolecular Genetics vol 12 no 6 pp 679ndash684 2003

[94] T J Jerde Z Wu D Theodorescu and W Bushman ldquoRegu-lation of phosphatase homologue of tensin protein expressionby bone morphogenetic proteins in prostate epithelial cellsrdquoProstate vol 71 no 8 pp 791ndash800 2011

[95] G Singh and A M Chan ldquoPost-translational modificationsof PTEN and their potential therapeutic implicationsrdquo CurrentCancer Drug Targets vol 11 no 5 pp 536ndash547 2011

[96] T Ikenoue K Inoki B Zhao and K-L Guan ldquoPTEN acety-lation modulates its interaction with PDZ domainrdquo CancerResearch vol 68 no 17 pp 6908ndash6912 2008

[97] L C Trotman X Wang A Alimonti et al ldquoUbiquitinationregulates PTEN nuclear import and tumor suppressionrdquo Cellvol 128 no 1 pp 141ndash156 2007

[98] T Tolkacheva M Boddapati A Sanfiz K Tsuchida A CKimmelman and AM-L Chan ldquoRegulation of PTEN bindingto MAGI-2 by two putative phosphorylation sites at threonine382 and 383rdquo Cancer Research vol 61 no 13 pp 4985ndash49892001

[99] E Lima-Fernandes H Enslen E Camand et al ldquoDistinct func-tional outputs of PTEN signalling are controlled by dynamicassociation with 120573-arrestinsrdquoThe EMBO Journal vol 30 no 13pp 2557ndash2568 2011

[100] M T van Diepen M Parsons C P Downes N R Leslie RHindges and B J Eickholt ldquoMyosinV controls PTEN functionand neuronal cell sizerdquo Nature Cell Biology vol 11 no 10 pp1191ndash1196 2009

[101] R B Chagpar P H Links M C Pastor et al ldquoDirect positiveregulation of PTEN by the p85 subunit of phosphatidylinositol3-kinaserdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 107 no 12 pp 5471ndash5476 2010

[102] Y Takahashi F C Morales E L Kreimann and M-MGeorgescu ldquoPTEN tumor suppressor associates with NHERFproteins to attenuate PDGF receptor signalingrdquo The EMBOJournal vol 25 no 4 pp 910ndash920 2006

[103] M Valiente A Andres-Pons B Gomar et al ldquoBinding ofPTEN to specific PDZ domains contributes to PTEN proteinstability and phosphorylation by microtubule-associated ser-inethreonine kinasesrdquoThe Journal of Biological Chemistry vol280 no 32 pp 28936ndash28943 2005

[104] SQuintes SGoebbels G SaherMH Schwab andK-ANaveldquoNeuron-glia signaling and the protection of axon function bySchwann cellsrdquo Journal of the Peripheral Nervous System vol 15no 1 pp 10ndash16 2010

[105] B Fine C Hodakoski S Koujak et al ldquoActivation of the PI3Kpathway in cancer through inhibition of PTEN by exchangefactor P-REX2ardquo Science vol 325 no 5945 pp 1261ndash1265 2009

Journal of Signal Transduction 13

[106] L He A Ingram A P Rybak and D Tang ldquoShank-interactingprotein-like 1 promotes tumorigenesis via PTEN inhibition inhuman tumor cellsrdquo The Journal of Clinical Investigation vol120 no 6 pp 2094ndash2108 2010

[107] L He C Fan A Kapoor et al ldquo120572-Mannosidase 2C1 attenuatesPTEN function in prostate cancer cellsrdquo Nature Communica-tions vol 2 no 1 article 307 2011

[108] Z Radisavljevic ldquoAKT as locus of cancer positive feedbackloops and extreme robustnessrdquo Journal of Cellular Physiologyvol 228 no 3 pp 522ndash524 2013

[109] M Y Lee HW Lim S H Lee andH J Han ldquoSmad PI3KAktand wnt-dependent signaling pathways are involved in BMP-4-induced ESC self-renewalrdquo Stem Cells vol 27 no 8 pp 1858ndash1868 2009

[110] K Song S C Cornelius M Reiss and D Danielpour ldquoInsulin-like growth factor-I inhibits transcriptional responses of trans-forming growth factor-120573 by phosphatidylinositol 3-kinaseAkt-dependent suppression of the activation of Smad3 but notSmad2rdquoThe Journal of Biological Chemistry vol 278 no 40 pp38342ndash38351 2003

[111] D Fang D Hawke Y Zheng et al ldquoPhosphorylation of 120573-catenin by AKT promotes 120573-catenin transcriptional activityrdquoThe Journal of Biological Chemistry vol 282 no 15 pp 11221ndash11229 2007

[112] Q Lei J Jiao L Xin et al ldquoNKX31 stabilizes p53 inhibitsAKT activation and blocks prostate cancer initiation caused byPTEN lossrdquo Cancer Cell vol 9 no 5 pp 367ndash378 2006

[113] A Sengupta J D Molkentin J-H Paik R A DePinho and KE Yutzey ldquoFoxO transcription factors promote cardiomyocytesurvival upon induction of oxidative stressrdquo The Journal ofBiological Chemistry vol 286 no 9 pp 7468ndash7478 2011

[114] C H M Jamieson L E Ailles S J Dylla et al ldquoGranulocyte-macrophage progenitors as candidate leukemic stem cells inblast-crisis CMLrdquoTheNewEngland Journal ofMedicine vol 351no 7 pp 657ndash667 2004

[115] A Androutsellis-Theotokis R R Leker F Soldner et al ldquoNotchsignalling regulates stem cell numbers in vitro and in vivordquoNature vol 442 no 7104 pp 823ndash826 2006

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Signal TransductionJournal of

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Microbiology

Page 6: Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling TravisJ.Jerde Department of Pharmacology

6 Journal of Signal Transduction

BMP Hh JagdeltaNOTCH

NICD

miRNA(17 19 21)

GF

PTEN mRNA

PTEN mRNA

PTENNICD

SMAD2 3

SMAD1 5 8 Gli2

AP -1

NICDAP -1

SMO

SMAD2 3

SMAD1 5 8 Gli2

SALL4

Cyt

p65p50

p65p50

ceRNAAkt

GSK3CK2

PCAF

SIRT1

PIP3 PIP2

PI3 kinase

TGF120573

Figure 3 Summary of regulation mechanisms for PTEN critical for its action in developmental biology PTEN transcription is regulatedby TGF120573 BMP Hh NOTCH and cytokine signaling in cells during development miRNAs and ceRNAs regulate PTEN message stabilityPhosphorylation or acetylation by then can regulate PTENrsquos protein stability enzymatic activity and cellular localization in a positive ornegative manner All told the regulation of PTEN is complex and precise during development and perturbations in this paradigm haveprofound effects

There is no question that mutations of PTEN play a criticalrole in this regard Studies over the last decade howeverhave discovered a tremendous diversity in the regulationof PTEN expression and found that PTEN is tightly con-trolled both transcriptionally and posttranscriptionally [67]Recent studies to date have implicated microRNAs in PTENsuppression [68] and the enzymatic phosphatase activityof PTEN is also regulated posttranslationally via phospho-rylation ubiquitination or oxidation [69 70] This sectionhighlights the multifaceted mechanisms of PTEN regulationsupported by the rapidly expanding literature on PTENrsquos rolein growth and patterning of tissues during development Inaddition special emphasis is given tomediators and pathwaysinvolved in development including insulin-like growth factortransforming growth factor bone morphogenetic proteinsNOTCH forkhead transcription factors (Fox) and othersPTENrsquos complex regulation at the levels of transcriptionmRNA stability posttranslational modifications andmiRNAlevels has become a critical series of mechanisms deserving acomprehensive review (for an overview see Figure 3)

32 Developmental Signaling Regulating PTEN Expressionand Action The regulation of PTEN expression occurs attranscriptional posttranscriptional posttranslational andprotein-protein interaction levels [71] PTENrsquos function isfurther controlled by its cellular location In this sectionwe highlight developmental pathways involved in regulating

PTEN expression at all these regulation points and makespecial reference to connections between signal transductionand development

321 Developmental Pathways in PTEN Gene ExpressionOne critical aspect of PTENrsquos regulation during developmentbegins at the transcriptional level To date PTEN expres-sion has been found to be regulated at the transcriptionallevel by pathways involving p53 PPAR120574 Egr-1 NF-120581Band SMADs and this regulation affects the developmentof proper immune function the vasculature the nervoussystem the gastrointestinal system and the airways [6372 73] While PTEN is constitutively expressed in manynormal adult tissues PTEN expression is altered dramat-ically through the course of development and in patho-logical settings and a primary source of this regulationcomes from bona fide developmental regulators In additionsuppressors of cytokine signaling (SOCS) and SNAIL alsoinduce PTEN and act by countering the growth-promotingactions of cytokines and growth factors in developmentand repair and recovery [74] This mechanism has beenclearly demonstrated in axonal outgrowth during neurondevelopment and regeneration [74] While the physiologicalramifications of this regulation remain unsolved mediatorsthat slow or inhibit cell proliferation are often involved ininducing this protein Developmental mediators includingNOTCH transforming growth factor beta (TGF120573) bone

Journal of Signal Transduction 7

morphogenetic proteins (BMPs) and hedgehogs (Hhs) allparticipate as players in external PTEN regulation [75ndash78] regulating such processes as proliferation and targetedepithelial budding and outgrowth of visceral organs [76 77]and outgrowth in neurons [75] As the direction of cell growthand differentiation balances on the fulcrum between theproliferative and differentiating actions of these mediatorstheir regulation to induce or repress PTEN expression isa critical aspect of their actions during development Thecritical developmental mediator TGF120573 contains both growthpromoting and inhibiting differentiation qualities and TGF120573induces PTEN during differentiation when growth is slowedand inhibits its expression during proliferation In additionthe developmental regulator DJ-1 was recently identified asa novel negative regulator of PTEN by a genetic screen inDrosophila [79] PTEN is also regulated through epigeneticsilencing by methylation of the PTEN promoter [80 81] Aninteresting zinc-finger transcription factor sal-like protein 4(SALL4) has been discovered as a critical negative regulatorof PTEN transcription by recruiting an epigenetic repressorcomplex involving anATPase and a histone deacetylase to thePTENpromoter [80] SALL4 plays a critical role in regulatingdevelopment by modulating self-renewal in stem cells andits function appears to at least partly involve methylation ofthe PTENpromoter andmodulation of its transcriptionDataon this mechanism are still limited but to date this processhas been shown to regulate kidney patterning during devel-opment as well as leukemogenesis [80] Current research inthe area of PTEN transcriptional regulation continues to bedynamic and more novel regulation patterns are likely to bediscovered in the near future

322 PTEN Regulation by Posttranscriptional RegulationRecent studies have identified several interesting develop-mentally expressed miRNAs that regulate PTEN mRNAmessage stability and translatability [82] These miRNAstypically downregulate PTEN mRNA levels by targeting itfor degradation and include miR-17 miR-19 and miR-21 [83ndash85] While several examples of miR-17 and miR-19-mediatedPTENRNA levels have been reported in the cancer literaturemiR-21 has been described to play a critical role in repairand recovery a developmental signaling-related processmiRNAs regulate this mechanism by modulating PTENRNA stability and ultimately downstream Akt signaling Forexample in the pancreas miR-21 regulates injury repair indiabetic models by targeting PTEN RNA for degradationInhibition of miR-21 results in autophagy in this model ina manner dependent on PTEN degradation [85] In anotherexample of novel miR-related PTEN regulation the PTENpseudogene 1 (PTENP1) acts as a decoy for PTEN-targetingmiRNAs and thereby regulates PTEN expression by coding-independent activity through sequestering these miRNAsand effectively inhibiting their effects on PTEN expression[86] Additionally combined bioinformatic and experimentalapproaches have identified ceRNA transcripts that controlPTEN expression by sequestering PTEN-targeting miRNAsduring development of both prostate and skin [87] Becausethis type of PTEN regulation and indeed this field of generegulation in general is in its infancy we are only beginning

to understand the PTEN regulation by coding and noncodingceRNAs Still this novel work provides a platform for furtherstudies investigating posttranscriptional regulation patternsof PTEN expression in both developmental biology anddisease conditions

323 PTENRegulation by PosttranslationalMechanisms Theprotein stability and enzyme activity of PTEN are regulatedin a number of ways at the posttranslational level FirstPTEN is phosphorylated in its C-terminal tail at Ser380Thr382 Thr383 and Ser385 and this functions to inhibitthe critical PTEN phosphatase activity thereby promotinggrowth in prostate and kidney cells [88] However thesephosphorylations also stabilize the PTEN protein by dis-suading ubiquitination While this may seem like a cellulardisconnect this paradoxical phenomenon is explained by thefinding that this closed more stable PTEN conformation isprevented from associating with membranes and thereforeis geographically separated from its substrates [88] PTENcan also be activated by phosphorylation in particular theC2 domain of PTEN is phosphorylated at Ser229 andThr321by RHOA-associated protein kinase (ROCK) [89] a phos-phorylation that results in its association with membranesand phosphoinositide substrates affecting differentiation inleukocytes PTEN is further phosphorylated at Tyr336 by theTyr protein kinase RAK and this phosphorylation resultsin its stabilization [90] Loss of this activity has the effectof promoting breast cell proliferation and migration FinallyPTEN is also phosphorylated at Ser370 and Thr366 by CK2and GSK3120573 [91 92] respectively however the consequencesof this phosphorylation are unclear The likely extensivesignaling networks that regulate these widespread phospho-rylations in PTEN are not fully studied but the TGFBMP-SMADdevelopmental pathways are known to regulate PTENphosphorylation [93 94] Given the widespread applicationof SMAD signaling to developmental biology the presence ofSMAD-regulated PTEN phosphorylation is a critical aspectof developmental regulation in cells

PTEN enzymatic activity is also regulated posttrans-lationally by acetylation [70 95ndash97] PTEN is acetylatedat Lys125ndashLys128 by p300CREB-binding protein- (CBP-)associated factor (PCAF) and at Lys402 by CBP itself [95]Acetylation at these residues inhibits PTENrsquos function as aphosphatase and has been shown to promote the growthof prostate epithelial cells and glial cells [95] In additionthe deacetylase Sirtuin 1 (SIRT1) is involved in excludingPTEN from the nucleus and therefore preventing its newlycharacterized nuclear functions [96]

324 PTEN Regulation by Protein-Protein Interactions Theconformation stability and subcellular distribution of PTENis regulated by critical interactions with other proteins withincells and these proteins are known to be critical for properdevelopment of a number of organ systems The guanylatekinase inverted 2 (MAGI2) and 120573-arrestins cooperate toenhance PTEN activity [98 99] MAGI2 phosphorylatesPTEN on threonine residues at positions 382 and 383 ofPTENrsquos carboxy terminus allowing recruitment to cell-cell

8 Journal of Signal Transduction

junctions [98] Mutations to these residues prevent PTENrecruitment Upon recruitment 120573-arrestins modulate PTENactivity by direct binding to the C2 domain and modulatingits protein phosphatase activity including that at the levelof small GTPases including RhoAROCK [99] In addi-tion Myosin V regulates PTENrsquos movement to and fromthe plasma membrane and this function is required forPTEN to access its phosphoinositide substrates [100] andfor disrupting the proper regulation of neuronal cell sizeThe p85 regulatory subunit of the PI

3kinase enzyme itself

interacts with PTEN in a novel mechanism of repressing thePI3KndashAKT pathway [101] independent of PTENrsquos action as a

phosphatase It is therefore proposed that p85 regulates thePI3KndashAKT pathway bidirectionally both through its binding

to catalytic p110 subunit resulting in the generation of phos-phoinositides and by binding PTEN leading to repressionThis work proposes a novel signaling model for PTEN-p85association in which p85120572 preferentially binds and stabilizesp110 preferentially when p85120572 levels are low but excess p85120572binds to and positively regulates PTEN phosphatase activitywhen p110 is saturated Therefore sustained activation ofPI3K signaling and activated p110-p85 complexing is modu-lated homeostatically by this mechanism

A fascinating group of recent studies have utilizedproteomic library screens to identify further novel PTENinteracting proteins First the Na+H+ exchanger regulatoryfactor (NHERF) binds to and recruits PTEN to the platelet-derived growth factor receptor (PDGFR) This representsanother action that restricts PI

3KndashAKT pathway activation

independent of phosphatase activity [102] This has the effectof inhibiting PDGF-induced cytoskeletal rearrangements andchemotactic migration of developing neurons In additionthe mammalian disks large homologue 1 (DLG1) MAGI-2 and MAST205 proteins directly interact with PTENand enhance PTEN stability and activity [103] Furtherneuregulin 1 (NRG1) has been shown to interact with bothDLG1 and PTEN in a stable complex that has the effect ofregulating myelin sheath thickness in developing mouse sci-atic nerves [104] Additional but less-characterized protein-protein interactions that modulate PTEN function includethe PIP

3-dependent RAC exchanger factor 2a (PREX2a)

[105] shank-interacting protein-like 1 (SIPL1) [106] and 120572-mannosidase 2C1 (MAN2C1) [107]

325 PTEN-Controlled Signal Transduction during Develop-ment PTEN is critically important in regulating signalingpathways involved in cell growth and animal developmentThrough its well-characterized function as a phosphataseof PIP

3 PTEN modulates a network of mitogen-activated

signals transduced through PI3KndashAkt signaling This pri-

mary action of PTEN has tremendous impact on cell growthcell migration cell death and cell differentiationmdashcellularprocesses that are all hallmarks of proper growth andpatterning during development The active phosphorylatedPIP3activates several signaling molecules including the

phosphatidylinositol-dependent kinases (PDKs) followed byAkt S6 kinase and mTOR Beyond this AKTrsquos targetsinclude the apoptotic factor BAD activator and executioner

caspases glycogen synthase kinase-3 (GSK-3) MDM2 p21and p27 forkhead transcription factors (FOXOs) and nuclearreceptors including the androgen and estrogen receptors[108] Akt-mediated phosphorylation of these moleculescauses activation translocation and increased stability

The PTENPI3kinaseAKT signaling cascade crosstalks

to several key signal transduction pathways that are criticalto developmental biology This includes the abovementionedTGF-120573SMAD pathway and the Wnt120573-catenin pathway[109] The TGF-120573SMAD pathway is one of the most seminalpathways in developmental biology and PTEN modulatesTGF120573SMAD signaling by reversing Akt-mediated phospho-rylation of SMAD3 the critical signaling intermediate ofTGF120573SMAD signaling [110] Similarly the Wnt signalingpathway is indispensable for properly regulated developmentcellular proliferation and differentiation [111] PTEN regu-lates this pathway by reversing AKT kinase phosphorylationand inhibition of GSK-3120573 resulting in 120573-catenin nucleartranslocation and activation Finally recent studies demon-strate that PTEN regulates the expression and action of thehomeobox genes NKX31 and hepatic nuclear factor [112]proteins that are critical to organ development

326 PTEN-Regulated Stem Cell Activities The scientificliterature in the field of tissue stem or stem-like ldquoprogen-itorrdquo cells and their role in tissue development growthrecovery and repair has become beyond extensive in recentyears Expansion of stemprogenitor cells is a hallmark ofgrowth and patterning during development and regulationof these cells including their proliferation maintenanceand differentiation is a critical factor of developmentalregulation Because of this a review of the current liter-ature on PTENrsquos role in stem and tissue progenitor cellsis warranted in this review PTEN plays an important rolein regulating the homeostasis of stemprogenitor cells inmultiple tissues Interestingly PTEN regulates both self-renewal and proliferation but paradoxically it also playsa role in stem cell exhaustion For example the FOXOfamily of transcription factors controls stem cell proliferationand survival in hematopoietic stem cells [113] and PTENsignaling is a critical modulator of FOXO activity FOXO3A-deficient HSCs exhibit increased proliferation rate decreasedquiescence and a reduced ability to repopulate bone marrowafter transplantation into recipient mice Additionally thepreviously mentioned Wnt120573-catenin signaling pathway iscritical for HSC self-renewal and its activation is well knownto be modulated by PTEN Interestingly PTEN loss and AKTactivation in HSCs lead to a moderate increase in the levelof unphosphorylated 120573-catenin but this is not sufficient tomaintain Pten-null HSC self-renewal [114] Finally NOTCHsignaling plays a key role in regulating neural stem cellexpansion [115] and as stated previously NOTCH pathwayactivation leads to reduced PTEN expression in neural andhematopoietic stem cells

4 Conclusions

PTEN acts as the key endogenous negative modulatorof phosphoinositide signaling in mammalian cells and

Journal of Signal Transduction 9

therefore its role in normal cell homeostasis proliferationapoptosis and many additional components of cell biologyis extensive Because PTEN regulates cancer progressionmuch of what has been studied regarding PTEN relates totumorigenesis and tumor growth While this is warrantedbecause of the relevance of cancer to humanhealth PTENhassubstantial but underappreciated effects in normal tissue andorgan development immune system development and reg-ulation axonal regeneration glucose regulation and benigngrowth disorders PTEN is often dogmatically thought ofas a constitutive protein that exhibits lost activity duringdiseases butwhat is underappreciated is that PTENhas a verycomplex regulation network that involves signaling path-ways that regulate PTEN transcription transcript stabilityposttranslationalmodifications protein-protein interactionsand cellular location PTEN then in turn regulates numerousdevelopmental signaling networks that are critical to devel-opment and adult tissue maintenance

Abbreviations

Bcl2 B-cell lymphoma 2Bim BCL-2-interacting mediatorCK2 Casein Kinase 2CREB Cyclic AMP response element binding

proteinDLG Disks large homolog 1Egr-1 Early growth response protein 1Erk Extracellular regulated kinaseFOX Forkhead transcription factorsGSK3120573 Glycogen synthase kinase 3JNK Jun-terminal kinaseMAGI2 Membrane-associated guanylate kinase

inverted 2MAN2C1 Mannosidase alpha class 2C member 1MDM2 Mouse double minute 2 homologmTOR Mechanistic target of rapamycinNHERF Sodium-hydrogen antiporter 3

regulator 1NRG1 Neuregulin 1PCAF P300CBP-associated factorPDZ Postsynaptic density proteinmdashDisc

large tumor suppressormdashZonulaoccludens-1 protein

PIP3 Phosphoinositide triphosphatePPAR120574 Peroxisome proliferating antigen

receptorPREX2a Phosphatidylinositol-345-

trisphosphate-dependent Rac exchangefactor A

PTEN Phosphatase and Tensin homologueROCK Rho-associated coiled-coil-containing

protein kinaseSALL Spalt-like transcription factor-1SIPL1 Shank-interacting protein-like 1SIRT1 Sirtuin 1SMAD Small mothers against decapentaplegicSOCS Suppressor of cytokine signalingTGF120573 Transforming growth factor-beta

Disclosure

Travis J Jerde carried out the extensive literature reviewrequired to write this paper and have written the entirepaper The author has therefore read and approved the papersubmitted

Conflict of Interests

The author has no financial or nonfinancial conflict ofinterests with the submission of this paper

Acknowledgments

The author gratefully acknowledges the financial supportof the Indiana University School of Medicine Departmentof Pharmacology and Toxicology and the Melvin and BrynSimon Cancer Center The author also gratefully acknowl-edges this paper as part of his training made possible byNational Institutes of Health-NIDDK (DK092366-01A1)

References

[1] M Milella I Falcone F Conciatori et al ldquoPTEN multiplefunctions in human malignant tumorsrdquo Frontiers in Oncologyvol 5 article 24 2015

[2] J-O Lee H Yang M-M Georgescu et al ldquoCrystal structure ofthe PTEN tumor suppressor implications for its phosphoinosi-tide phosphatase activity and membrane associationrdquo Cell vol99 no 3 pp 323ndash334 1999

[3] W-L Yang G Jin C-F Li et al ldquoCycles of ubiquitinationand deubiquitination critically regulate growth factor-mediatedactivation of Akt signalingrdquo Science Signaling vol 6 no 257article ra3 2013

[4] J Gu S Nada M Okada and K Sekiguchi ldquoCsk regulatesintegrin-mediated signals involvement of differential activa-tion of ERK and Aktrdquo Biochemical and Biophysical ResearchCommunications vol 303 no 3 pp 973ndash977 2003

[5] A Clerk and P H Sugden ldquoActivation of protein kinase cas-cades in the heart by hypertrophic G protein-coupled receptoragonistsrdquoTheAmerican Journal of Cardiology vol 83 no 12 pp64Hndash69H 1999

[6] I Tonic W-N Yu Y Park C-C Chen and N Hay ldquoAktactivation emulates Chk1 inhibition and Bcl2 overexpressionand abrogates G2 cell cycle checkpoint by inhibiting BRCA1focirdquo The Journal of Biological Chemistry vol 285 no 31 pp23790ndash23798 2010

[7] S Fatrai L Elghazi N Balcazar et al ldquoAkt induces 120573-cellproliferation by regulating cyclin D1 cyclin D2 and p21 levelsand cyclin-dependent kinase-4 activityrdquo Diabetes vol 55 no 2pp 318ndash325 2006

[8] M Aoki E Blazek and P K Vogt ldquoA role of the kinase mTORin cellular transformation induced by the oncoproteins P3k andAktrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 98 no 1 pp 136ndash141 2001

[9] H Guan L Song J Cai et al ldquoSphingosine kinase 1 regulatesthe AktFOXO3aBim pathway and contributes to apoptosisresistance in glioma cellsrdquo PLoS ONE vol 6 no 5 Article IDe19946 2011

[10] T D Dung C H Day T V Binh et al ldquoPP2Amediates diosminp53 activation to block HA22T cell proliferation and tumor

10 Journal of Signal Transduction

growth in xenografted nude mice through PI3K-Akt-MDM2signaling suppressionrdquo Food and Chemical Toxicology vol 50no 5 pp 1802ndash1810 2012

[11] K Shanmugasundaram K Block B K Nayak C B Livi MA Venkatachalam and S Sudarshan ldquoPI3K regulation of theSKP-2p27 axis through mTORC2rdquo Oncogene vol 32 no 16pp 2027ndash2036 2013

[12] J-C Chang H-H Chang C-T Lin and S J Lo ldquoThe integrin12057261205731modulation of PI3K andCdc42 activities induces dynamicfilopodium formation in humanplateletsrdquo Journal of BiomedicalScience vol 12 no 6 pp 881ndash898 2005

[13] E Hajduch G J Litherland and H S Hundal ldquoProtein kinaseB (PKBAkt)mdasha key regulator of glucose transportrdquo FEBSLetters vol 492 no 3 pp 199ndash203 2001

[14] M M Martin J A Buckenberger J Jiang et al ldquoTGF-beta1stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[15] M M Martin J A Buckenberger J Jiang et al ldquoTGF-1205731stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[16] K Abell and C J Watson ldquoThe JakStat pathway a novel wayto regulate PI3K activityrdquo Cell Cycle vol 4 no 7 pp 897ndash9002005

[17] J-Y Hwang R S Duncan C Madry M Singh and P KoulenldquoProgesterone potentiates calcium release through IP3 recep-tors by an Akt-mediated mechanism in hippocampal neuronsrdquoCell Calcium vol 45 no 3 pp 233ndash242 2009

[18] G Pappas L A Zumstein A Munshi M Hobbs and R EMeyn ldquoAdenoviral-mediated PTEN expression radiosensitizesnon-small cell lung cancer cells by suppressing DNA repaircapacityrdquoCancer GeneTherapy vol 14 no 6 pp 543ndash549 2007

[19] A Di Cristofano B Pesce C Cordon-Cardo and P P PandolfildquoPten is essential for embryonic development and tumoursuppressionrdquo Nature Genetics vol 19 no 4 pp 348ndash355 1998

[20] J Bloomekatz J Grego-Bessa I Migeotte and K V AndersonldquoPten regulates collective cell migration during specification ofthe anterior-posterior axis of the mouse embryordquo Developmen-tal Biology vol 364 no 2 pp 192ndash201 2012

[21] S Ueno R Kono andY Iwao ldquoPTEN is required for the normalprogression of gastrulation by repressing cell proliferation afterMBT in Xenopus embryosrdquoDevelopmental Biology vol 297 no1 pp 274ndash283 2006

[22] C B Knobbe A Merlo and G Reifenberger ldquoPten signaling ingliomasrdquo Neuro Oncology vol 4 pp 196ndash211 2002

[23] E Kirches J Steiner T Schneider et al ldquoLhermitte-Duclosdisease caused by a novel germline PTEN mutation R173P in apatient presenting with psychosisrdquoNeuropathology and AppliedNeurobiology vol 36 no 1 pp 86ndash89 2010

[24] J-I Murata M Tada Y Sawamura K Mitsumori H Abe andK Nagashima ldquoDysplastic gangliocytoma (Lhermitte-Duclosdisease) associated with Cowden disease report of a case andreview of the literature for the genetic relationship between thetwo diseasesrdquo Journal of Neuro-Oncology vol 41 no 2 pp 129ndash136 1999

[25] G Zhu L M L Chow I T Bayazitov et al ldquoPten deletioncauses mTorc1-dependent ectopic neuroblast differentiation

without causing uniform migration defectsrdquo Development vol139 no 18 pp 3422ndash3431 2012

[26] K L McBride E A Varga M T Pastore et al ldquoConfirmationstudy of PTEN mutations among individuals with autism ordevelopmental delaysmental retardation and macrocephalyrdquoAutism Research vol 3 no 3 pp 137ndash141 2010

[27] J Zhou and L F Parada ldquoPTEN signaling in autism spectrumdisordersrdquo Current Opinion in Neurobiology vol 22 no 5 pp873ndash879 2012

[28] S A Backman V Stambolic A Suzuki et al ldquoDeletion of Ptenin mouse brain causes seizures ataxia and defects in soma sizeresembling Lhermitte-Duclos diseaserdquo Nature Genetics vol 29no 4 pp 396ndash403 2001

[29] L Cotter M Ozcelik C Jacob et al ldquoDlg1-PTEN interactionregulates myelin thickness to prevent damaging peripheralnerve overmyelinationrdquo Science vol 328 no 5984 pp 1415ndash1418 2010

[30] S Ogawa C-H Kwon J Zhou D Koovakkattu L F Paradaand C M Sinton ldquoA seizure-prone phenotype is associatedwith altered free-running rhythm in Pten mutant micerdquo BrainResearch vol 1168 no 1 pp 112ndash123 2007

[31] C-H Kwon X Zhu J Zhang and S J Baker ldquomTor isrequired for hypertrophy of Pten-deficient neuronal soma invivordquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 22 pp 12923ndash12928 2003

[32] C-H Kwon B W Luikart C M Powell et al ldquoPten regulatesneuronal arborization and social interaction in micerdquo Neuronvol 50 no 3 pp 377ndash388 2006

[33] A Suzuki S Itami M Ohishi et al ldquoKeratinocyte-specific Ptendeficiency results in epidermal hyperplasia accelerated hairfollicle morphogenesis and tumor formationrdquo Cancer Researchvol 63 no 3 pp 674ndash681 2003

[34] T Inoue-Narita K Hamada T Sasaki et al ldquoPten deficiency inmelanocytes results in resistance to hair graying and susceptibil-ity to carcinogen-induced melanomagenesisrdquo Cancer Researchvol 68 no 14 pp 5760ndash5768 2008

[35] R K Patel and C Mohan ldquoPI3KAKT signaling and systemicautoimmunityrdquo Immunologic Research vol 31 no 1 pp 47ndash552005

[36] K Podsypanina L H Ellenson A Nemes et al ldquoMutationof PtenMmac1 in mice causes neoplasia in multiple organsystemsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 4 pp 1563ndash1568 1999

[37] M Kashiwada P Lu and P B Rothman ldquoPIP3 pathway inregulatory T cells and autoimmunityrdquo Immunologic Researchvol 39 no 1ndash3 pp 194ndash224 2007

[38] A Suzuki M T Yamaguchi T Ohteki et al ldquoT cell-specificloss of Pten leads to defects in central and peripheral tolerancerdquoImmunity vol 14 no 5 pp 523ndash534 2001

[39] Y Yamanaka H Tagawa N Takahashi et al ldquoAberrant over-expression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lym-phomaleukemiardquo Blood vol 114 no 15 pp 3265ndash3275 2009

[40] H Kishimoto T Ohteki N Yajima et al ldquoThe PtenPI3Kpathway governs the homeostasis of V12057214iNKT cellsrdquo Bloodvol 109 no 8 pp 3316ndash3324 2007

[41] A Suzuki T Kaisho M Ohishi et al ldquoCritical roles ofPten in B cell homeostasis and immunoglobulin class switchrecombinationrdquo Journal of Experimental Medicine vol 197 no5 pp 657ndash667 2003

Journal of Signal Transduction 11

[42] M Nishio K-IWatanabe J Sasaki et al ldquoControl of cell polar-ity and motility by the PtdIns(345)P

3phosphatase SHIP1rdquo

Nature Cell Biology vol 9 no 1 pp 36ndash44 2007[43] S Kuroda M Nishio T Sasaki et al ldquoEffective clearance

of intracellular Leishmania major in vivo requires Pten inmacrophagesrdquo European Journal of Immunology vol 38 no 5pp 1331ndash1340 2008

[44] O H Yilmaz R Valdez B K Theisen et al ldquoPten depen-dence distinguishes haematopoietic stem cells from leukaemia-initiating cellsrdquo Nature vol 441 no 7092 pp 475ndash482 2006

[45] Y Li K Podsypanina X Liu et al ldquoDeficiency of Ptenaccelerates mammary oncogenesis in MMTV-Wnt-1 transgenicmicerdquo BMCMolecular Biology vol 2 article 2 2001

[46] P Reddy L Liu D Adhikari et al ldquoOocyte-specific deletion ofpten causes premature activation of the primordial follicle poolrdquoScience vol 319 no 5863 pp 611ndash613 2008

[47] H Tsuruta H Kishimoto T Sasaki et al ldquoHyperplasia andcarcinomas in Pten-deficient mice and reduced PTEN proteinin human bladder cancer patientsrdquoCancer Research vol 66 no17 pp 8389ndash8396 2006

[48] L I Yoo D W Liu S Le Vu R T Bronson H Wu and JYuan ldquoPten deficiency activates distinct downstream signalingpathways in a tissue-specific mannerrdquo Cancer Research vol 66no 4 pp 1929ndash1939 2006

[49] J Li C Yen D Liaw et al ldquoPTEN a putative protein tyrosinephosphatase gene mutated in human brain breast and prostatecancerrdquo Science vol 275 no 5308 pp 1943ndash1947 1997

[50] N D Deocampo H Huang and D J Tindall ldquoThe role ofPTEN in the progression and survival of prostate cancerrdquoMinerva Endocrinologica vol 28 no 2 pp 145ndash153 2003

[51] S A Backman D Ghazarian K So et al ldquoEarly onset ofneoplasia in the prostate and skin of mice with tissue-specificdeletion of Ptenrdquo Proceedings of the National Academy ofSciences of the United States of America vol 101 no 6 pp 1725ndash1730 2004

[52] X Wu K Xu L Zhang et al ldquoDifferentiation of the ductalepithelium and smooth muscle in the prostate gland areregulated by the NotchPTEN-dependent mechanismrdquo Devel-opmental Biology vol 356 no 2 pp 337ndash349 2011

[53] D Kim and G R Dressler ldquoPTEN modulates GDNFRETmediated chemotaxis and branching morphogenesis in thedeveloping kidneyrdquo Developmental Biology vol 307 no 2 pp290ndash299 2007

[54] N O Lindstrom M L Lawrence S F Burn et al ldquoIntegrated120573-catenin BMP PTEN and notch signalling patterns thenephronrdquo eLife no 4 Article ID e04000 2015

[55] V Marsh D J Winton G T Williams et al ldquoEpithelialPten is dispensable for intestinal homeostasis but suppressesadenoma development and progression after Apc mutationrdquoNature Genetics vol 40 no 12 pp 1436ndash1444 2008

[56] S Matsuda M Kobayashi and Y Kitagishi ldquoRoles forPI3KAKTPTEN pathway in cell signaling of nonalcoholicfatty liver diseaserdquo ISRN Endocrinology vol 2013 Article ID472432 7 pages 2013

[57] X Qi J Xu P Gu X Yang and X Gao ldquoPTEN in smoothmuscle cells is essential for colonic immune homeostasisrdquoInternational Journal of Biochemistry and Cell Biology vol 53pp 108ndash114 2014

[58] A Pal T M Barber M Van de Bunt et al ldquoPTENmutations asa cause of constitutive insulin sensitivity and obesityrdquoThe NewEngland Journal of Medicine vol 367 no 11 pp 1002ndash1011 2012

[59] B L Stiles C Kuralwalla-Martinez W Guo et al ldquoSelectivedeletion of Pten in pancreatic 120573 cells leads to increased isletmass and resistance to STZ-induced diabetesrdquo Molecular andCellular Biology vol 26 no 7 pp 2772ndash2781 2006

[60] LWang C T Luk E P Cai et al ldquoPTEN deletion in pancreatic120572-cells protects against high-fat diet-induced hyperglucagone-mia and insulin resistancerdquo Diabetes vol 64 no 1 pp 147ndash1572015

[61] C Kurlawalla-Martinez B Stiles Y Wang S U Devaskar BB Kahn and H Wu ldquoInsulin hypersensitivity and resistanceto streptozotocin-induced diabetes in mice lacking PTEN inadipose tissuerdquo Molecular and Cellular Biology vol 25 no 6pp 2498ndash2510 2005

[62] N Wijesekara D Konrad M Eweida et al ldquoMuscle-specificPten deletion protects against insulin resistance and diabetesrdquoMolecular and Cellular Biology vol 25 no 3 pp 1135ndash11452005

[63] K Hamada T Sasaki P A Koni et al ldquoThe PTENPI3Kpathway governs normal vascular development and tumorangiogenesisrdquo Genes and Development vol 19 no 17 pp 2054ndash2065 2005

[64] N D Roe X Xu M R Kandadi et al ldquoTargeted deletionof PTEN in cardiomyocytes renders cardiac contractile dys-function through interruption of Pink1-AMPK signaling andautophagyrdquo Biochimica et Biophysica Acta Molecular Basis ofDisease vol 1852 no 2 pp 290ndash298 2015

[65] A F Ford-Hutchinson Z Ali S E Lines B HallgrımssonS K Boyd and F R Jirik ldquoInactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnor-malities and skeletal overgrowthrdquo Journal of Bone and MineralResearch vol 22 no 8 pp 1245ndash1259 2007

[66] T A Burgers M F Hoffmann C J Collins et al ldquoMice lackingpten in osteoblasts have improved intramembranous and lateendochondral fracture healingrdquo PLoS ONE vol 8 no 5 ArticleID e63857 2013

[67] N R Leslie L Spinelli P Tibarewal et al ldquoIndirect mecha-nisms of carcinogenesis via downregulation of PTEN functionrdquoAdvances in Enzyme Regulation vol 50 no 1 pp 112ndash118 2010

[68] L He ldquoPosttranscriptional regulation of PTEN dosage bynoncoding RNAsrdquo Science Signaling vol 3 no 146 article pe392010

[69] F Vazquez S R Grossman Y Takahashi M V Rokas NNakamura andWR Sellers ldquoPhosphorylation of the PTEN tailacts as an inhibitory switch by preventing its recruitment into aprotein complexrdquo The Journal of Biological Chemistry vol 276no 52 pp 48627ndash48630 2001

[70] X Wang L C Trotman T Koppie et al ldquoNEDD4-1 is a proto-oncogenic ubiquitin ligase for PTENrdquo Cell vol 128 no 1 pp129ndash139 2007

[71] N R Leslie and M Foti ldquoNon-genomic loss of PTEN functionin cancer not in my genesrdquo Trends in Pharmacological Sciencesvol 32 no 3 pp 131ndash140 2011

[72] Y Xing C Li L Hu et al ldquoMechanisms of TGF120573 inhibition ofLUNG endodermal morphogenesis the role of T120573RII SmadsNkx21 and Ptenrdquo Developmental Biology vol 320 no 2 pp340ndash350 2008

[73] J P Luyendyk G A Schabbauer M Tencati T Holscher RPawlinski and N Mackman ldquoGenetic analysis of the role ofthe PI3K-Akt pathway in lipopolysaccharide-induced cytokineand tissue factor gene expression in monocytesmacrophagesrdquoJournal of Immunology vol 180 no 6 pp 4218ndash4226 2008

12 Journal of Signal Transduction

[74] F Sun K K Park S Belin et al ldquoSustained axon regenerationinduced by co-deletion of PTEN and SOCS3rdquo Nature vol 480no 7377 pp 372ndash375 2011

[75] C B Knobbe V Lapin A Suzuki and T W Mak ldquoThe roles ofPTEN in development physiology and tumorigenesis in mousemodels a tissue-by-tissue surveyrdquo Oncogene vol 27 no 41 pp5398ndash5415 2008

[76] S J Assinder Q Dong Z Kovacevic and D R RichardsonldquoThe TGF-beta PI3KAkt and PTEN pathways establishedand proposed biochemical integration in prostate cancerrdquoBiochemical Journal vol 417 no 2 pp 411ndash421 2009

[77] K A Waite and C Eng ldquoFrom developmental disorder toheritable cancer itrsquos all in the BMPTGF-120573 familyrdquo NatureReviews Genetics vol 4 no 10 pp 763ndash773 2003

[78] H B Newton ldquoMolecular neuro-oncology and developmentof targeted therapeutic strategies for brain tumors Part2 PI3KAktPTEN mTOR SHHPTCH and angiogenesisrdquoExpert Review of Anticancer Therapy vol 4 no 1 pp 105ndash1282004

[79] R H KimM Peters Y Jang et al ldquoDJ-1 a novel regulator of thetumor suppressor PTENrdquo Cancer Cell vol 7 no 3 pp 263ndash2732005

[80] J Lu H W Jeong N Kong et al ldquoStem cell factor SALL4represses the transcriptions of PTEN and SALL1 through anepigenetic repressor complexrdquo PLoS ONE vol 4 no 5 ArticleID e5577 2009

[81] M M A Rizvi M S Alam A Ali S J Mehdi S Batra andA KMandal ldquoAberrant promotermethylation and inactivationof PTEN gene in cervical carcinoma from Indian populationrdquoJournal of Cancer Research and Clinical Oncology vol 137 no 8pp 1255ndash1262 2011

[82] J Liu ldquoControl of protein synthesis and mRNA degradation bymicroRNAsrdquo Current Opinion in Cell Biology vol 20 no 2 pp214ndash221 2008

[83] S W Shan L Fang T Shatseva et al ldquoMature miR-17-5pand passenger miR-17-3p induce hepatocellular carcinoma bytargeting PTEN GalNT7 and vimentin in different signalpathwaysrdquo Journal of Cell Science vol 126 part 6 pp 1517ndash15302013

[84] Z Liang Y Li K Huang N Wagar and H Shim ldquoRegulationof miR-19 to breast cancer chemoresistance through targetingPTENrdquo Pharmaceutical Research vol 28 no 12 pp 3091ndash31002011

[85] X Lu Q Fan L Xu et al ldquoUrsolic acid attenuates diabeticmesangial cell injury through the up-regulation of autophagyvia miRNA-21PTENAktmTOR suppressionrdquo PLoS ONE vol10 no 2 Article ID e0117400 2015

[86] L Poliseno L Salmena J Zhang B Carver W J Havemanand P P Pandolfi ldquoA coding-independent function of geneand pseudogenemRNAs regulates tumour biologyrdquoNature vol465 no 7301 pp 1033ndash1038 2010

[87] Y Tay L Kats L Salmena et al ldquoCoding-independent regula-tion of the tumor suppressor PTEN by competing endogenousmRNAsrdquo Cell vol 147 no 2 pp 344ndash357 2011

[88] L Odriozola G Singh T Hoang and A M Chan ldquoRegula-tion of PTEN activity by its carboxyl-terminal autoinhibitorydomainrdquo The Journal of Biological Chemistry vol 282 no 32pp 23306ndash23315 2007

[89] Z Li X Dong Z Wang et al ldquoRegulation of PTEN by Rhosmall GTPasesrdquo Nature Cell Biology vol 7 no 4 pp 399ndash4042005

[90] E-K Yim G Peng H Dai et al ldquoRak functions as a tumorsuppressor by regulating PTEN protein stability and functionrdquoCancer Cell vol 15 no 4 pp 304ndash314 2009

[91] AMAl-Khouri YMa SH Togo SWilliams andTMustelinldquoCooperative phosphorylation of the tumor suppressor phos-phatase and tensin homologue (PTEN) by casein kinasesand glycogen synthase kinase 3120573rdquo The Journal of BiologicalChemistry vol 280 no 42 pp 35195ndash35202 2005

[92] H Maccario N M Perera L Davidson C P Downes and NR Leslie ldquoPTEN is destabilized by phosphorylation onThr366rdquoBiochemical Journal vol 405 no 3 pp 439ndash444 2007

[93] K A Waite and C Eng ldquoBMP2 exposure results in decreasedPTEN protein degradation and increased PTEN levelsrdquoHumanMolecular Genetics vol 12 no 6 pp 679ndash684 2003

[94] T J Jerde Z Wu D Theodorescu and W Bushman ldquoRegu-lation of phosphatase homologue of tensin protein expressionby bone morphogenetic proteins in prostate epithelial cellsrdquoProstate vol 71 no 8 pp 791ndash800 2011

[95] G Singh and A M Chan ldquoPost-translational modificationsof PTEN and their potential therapeutic implicationsrdquo CurrentCancer Drug Targets vol 11 no 5 pp 536ndash547 2011

[96] T Ikenoue K Inoki B Zhao and K-L Guan ldquoPTEN acety-lation modulates its interaction with PDZ domainrdquo CancerResearch vol 68 no 17 pp 6908ndash6912 2008

[97] L C Trotman X Wang A Alimonti et al ldquoUbiquitinationregulates PTEN nuclear import and tumor suppressionrdquo Cellvol 128 no 1 pp 141ndash156 2007

[98] T Tolkacheva M Boddapati A Sanfiz K Tsuchida A CKimmelman and AM-L Chan ldquoRegulation of PTEN bindingto MAGI-2 by two putative phosphorylation sites at threonine382 and 383rdquo Cancer Research vol 61 no 13 pp 4985ndash49892001

[99] E Lima-Fernandes H Enslen E Camand et al ldquoDistinct func-tional outputs of PTEN signalling are controlled by dynamicassociation with 120573-arrestinsrdquoThe EMBO Journal vol 30 no 13pp 2557ndash2568 2011

[100] M T van Diepen M Parsons C P Downes N R Leslie RHindges and B J Eickholt ldquoMyosinV controls PTEN functionand neuronal cell sizerdquo Nature Cell Biology vol 11 no 10 pp1191ndash1196 2009

[101] R B Chagpar P H Links M C Pastor et al ldquoDirect positiveregulation of PTEN by the p85 subunit of phosphatidylinositol3-kinaserdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 107 no 12 pp 5471ndash5476 2010

[102] Y Takahashi F C Morales E L Kreimann and M-MGeorgescu ldquoPTEN tumor suppressor associates with NHERFproteins to attenuate PDGF receptor signalingrdquo The EMBOJournal vol 25 no 4 pp 910ndash920 2006

[103] M Valiente A Andres-Pons B Gomar et al ldquoBinding ofPTEN to specific PDZ domains contributes to PTEN proteinstability and phosphorylation by microtubule-associated ser-inethreonine kinasesrdquoThe Journal of Biological Chemistry vol280 no 32 pp 28936ndash28943 2005

[104] SQuintes SGoebbels G SaherMH Schwab andK-ANaveldquoNeuron-glia signaling and the protection of axon function bySchwann cellsrdquo Journal of the Peripheral Nervous System vol 15no 1 pp 10ndash16 2010

[105] B Fine C Hodakoski S Koujak et al ldquoActivation of the PI3Kpathway in cancer through inhibition of PTEN by exchangefactor P-REX2ardquo Science vol 325 no 5945 pp 1261ndash1265 2009

Journal of Signal Transduction 13

[106] L He A Ingram A P Rybak and D Tang ldquoShank-interactingprotein-like 1 promotes tumorigenesis via PTEN inhibition inhuman tumor cellsrdquo The Journal of Clinical Investigation vol120 no 6 pp 2094ndash2108 2010

[107] L He C Fan A Kapoor et al ldquo120572-Mannosidase 2C1 attenuatesPTEN function in prostate cancer cellsrdquo Nature Communica-tions vol 2 no 1 article 307 2011

[108] Z Radisavljevic ldquoAKT as locus of cancer positive feedbackloops and extreme robustnessrdquo Journal of Cellular Physiologyvol 228 no 3 pp 522ndash524 2013

[109] M Y Lee HW Lim S H Lee andH J Han ldquoSmad PI3KAktand wnt-dependent signaling pathways are involved in BMP-4-induced ESC self-renewalrdquo Stem Cells vol 27 no 8 pp 1858ndash1868 2009

[110] K Song S C Cornelius M Reiss and D Danielpour ldquoInsulin-like growth factor-I inhibits transcriptional responses of trans-forming growth factor-120573 by phosphatidylinositol 3-kinaseAkt-dependent suppression of the activation of Smad3 but notSmad2rdquoThe Journal of Biological Chemistry vol 278 no 40 pp38342ndash38351 2003

[111] D Fang D Hawke Y Zheng et al ldquoPhosphorylation of 120573-catenin by AKT promotes 120573-catenin transcriptional activityrdquoThe Journal of Biological Chemistry vol 282 no 15 pp 11221ndash11229 2007

[112] Q Lei J Jiao L Xin et al ldquoNKX31 stabilizes p53 inhibitsAKT activation and blocks prostate cancer initiation caused byPTEN lossrdquo Cancer Cell vol 9 no 5 pp 367ndash378 2006

[113] A Sengupta J D Molkentin J-H Paik R A DePinho and KE Yutzey ldquoFoxO transcription factors promote cardiomyocytesurvival upon induction of oxidative stressrdquo The Journal ofBiological Chemistry vol 286 no 9 pp 7468ndash7478 2011

[114] C H M Jamieson L E Ailles S J Dylla et al ldquoGranulocyte-macrophage progenitors as candidate leukemic stem cells inblast-crisis CMLrdquoTheNewEngland Journal ofMedicine vol 351no 7 pp 657ndash667 2004

[115] A Androutsellis-Theotokis R R Leker F Soldner et al ldquoNotchsignalling regulates stem cell numbers in vitro and in vivordquoNature vol 442 no 7104 pp 823ndash826 2006

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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PeptidesInternational Journal of

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Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

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BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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International Journal of

Microbiology

Page 7: Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling TravisJ.Jerde Department of Pharmacology

Journal of Signal Transduction 7

morphogenetic proteins (BMPs) and hedgehogs (Hhs) allparticipate as players in external PTEN regulation [75ndash78] regulating such processes as proliferation and targetedepithelial budding and outgrowth of visceral organs [76 77]and outgrowth in neurons [75] As the direction of cell growthand differentiation balances on the fulcrum between theproliferative and differentiating actions of these mediatorstheir regulation to induce or repress PTEN expression isa critical aspect of their actions during development Thecritical developmental mediator TGF120573 contains both growthpromoting and inhibiting differentiation qualities and TGF120573induces PTEN during differentiation when growth is slowedand inhibits its expression during proliferation In additionthe developmental regulator DJ-1 was recently identified asa novel negative regulator of PTEN by a genetic screen inDrosophila [79] PTEN is also regulated through epigeneticsilencing by methylation of the PTEN promoter [80 81] Aninteresting zinc-finger transcription factor sal-like protein 4(SALL4) has been discovered as a critical negative regulatorof PTEN transcription by recruiting an epigenetic repressorcomplex involving anATPase and a histone deacetylase to thePTENpromoter [80] SALL4 plays a critical role in regulatingdevelopment by modulating self-renewal in stem cells andits function appears to at least partly involve methylation ofthe PTENpromoter andmodulation of its transcriptionDataon this mechanism are still limited but to date this processhas been shown to regulate kidney patterning during devel-opment as well as leukemogenesis [80] Current research inthe area of PTEN transcriptional regulation continues to bedynamic and more novel regulation patterns are likely to bediscovered in the near future

322 PTEN Regulation by Posttranscriptional RegulationRecent studies have identified several interesting develop-mentally expressed miRNAs that regulate PTEN mRNAmessage stability and translatability [82] These miRNAstypically downregulate PTEN mRNA levels by targeting itfor degradation and include miR-17 miR-19 and miR-21 [83ndash85] While several examples of miR-17 and miR-19-mediatedPTENRNA levels have been reported in the cancer literaturemiR-21 has been described to play a critical role in repairand recovery a developmental signaling-related processmiRNAs regulate this mechanism by modulating PTENRNA stability and ultimately downstream Akt signaling Forexample in the pancreas miR-21 regulates injury repair indiabetic models by targeting PTEN RNA for degradationInhibition of miR-21 results in autophagy in this model ina manner dependent on PTEN degradation [85] In anotherexample of novel miR-related PTEN regulation the PTENpseudogene 1 (PTENP1) acts as a decoy for PTEN-targetingmiRNAs and thereby regulates PTEN expression by coding-independent activity through sequestering these miRNAsand effectively inhibiting their effects on PTEN expression[86] Additionally combined bioinformatic and experimentalapproaches have identified ceRNA transcripts that controlPTEN expression by sequestering PTEN-targeting miRNAsduring development of both prostate and skin [87] Becausethis type of PTEN regulation and indeed this field of generegulation in general is in its infancy we are only beginning

to understand the PTEN regulation by coding and noncodingceRNAs Still this novel work provides a platform for furtherstudies investigating posttranscriptional regulation patternsof PTEN expression in both developmental biology anddisease conditions

323 PTENRegulation by PosttranslationalMechanisms Theprotein stability and enzyme activity of PTEN are regulatedin a number of ways at the posttranslational level FirstPTEN is phosphorylated in its C-terminal tail at Ser380Thr382 Thr383 and Ser385 and this functions to inhibitthe critical PTEN phosphatase activity thereby promotinggrowth in prostate and kidney cells [88] However thesephosphorylations also stabilize the PTEN protein by dis-suading ubiquitination While this may seem like a cellulardisconnect this paradoxical phenomenon is explained by thefinding that this closed more stable PTEN conformation isprevented from associating with membranes and thereforeis geographically separated from its substrates [88] PTENcan also be activated by phosphorylation in particular theC2 domain of PTEN is phosphorylated at Ser229 andThr321by RHOA-associated protein kinase (ROCK) [89] a phos-phorylation that results in its association with membranesand phosphoinositide substrates affecting differentiation inleukocytes PTEN is further phosphorylated at Tyr336 by theTyr protein kinase RAK and this phosphorylation resultsin its stabilization [90] Loss of this activity has the effectof promoting breast cell proliferation and migration FinallyPTEN is also phosphorylated at Ser370 and Thr366 by CK2and GSK3120573 [91 92] respectively however the consequencesof this phosphorylation are unclear The likely extensivesignaling networks that regulate these widespread phospho-rylations in PTEN are not fully studied but the TGFBMP-SMADdevelopmental pathways are known to regulate PTENphosphorylation [93 94] Given the widespread applicationof SMAD signaling to developmental biology the presence ofSMAD-regulated PTEN phosphorylation is a critical aspectof developmental regulation in cells

PTEN enzymatic activity is also regulated posttrans-lationally by acetylation [70 95ndash97] PTEN is acetylatedat Lys125ndashLys128 by p300CREB-binding protein- (CBP-)associated factor (PCAF) and at Lys402 by CBP itself [95]Acetylation at these residues inhibits PTENrsquos function as aphosphatase and has been shown to promote the growthof prostate epithelial cells and glial cells [95] In additionthe deacetylase Sirtuin 1 (SIRT1) is involved in excludingPTEN from the nucleus and therefore preventing its newlycharacterized nuclear functions [96]

324 PTEN Regulation by Protein-Protein Interactions Theconformation stability and subcellular distribution of PTENis regulated by critical interactions with other proteins withincells and these proteins are known to be critical for properdevelopment of a number of organ systems The guanylatekinase inverted 2 (MAGI2) and 120573-arrestins cooperate toenhance PTEN activity [98 99] MAGI2 phosphorylatesPTEN on threonine residues at positions 382 and 383 ofPTENrsquos carboxy terminus allowing recruitment to cell-cell

8 Journal of Signal Transduction

junctions [98] Mutations to these residues prevent PTENrecruitment Upon recruitment 120573-arrestins modulate PTENactivity by direct binding to the C2 domain and modulatingits protein phosphatase activity including that at the levelof small GTPases including RhoAROCK [99] In addi-tion Myosin V regulates PTENrsquos movement to and fromthe plasma membrane and this function is required forPTEN to access its phosphoinositide substrates [100] andfor disrupting the proper regulation of neuronal cell sizeThe p85 regulatory subunit of the PI

3kinase enzyme itself

interacts with PTEN in a novel mechanism of repressing thePI3KndashAKT pathway [101] independent of PTENrsquos action as a

phosphatase It is therefore proposed that p85 regulates thePI3KndashAKT pathway bidirectionally both through its binding

to catalytic p110 subunit resulting in the generation of phos-phoinositides and by binding PTEN leading to repressionThis work proposes a novel signaling model for PTEN-p85association in which p85120572 preferentially binds and stabilizesp110 preferentially when p85120572 levels are low but excess p85120572binds to and positively regulates PTEN phosphatase activitywhen p110 is saturated Therefore sustained activation ofPI3K signaling and activated p110-p85 complexing is modu-lated homeostatically by this mechanism

A fascinating group of recent studies have utilizedproteomic library screens to identify further novel PTENinteracting proteins First the Na+H+ exchanger regulatoryfactor (NHERF) binds to and recruits PTEN to the platelet-derived growth factor receptor (PDGFR) This representsanother action that restricts PI

3KndashAKT pathway activation

independent of phosphatase activity [102] This has the effectof inhibiting PDGF-induced cytoskeletal rearrangements andchemotactic migration of developing neurons In additionthe mammalian disks large homologue 1 (DLG1) MAGI-2 and MAST205 proteins directly interact with PTENand enhance PTEN stability and activity [103] Furtherneuregulin 1 (NRG1) has been shown to interact with bothDLG1 and PTEN in a stable complex that has the effect ofregulating myelin sheath thickness in developing mouse sci-atic nerves [104] Additional but less-characterized protein-protein interactions that modulate PTEN function includethe PIP

3-dependent RAC exchanger factor 2a (PREX2a)

[105] shank-interacting protein-like 1 (SIPL1) [106] and 120572-mannosidase 2C1 (MAN2C1) [107]

325 PTEN-Controlled Signal Transduction during Develop-ment PTEN is critically important in regulating signalingpathways involved in cell growth and animal developmentThrough its well-characterized function as a phosphataseof PIP

3 PTEN modulates a network of mitogen-activated

signals transduced through PI3KndashAkt signaling This pri-

mary action of PTEN has tremendous impact on cell growthcell migration cell death and cell differentiationmdashcellularprocesses that are all hallmarks of proper growth andpatterning during development The active phosphorylatedPIP3activates several signaling molecules including the

phosphatidylinositol-dependent kinases (PDKs) followed byAkt S6 kinase and mTOR Beyond this AKTrsquos targetsinclude the apoptotic factor BAD activator and executioner

caspases glycogen synthase kinase-3 (GSK-3) MDM2 p21and p27 forkhead transcription factors (FOXOs) and nuclearreceptors including the androgen and estrogen receptors[108] Akt-mediated phosphorylation of these moleculescauses activation translocation and increased stability

The PTENPI3kinaseAKT signaling cascade crosstalks

to several key signal transduction pathways that are criticalto developmental biology This includes the abovementionedTGF-120573SMAD pathway and the Wnt120573-catenin pathway[109] The TGF-120573SMAD pathway is one of the most seminalpathways in developmental biology and PTEN modulatesTGF120573SMAD signaling by reversing Akt-mediated phospho-rylation of SMAD3 the critical signaling intermediate ofTGF120573SMAD signaling [110] Similarly the Wnt signalingpathway is indispensable for properly regulated developmentcellular proliferation and differentiation [111] PTEN regu-lates this pathway by reversing AKT kinase phosphorylationand inhibition of GSK-3120573 resulting in 120573-catenin nucleartranslocation and activation Finally recent studies demon-strate that PTEN regulates the expression and action of thehomeobox genes NKX31 and hepatic nuclear factor [112]proteins that are critical to organ development

326 PTEN-Regulated Stem Cell Activities The scientificliterature in the field of tissue stem or stem-like ldquoprogen-itorrdquo cells and their role in tissue development growthrecovery and repair has become beyond extensive in recentyears Expansion of stemprogenitor cells is a hallmark ofgrowth and patterning during development and regulationof these cells including their proliferation maintenanceand differentiation is a critical factor of developmentalregulation Because of this a review of the current liter-ature on PTENrsquos role in stem and tissue progenitor cellsis warranted in this review PTEN plays an important rolein regulating the homeostasis of stemprogenitor cells inmultiple tissues Interestingly PTEN regulates both self-renewal and proliferation but paradoxically it also playsa role in stem cell exhaustion For example the FOXOfamily of transcription factors controls stem cell proliferationand survival in hematopoietic stem cells [113] and PTENsignaling is a critical modulator of FOXO activity FOXO3A-deficient HSCs exhibit increased proliferation rate decreasedquiescence and a reduced ability to repopulate bone marrowafter transplantation into recipient mice Additionally thepreviously mentioned Wnt120573-catenin signaling pathway iscritical for HSC self-renewal and its activation is well knownto be modulated by PTEN Interestingly PTEN loss and AKTactivation in HSCs lead to a moderate increase in the levelof unphosphorylated 120573-catenin but this is not sufficient tomaintain Pten-null HSC self-renewal [114] Finally NOTCHsignaling plays a key role in regulating neural stem cellexpansion [115] and as stated previously NOTCH pathwayactivation leads to reduced PTEN expression in neural andhematopoietic stem cells

4 Conclusions

PTEN acts as the key endogenous negative modulatorof phosphoinositide signaling in mammalian cells and

Journal of Signal Transduction 9

therefore its role in normal cell homeostasis proliferationapoptosis and many additional components of cell biologyis extensive Because PTEN regulates cancer progressionmuch of what has been studied regarding PTEN relates totumorigenesis and tumor growth While this is warrantedbecause of the relevance of cancer to humanhealth PTENhassubstantial but underappreciated effects in normal tissue andorgan development immune system development and reg-ulation axonal regeneration glucose regulation and benigngrowth disorders PTEN is often dogmatically thought ofas a constitutive protein that exhibits lost activity duringdiseases butwhat is underappreciated is that PTENhas a verycomplex regulation network that involves signaling path-ways that regulate PTEN transcription transcript stabilityposttranslationalmodifications protein-protein interactionsand cellular location PTEN then in turn regulates numerousdevelopmental signaling networks that are critical to devel-opment and adult tissue maintenance

Abbreviations

Bcl2 B-cell lymphoma 2Bim BCL-2-interacting mediatorCK2 Casein Kinase 2CREB Cyclic AMP response element binding

proteinDLG Disks large homolog 1Egr-1 Early growth response protein 1Erk Extracellular regulated kinaseFOX Forkhead transcription factorsGSK3120573 Glycogen synthase kinase 3JNK Jun-terminal kinaseMAGI2 Membrane-associated guanylate kinase

inverted 2MAN2C1 Mannosidase alpha class 2C member 1MDM2 Mouse double minute 2 homologmTOR Mechanistic target of rapamycinNHERF Sodium-hydrogen antiporter 3

regulator 1NRG1 Neuregulin 1PCAF P300CBP-associated factorPDZ Postsynaptic density proteinmdashDisc

large tumor suppressormdashZonulaoccludens-1 protein

PIP3 Phosphoinositide triphosphatePPAR120574 Peroxisome proliferating antigen

receptorPREX2a Phosphatidylinositol-345-

trisphosphate-dependent Rac exchangefactor A

PTEN Phosphatase and Tensin homologueROCK Rho-associated coiled-coil-containing

protein kinaseSALL Spalt-like transcription factor-1SIPL1 Shank-interacting protein-like 1SIRT1 Sirtuin 1SMAD Small mothers against decapentaplegicSOCS Suppressor of cytokine signalingTGF120573 Transforming growth factor-beta

Disclosure

Travis J Jerde carried out the extensive literature reviewrequired to write this paper and have written the entirepaper The author has therefore read and approved the papersubmitted

Conflict of Interests

The author has no financial or nonfinancial conflict ofinterests with the submission of this paper

Acknowledgments

The author gratefully acknowledges the financial supportof the Indiana University School of Medicine Departmentof Pharmacology and Toxicology and the Melvin and BrynSimon Cancer Center The author also gratefully acknowl-edges this paper as part of his training made possible byNational Institutes of Health-NIDDK (DK092366-01A1)

References

[1] M Milella I Falcone F Conciatori et al ldquoPTEN multiplefunctions in human malignant tumorsrdquo Frontiers in Oncologyvol 5 article 24 2015

[2] J-O Lee H Yang M-M Georgescu et al ldquoCrystal structure ofthe PTEN tumor suppressor implications for its phosphoinosi-tide phosphatase activity and membrane associationrdquo Cell vol99 no 3 pp 323ndash334 1999

[3] W-L Yang G Jin C-F Li et al ldquoCycles of ubiquitinationand deubiquitination critically regulate growth factor-mediatedactivation of Akt signalingrdquo Science Signaling vol 6 no 257article ra3 2013

[4] J Gu S Nada M Okada and K Sekiguchi ldquoCsk regulatesintegrin-mediated signals involvement of differential activa-tion of ERK and Aktrdquo Biochemical and Biophysical ResearchCommunications vol 303 no 3 pp 973ndash977 2003

[5] A Clerk and P H Sugden ldquoActivation of protein kinase cas-cades in the heart by hypertrophic G protein-coupled receptoragonistsrdquoTheAmerican Journal of Cardiology vol 83 no 12 pp64Hndash69H 1999

[6] I Tonic W-N Yu Y Park C-C Chen and N Hay ldquoAktactivation emulates Chk1 inhibition and Bcl2 overexpressionand abrogates G2 cell cycle checkpoint by inhibiting BRCA1focirdquo The Journal of Biological Chemistry vol 285 no 31 pp23790ndash23798 2010

[7] S Fatrai L Elghazi N Balcazar et al ldquoAkt induces 120573-cellproliferation by regulating cyclin D1 cyclin D2 and p21 levelsand cyclin-dependent kinase-4 activityrdquo Diabetes vol 55 no 2pp 318ndash325 2006

[8] M Aoki E Blazek and P K Vogt ldquoA role of the kinase mTORin cellular transformation induced by the oncoproteins P3k andAktrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 98 no 1 pp 136ndash141 2001

[9] H Guan L Song J Cai et al ldquoSphingosine kinase 1 regulatesthe AktFOXO3aBim pathway and contributes to apoptosisresistance in glioma cellsrdquo PLoS ONE vol 6 no 5 Article IDe19946 2011

[10] T D Dung C H Day T V Binh et al ldquoPP2Amediates diosminp53 activation to block HA22T cell proliferation and tumor

10 Journal of Signal Transduction

growth in xenografted nude mice through PI3K-Akt-MDM2signaling suppressionrdquo Food and Chemical Toxicology vol 50no 5 pp 1802ndash1810 2012

[11] K Shanmugasundaram K Block B K Nayak C B Livi MA Venkatachalam and S Sudarshan ldquoPI3K regulation of theSKP-2p27 axis through mTORC2rdquo Oncogene vol 32 no 16pp 2027ndash2036 2013

[12] J-C Chang H-H Chang C-T Lin and S J Lo ldquoThe integrin12057261205731modulation of PI3K andCdc42 activities induces dynamicfilopodium formation in humanplateletsrdquo Journal of BiomedicalScience vol 12 no 6 pp 881ndash898 2005

[13] E Hajduch G J Litherland and H S Hundal ldquoProtein kinaseB (PKBAkt)mdasha key regulator of glucose transportrdquo FEBSLetters vol 492 no 3 pp 199ndash203 2001

[14] M M Martin J A Buckenberger J Jiang et al ldquoTGF-beta1stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[15] M M Martin J A Buckenberger J Jiang et al ldquoTGF-1205731stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[16] K Abell and C J Watson ldquoThe JakStat pathway a novel wayto regulate PI3K activityrdquo Cell Cycle vol 4 no 7 pp 897ndash9002005

[17] J-Y Hwang R S Duncan C Madry M Singh and P KoulenldquoProgesterone potentiates calcium release through IP3 recep-tors by an Akt-mediated mechanism in hippocampal neuronsrdquoCell Calcium vol 45 no 3 pp 233ndash242 2009

[18] G Pappas L A Zumstein A Munshi M Hobbs and R EMeyn ldquoAdenoviral-mediated PTEN expression radiosensitizesnon-small cell lung cancer cells by suppressing DNA repaircapacityrdquoCancer GeneTherapy vol 14 no 6 pp 543ndash549 2007

[19] A Di Cristofano B Pesce C Cordon-Cardo and P P PandolfildquoPten is essential for embryonic development and tumoursuppressionrdquo Nature Genetics vol 19 no 4 pp 348ndash355 1998

[20] J Bloomekatz J Grego-Bessa I Migeotte and K V AndersonldquoPten regulates collective cell migration during specification ofthe anterior-posterior axis of the mouse embryordquo Developmen-tal Biology vol 364 no 2 pp 192ndash201 2012

[21] S Ueno R Kono andY Iwao ldquoPTEN is required for the normalprogression of gastrulation by repressing cell proliferation afterMBT in Xenopus embryosrdquoDevelopmental Biology vol 297 no1 pp 274ndash283 2006

[22] C B Knobbe A Merlo and G Reifenberger ldquoPten signaling ingliomasrdquo Neuro Oncology vol 4 pp 196ndash211 2002

[23] E Kirches J Steiner T Schneider et al ldquoLhermitte-Duclosdisease caused by a novel germline PTEN mutation R173P in apatient presenting with psychosisrdquoNeuropathology and AppliedNeurobiology vol 36 no 1 pp 86ndash89 2010

[24] J-I Murata M Tada Y Sawamura K Mitsumori H Abe andK Nagashima ldquoDysplastic gangliocytoma (Lhermitte-Duclosdisease) associated with Cowden disease report of a case andreview of the literature for the genetic relationship between thetwo diseasesrdquo Journal of Neuro-Oncology vol 41 no 2 pp 129ndash136 1999

[25] G Zhu L M L Chow I T Bayazitov et al ldquoPten deletioncauses mTorc1-dependent ectopic neuroblast differentiation

without causing uniform migration defectsrdquo Development vol139 no 18 pp 3422ndash3431 2012

[26] K L McBride E A Varga M T Pastore et al ldquoConfirmationstudy of PTEN mutations among individuals with autism ordevelopmental delaysmental retardation and macrocephalyrdquoAutism Research vol 3 no 3 pp 137ndash141 2010

[27] J Zhou and L F Parada ldquoPTEN signaling in autism spectrumdisordersrdquo Current Opinion in Neurobiology vol 22 no 5 pp873ndash879 2012

[28] S A Backman V Stambolic A Suzuki et al ldquoDeletion of Ptenin mouse brain causes seizures ataxia and defects in soma sizeresembling Lhermitte-Duclos diseaserdquo Nature Genetics vol 29no 4 pp 396ndash403 2001

[29] L Cotter M Ozcelik C Jacob et al ldquoDlg1-PTEN interactionregulates myelin thickness to prevent damaging peripheralnerve overmyelinationrdquo Science vol 328 no 5984 pp 1415ndash1418 2010

[30] S Ogawa C-H Kwon J Zhou D Koovakkattu L F Paradaand C M Sinton ldquoA seizure-prone phenotype is associatedwith altered free-running rhythm in Pten mutant micerdquo BrainResearch vol 1168 no 1 pp 112ndash123 2007

[31] C-H Kwon X Zhu J Zhang and S J Baker ldquomTor isrequired for hypertrophy of Pten-deficient neuronal soma invivordquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 22 pp 12923ndash12928 2003

[32] C-H Kwon B W Luikart C M Powell et al ldquoPten regulatesneuronal arborization and social interaction in micerdquo Neuronvol 50 no 3 pp 377ndash388 2006

[33] A Suzuki S Itami M Ohishi et al ldquoKeratinocyte-specific Ptendeficiency results in epidermal hyperplasia accelerated hairfollicle morphogenesis and tumor formationrdquo Cancer Researchvol 63 no 3 pp 674ndash681 2003

[34] T Inoue-Narita K Hamada T Sasaki et al ldquoPten deficiency inmelanocytes results in resistance to hair graying and susceptibil-ity to carcinogen-induced melanomagenesisrdquo Cancer Researchvol 68 no 14 pp 5760ndash5768 2008

[35] R K Patel and C Mohan ldquoPI3KAKT signaling and systemicautoimmunityrdquo Immunologic Research vol 31 no 1 pp 47ndash552005

[36] K Podsypanina L H Ellenson A Nemes et al ldquoMutationof PtenMmac1 in mice causes neoplasia in multiple organsystemsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 4 pp 1563ndash1568 1999

[37] M Kashiwada P Lu and P B Rothman ldquoPIP3 pathway inregulatory T cells and autoimmunityrdquo Immunologic Researchvol 39 no 1ndash3 pp 194ndash224 2007

[38] A Suzuki M T Yamaguchi T Ohteki et al ldquoT cell-specificloss of Pten leads to defects in central and peripheral tolerancerdquoImmunity vol 14 no 5 pp 523ndash534 2001

[39] Y Yamanaka H Tagawa N Takahashi et al ldquoAberrant over-expression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lym-phomaleukemiardquo Blood vol 114 no 15 pp 3265ndash3275 2009

[40] H Kishimoto T Ohteki N Yajima et al ldquoThe PtenPI3Kpathway governs the homeostasis of V12057214iNKT cellsrdquo Bloodvol 109 no 8 pp 3316ndash3324 2007

[41] A Suzuki T Kaisho M Ohishi et al ldquoCritical roles ofPten in B cell homeostasis and immunoglobulin class switchrecombinationrdquo Journal of Experimental Medicine vol 197 no5 pp 657ndash667 2003

Journal of Signal Transduction 11

[42] M Nishio K-IWatanabe J Sasaki et al ldquoControl of cell polar-ity and motility by the PtdIns(345)P

3phosphatase SHIP1rdquo

Nature Cell Biology vol 9 no 1 pp 36ndash44 2007[43] S Kuroda M Nishio T Sasaki et al ldquoEffective clearance

of intracellular Leishmania major in vivo requires Pten inmacrophagesrdquo European Journal of Immunology vol 38 no 5pp 1331ndash1340 2008

[44] O H Yilmaz R Valdez B K Theisen et al ldquoPten depen-dence distinguishes haematopoietic stem cells from leukaemia-initiating cellsrdquo Nature vol 441 no 7092 pp 475ndash482 2006

[45] Y Li K Podsypanina X Liu et al ldquoDeficiency of Ptenaccelerates mammary oncogenesis in MMTV-Wnt-1 transgenicmicerdquo BMCMolecular Biology vol 2 article 2 2001

[46] P Reddy L Liu D Adhikari et al ldquoOocyte-specific deletion ofpten causes premature activation of the primordial follicle poolrdquoScience vol 319 no 5863 pp 611ndash613 2008

[47] H Tsuruta H Kishimoto T Sasaki et al ldquoHyperplasia andcarcinomas in Pten-deficient mice and reduced PTEN proteinin human bladder cancer patientsrdquoCancer Research vol 66 no17 pp 8389ndash8396 2006

[48] L I Yoo D W Liu S Le Vu R T Bronson H Wu and JYuan ldquoPten deficiency activates distinct downstream signalingpathways in a tissue-specific mannerrdquo Cancer Research vol 66no 4 pp 1929ndash1939 2006

[49] J Li C Yen D Liaw et al ldquoPTEN a putative protein tyrosinephosphatase gene mutated in human brain breast and prostatecancerrdquo Science vol 275 no 5308 pp 1943ndash1947 1997

[50] N D Deocampo H Huang and D J Tindall ldquoThe role ofPTEN in the progression and survival of prostate cancerrdquoMinerva Endocrinologica vol 28 no 2 pp 145ndash153 2003

[51] S A Backman D Ghazarian K So et al ldquoEarly onset ofneoplasia in the prostate and skin of mice with tissue-specificdeletion of Ptenrdquo Proceedings of the National Academy ofSciences of the United States of America vol 101 no 6 pp 1725ndash1730 2004

[52] X Wu K Xu L Zhang et al ldquoDifferentiation of the ductalepithelium and smooth muscle in the prostate gland areregulated by the NotchPTEN-dependent mechanismrdquo Devel-opmental Biology vol 356 no 2 pp 337ndash349 2011

[53] D Kim and G R Dressler ldquoPTEN modulates GDNFRETmediated chemotaxis and branching morphogenesis in thedeveloping kidneyrdquo Developmental Biology vol 307 no 2 pp290ndash299 2007

[54] N O Lindstrom M L Lawrence S F Burn et al ldquoIntegrated120573-catenin BMP PTEN and notch signalling patterns thenephronrdquo eLife no 4 Article ID e04000 2015

[55] V Marsh D J Winton G T Williams et al ldquoEpithelialPten is dispensable for intestinal homeostasis but suppressesadenoma development and progression after Apc mutationrdquoNature Genetics vol 40 no 12 pp 1436ndash1444 2008

[56] S Matsuda M Kobayashi and Y Kitagishi ldquoRoles forPI3KAKTPTEN pathway in cell signaling of nonalcoholicfatty liver diseaserdquo ISRN Endocrinology vol 2013 Article ID472432 7 pages 2013

[57] X Qi J Xu P Gu X Yang and X Gao ldquoPTEN in smoothmuscle cells is essential for colonic immune homeostasisrdquoInternational Journal of Biochemistry and Cell Biology vol 53pp 108ndash114 2014

[58] A Pal T M Barber M Van de Bunt et al ldquoPTENmutations asa cause of constitutive insulin sensitivity and obesityrdquoThe NewEngland Journal of Medicine vol 367 no 11 pp 1002ndash1011 2012

[59] B L Stiles C Kuralwalla-Martinez W Guo et al ldquoSelectivedeletion of Pten in pancreatic 120573 cells leads to increased isletmass and resistance to STZ-induced diabetesrdquo Molecular andCellular Biology vol 26 no 7 pp 2772ndash2781 2006

[60] LWang C T Luk E P Cai et al ldquoPTEN deletion in pancreatic120572-cells protects against high-fat diet-induced hyperglucagone-mia and insulin resistancerdquo Diabetes vol 64 no 1 pp 147ndash1572015

[61] C Kurlawalla-Martinez B Stiles Y Wang S U Devaskar BB Kahn and H Wu ldquoInsulin hypersensitivity and resistanceto streptozotocin-induced diabetes in mice lacking PTEN inadipose tissuerdquo Molecular and Cellular Biology vol 25 no 6pp 2498ndash2510 2005

[62] N Wijesekara D Konrad M Eweida et al ldquoMuscle-specificPten deletion protects against insulin resistance and diabetesrdquoMolecular and Cellular Biology vol 25 no 3 pp 1135ndash11452005

[63] K Hamada T Sasaki P A Koni et al ldquoThe PTENPI3Kpathway governs normal vascular development and tumorangiogenesisrdquo Genes and Development vol 19 no 17 pp 2054ndash2065 2005

[64] N D Roe X Xu M R Kandadi et al ldquoTargeted deletionof PTEN in cardiomyocytes renders cardiac contractile dys-function through interruption of Pink1-AMPK signaling andautophagyrdquo Biochimica et Biophysica Acta Molecular Basis ofDisease vol 1852 no 2 pp 290ndash298 2015

[65] A F Ford-Hutchinson Z Ali S E Lines B HallgrımssonS K Boyd and F R Jirik ldquoInactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnor-malities and skeletal overgrowthrdquo Journal of Bone and MineralResearch vol 22 no 8 pp 1245ndash1259 2007

[66] T A Burgers M F Hoffmann C J Collins et al ldquoMice lackingpten in osteoblasts have improved intramembranous and lateendochondral fracture healingrdquo PLoS ONE vol 8 no 5 ArticleID e63857 2013

[67] N R Leslie L Spinelli P Tibarewal et al ldquoIndirect mecha-nisms of carcinogenesis via downregulation of PTEN functionrdquoAdvances in Enzyme Regulation vol 50 no 1 pp 112ndash118 2010

[68] L He ldquoPosttranscriptional regulation of PTEN dosage bynoncoding RNAsrdquo Science Signaling vol 3 no 146 article pe392010

[69] F Vazquez S R Grossman Y Takahashi M V Rokas NNakamura andWR Sellers ldquoPhosphorylation of the PTEN tailacts as an inhibitory switch by preventing its recruitment into aprotein complexrdquo The Journal of Biological Chemistry vol 276no 52 pp 48627ndash48630 2001

[70] X Wang L C Trotman T Koppie et al ldquoNEDD4-1 is a proto-oncogenic ubiquitin ligase for PTENrdquo Cell vol 128 no 1 pp129ndash139 2007

[71] N R Leslie and M Foti ldquoNon-genomic loss of PTEN functionin cancer not in my genesrdquo Trends in Pharmacological Sciencesvol 32 no 3 pp 131ndash140 2011

[72] Y Xing C Li L Hu et al ldquoMechanisms of TGF120573 inhibition ofLUNG endodermal morphogenesis the role of T120573RII SmadsNkx21 and Ptenrdquo Developmental Biology vol 320 no 2 pp340ndash350 2008

[73] J P Luyendyk G A Schabbauer M Tencati T Holscher RPawlinski and N Mackman ldquoGenetic analysis of the role ofthe PI3K-Akt pathway in lipopolysaccharide-induced cytokineand tissue factor gene expression in monocytesmacrophagesrdquoJournal of Immunology vol 180 no 6 pp 4218ndash4226 2008

12 Journal of Signal Transduction

[74] F Sun K K Park S Belin et al ldquoSustained axon regenerationinduced by co-deletion of PTEN and SOCS3rdquo Nature vol 480no 7377 pp 372ndash375 2011

[75] C B Knobbe V Lapin A Suzuki and T W Mak ldquoThe roles ofPTEN in development physiology and tumorigenesis in mousemodels a tissue-by-tissue surveyrdquo Oncogene vol 27 no 41 pp5398ndash5415 2008

[76] S J Assinder Q Dong Z Kovacevic and D R RichardsonldquoThe TGF-beta PI3KAkt and PTEN pathways establishedand proposed biochemical integration in prostate cancerrdquoBiochemical Journal vol 417 no 2 pp 411ndash421 2009

[77] K A Waite and C Eng ldquoFrom developmental disorder toheritable cancer itrsquos all in the BMPTGF-120573 familyrdquo NatureReviews Genetics vol 4 no 10 pp 763ndash773 2003

[78] H B Newton ldquoMolecular neuro-oncology and developmentof targeted therapeutic strategies for brain tumors Part2 PI3KAktPTEN mTOR SHHPTCH and angiogenesisrdquoExpert Review of Anticancer Therapy vol 4 no 1 pp 105ndash1282004

[79] R H KimM Peters Y Jang et al ldquoDJ-1 a novel regulator of thetumor suppressor PTENrdquo Cancer Cell vol 7 no 3 pp 263ndash2732005

[80] J Lu H W Jeong N Kong et al ldquoStem cell factor SALL4represses the transcriptions of PTEN and SALL1 through anepigenetic repressor complexrdquo PLoS ONE vol 4 no 5 ArticleID e5577 2009

[81] M M A Rizvi M S Alam A Ali S J Mehdi S Batra andA KMandal ldquoAberrant promotermethylation and inactivationof PTEN gene in cervical carcinoma from Indian populationrdquoJournal of Cancer Research and Clinical Oncology vol 137 no 8pp 1255ndash1262 2011

[82] J Liu ldquoControl of protein synthesis and mRNA degradation bymicroRNAsrdquo Current Opinion in Cell Biology vol 20 no 2 pp214ndash221 2008

[83] S W Shan L Fang T Shatseva et al ldquoMature miR-17-5pand passenger miR-17-3p induce hepatocellular carcinoma bytargeting PTEN GalNT7 and vimentin in different signalpathwaysrdquo Journal of Cell Science vol 126 part 6 pp 1517ndash15302013

[84] Z Liang Y Li K Huang N Wagar and H Shim ldquoRegulationof miR-19 to breast cancer chemoresistance through targetingPTENrdquo Pharmaceutical Research vol 28 no 12 pp 3091ndash31002011

[85] X Lu Q Fan L Xu et al ldquoUrsolic acid attenuates diabeticmesangial cell injury through the up-regulation of autophagyvia miRNA-21PTENAktmTOR suppressionrdquo PLoS ONE vol10 no 2 Article ID e0117400 2015

[86] L Poliseno L Salmena J Zhang B Carver W J Havemanand P P Pandolfi ldquoA coding-independent function of geneand pseudogenemRNAs regulates tumour biologyrdquoNature vol465 no 7301 pp 1033ndash1038 2010

[87] Y Tay L Kats L Salmena et al ldquoCoding-independent regula-tion of the tumor suppressor PTEN by competing endogenousmRNAsrdquo Cell vol 147 no 2 pp 344ndash357 2011

[88] L Odriozola G Singh T Hoang and A M Chan ldquoRegula-tion of PTEN activity by its carboxyl-terminal autoinhibitorydomainrdquo The Journal of Biological Chemistry vol 282 no 32pp 23306ndash23315 2007

[89] Z Li X Dong Z Wang et al ldquoRegulation of PTEN by Rhosmall GTPasesrdquo Nature Cell Biology vol 7 no 4 pp 399ndash4042005

[90] E-K Yim G Peng H Dai et al ldquoRak functions as a tumorsuppressor by regulating PTEN protein stability and functionrdquoCancer Cell vol 15 no 4 pp 304ndash314 2009

[91] AMAl-Khouri YMa SH Togo SWilliams andTMustelinldquoCooperative phosphorylation of the tumor suppressor phos-phatase and tensin homologue (PTEN) by casein kinasesand glycogen synthase kinase 3120573rdquo The Journal of BiologicalChemistry vol 280 no 42 pp 35195ndash35202 2005

[92] H Maccario N M Perera L Davidson C P Downes and NR Leslie ldquoPTEN is destabilized by phosphorylation onThr366rdquoBiochemical Journal vol 405 no 3 pp 439ndash444 2007

[93] K A Waite and C Eng ldquoBMP2 exposure results in decreasedPTEN protein degradation and increased PTEN levelsrdquoHumanMolecular Genetics vol 12 no 6 pp 679ndash684 2003

[94] T J Jerde Z Wu D Theodorescu and W Bushman ldquoRegu-lation of phosphatase homologue of tensin protein expressionby bone morphogenetic proteins in prostate epithelial cellsrdquoProstate vol 71 no 8 pp 791ndash800 2011

[95] G Singh and A M Chan ldquoPost-translational modificationsof PTEN and their potential therapeutic implicationsrdquo CurrentCancer Drug Targets vol 11 no 5 pp 536ndash547 2011

[96] T Ikenoue K Inoki B Zhao and K-L Guan ldquoPTEN acety-lation modulates its interaction with PDZ domainrdquo CancerResearch vol 68 no 17 pp 6908ndash6912 2008

[97] L C Trotman X Wang A Alimonti et al ldquoUbiquitinationregulates PTEN nuclear import and tumor suppressionrdquo Cellvol 128 no 1 pp 141ndash156 2007

[98] T Tolkacheva M Boddapati A Sanfiz K Tsuchida A CKimmelman and AM-L Chan ldquoRegulation of PTEN bindingto MAGI-2 by two putative phosphorylation sites at threonine382 and 383rdquo Cancer Research vol 61 no 13 pp 4985ndash49892001

[99] E Lima-Fernandes H Enslen E Camand et al ldquoDistinct func-tional outputs of PTEN signalling are controlled by dynamicassociation with 120573-arrestinsrdquoThe EMBO Journal vol 30 no 13pp 2557ndash2568 2011

[100] M T van Diepen M Parsons C P Downes N R Leslie RHindges and B J Eickholt ldquoMyosinV controls PTEN functionand neuronal cell sizerdquo Nature Cell Biology vol 11 no 10 pp1191ndash1196 2009

[101] R B Chagpar P H Links M C Pastor et al ldquoDirect positiveregulation of PTEN by the p85 subunit of phosphatidylinositol3-kinaserdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 107 no 12 pp 5471ndash5476 2010

[102] Y Takahashi F C Morales E L Kreimann and M-MGeorgescu ldquoPTEN tumor suppressor associates with NHERFproteins to attenuate PDGF receptor signalingrdquo The EMBOJournal vol 25 no 4 pp 910ndash920 2006

[103] M Valiente A Andres-Pons B Gomar et al ldquoBinding ofPTEN to specific PDZ domains contributes to PTEN proteinstability and phosphorylation by microtubule-associated ser-inethreonine kinasesrdquoThe Journal of Biological Chemistry vol280 no 32 pp 28936ndash28943 2005

[104] SQuintes SGoebbels G SaherMH Schwab andK-ANaveldquoNeuron-glia signaling and the protection of axon function bySchwann cellsrdquo Journal of the Peripheral Nervous System vol 15no 1 pp 10ndash16 2010

[105] B Fine C Hodakoski S Koujak et al ldquoActivation of the PI3Kpathway in cancer through inhibition of PTEN by exchangefactor P-REX2ardquo Science vol 325 no 5945 pp 1261ndash1265 2009

Journal of Signal Transduction 13

[106] L He A Ingram A P Rybak and D Tang ldquoShank-interactingprotein-like 1 promotes tumorigenesis via PTEN inhibition inhuman tumor cellsrdquo The Journal of Clinical Investigation vol120 no 6 pp 2094ndash2108 2010

[107] L He C Fan A Kapoor et al ldquo120572-Mannosidase 2C1 attenuatesPTEN function in prostate cancer cellsrdquo Nature Communica-tions vol 2 no 1 article 307 2011

[108] Z Radisavljevic ldquoAKT as locus of cancer positive feedbackloops and extreme robustnessrdquo Journal of Cellular Physiologyvol 228 no 3 pp 522ndash524 2013

[109] M Y Lee HW Lim S H Lee andH J Han ldquoSmad PI3KAktand wnt-dependent signaling pathways are involved in BMP-4-induced ESC self-renewalrdquo Stem Cells vol 27 no 8 pp 1858ndash1868 2009

[110] K Song S C Cornelius M Reiss and D Danielpour ldquoInsulin-like growth factor-I inhibits transcriptional responses of trans-forming growth factor-120573 by phosphatidylinositol 3-kinaseAkt-dependent suppression of the activation of Smad3 but notSmad2rdquoThe Journal of Biological Chemistry vol 278 no 40 pp38342ndash38351 2003

[111] D Fang D Hawke Y Zheng et al ldquoPhosphorylation of 120573-catenin by AKT promotes 120573-catenin transcriptional activityrdquoThe Journal of Biological Chemistry vol 282 no 15 pp 11221ndash11229 2007

[112] Q Lei J Jiao L Xin et al ldquoNKX31 stabilizes p53 inhibitsAKT activation and blocks prostate cancer initiation caused byPTEN lossrdquo Cancer Cell vol 9 no 5 pp 367ndash378 2006

[113] A Sengupta J D Molkentin J-H Paik R A DePinho and KE Yutzey ldquoFoxO transcription factors promote cardiomyocytesurvival upon induction of oxidative stressrdquo The Journal ofBiological Chemistry vol 286 no 9 pp 7468ndash7478 2011

[114] C H M Jamieson L E Ailles S J Dylla et al ldquoGranulocyte-macrophage progenitors as candidate leukemic stem cells inblast-crisis CMLrdquoTheNewEngland Journal ofMedicine vol 351no 7 pp 657ndash667 2004

[115] A Androutsellis-Theotokis R R Leker F Soldner et al ldquoNotchsignalling regulates stem cell numbers in vitro and in vivordquoNature vol 442 no 7104 pp 823ndash826 2006

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Page 8: Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling TravisJ.Jerde Department of Pharmacology

8 Journal of Signal Transduction

junctions [98] Mutations to these residues prevent PTENrecruitment Upon recruitment 120573-arrestins modulate PTENactivity by direct binding to the C2 domain and modulatingits protein phosphatase activity including that at the levelof small GTPases including RhoAROCK [99] In addi-tion Myosin V regulates PTENrsquos movement to and fromthe plasma membrane and this function is required forPTEN to access its phosphoinositide substrates [100] andfor disrupting the proper regulation of neuronal cell sizeThe p85 regulatory subunit of the PI

3kinase enzyme itself

interacts with PTEN in a novel mechanism of repressing thePI3KndashAKT pathway [101] independent of PTENrsquos action as a

phosphatase It is therefore proposed that p85 regulates thePI3KndashAKT pathway bidirectionally both through its binding

to catalytic p110 subunit resulting in the generation of phos-phoinositides and by binding PTEN leading to repressionThis work proposes a novel signaling model for PTEN-p85association in which p85120572 preferentially binds and stabilizesp110 preferentially when p85120572 levels are low but excess p85120572binds to and positively regulates PTEN phosphatase activitywhen p110 is saturated Therefore sustained activation ofPI3K signaling and activated p110-p85 complexing is modu-lated homeostatically by this mechanism

A fascinating group of recent studies have utilizedproteomic library screens to identify further novel PTENinteracting proteins First the Na+H+ exchanger regulatoryfactor (NHERF) binds to and recruits PTEN to the platelet-derived growth factor receptor (PDGFR) This representsanother action that restricts PI

3KndashAKT pathway activation

independent of phosphatase activity [102] This has the effectof inhibiting PDGF-induced cytoskeletal rearrangements andchemotactic migration of developing neurons In additionthe mammalian disks large homologue 1 (DLG1) MAGI-2 and MAST205 proteins directly interact with PTENand enhance PTEN stability and activity [103] Furtherneuregulin 1 (NRG1) has been shown to interact with bothDLG1 and PTEN in a stable complex that has the effect ofregulating myelin sheath thickness in developing mouse sci-atic nerves [104] Additional but less-characterized protein-protein interactions that modulate PTEN function includethe PIP

3-dependent RAC exchanger factor 2a (PREX2a)

[105] shank-interacting protein-like 1 (SIPL1) [106] and 120572-mannosidase 2C1 (MAN2C1) [107]

325 PTEN-Controlled Signal Transduction during Develop-ment PTEN is critically important in regulating signalingpathways involved in cell growth and animal developmentThrough its well-characterized function as a phosphataseof PIP

3 PTEN modulates a network of mitogen-activated

signals transduced through PI3KndashAkt signaling This pri-

mary action of PTEN has tremendous impact on cell growthcell migration cell death and cell differentiationmdashcellularprocesses that are all hallmarks of proper growth andpatterning during development The active phosphorylatedPIP3activates several signaling molecules including the

phosphatidylinositol-dependent kinases (PDKs) followed byAkt S6 kinase and mTOR Beyond this AKTrsquos targetsinclude the apoptotic factor BAD activator and executioner

caspases glycogen synthase kinase-3 (GSK-3) MDM2 p21and p27 forkhead transcription factors (FOXOs) and nuclearreceptors including the androgen and estrogen receptors[108] Akt-mediated phosphorylation of these moleculescauses activation translocation and increased stability

The PTENPI3kinaseAKT signaling cascade crosstalks

to several key signal transduction pathways that are criticalto developmental biology This includes the abovementionedTGF-120573SMAD pathway and the Wnt120573-catenin pathway[109] The TGF-120573SMAD pathway is one of the most seminalpathways in developmental biology and PTEN modulatesTGF120573SMAD signaling by reversing Akt-mediated phospho-rylation of SMAD3 the critical signaling intermediate ofTGF120573SMAD signaling [110] Similarly the Wnt signalingpathway is indispensable for properly regulated developmentcellular proliferation and differentiation [111] PTEN regu-lates this pathway by reversing AKT kinase phosphorylationand inhibition of GSK-3120573 resulting in 120573-catenin nucleartranslocation and activation Finally recent studies demon-strate that PTEN regulates the expression and action of thehomeobox genes NKX31 and hepatic nuclear factor [112]proteins that are critical to organ development

326 PTEN-Regulated Stem Cell Activities The scientificliterature in the field of tissue stem or stem-like ldquoprogen-itorrdquo cells and their role in tissue development growthrecovery and repair has become beyond extensive in recentyears Expansion of stemprogenitor cells is a hallmark ofgrowth and patterning during development and regulationof these cells including their proliferation maintenanceand differentiation is a critical factor of developmentalregulation Because of this a review of the current liter-ature on PTENrsquos role in stem and tissue progenitor cellsis warranted in this review PTEN plays an important rolein regulating the homeostasis of stemprogenitor cells inmultiple tissues Interestingly PTEN regulates both self-renewal and proliferation but paradoxically it also playsa role in stem cell exhaustion For example the FOXOfamily of transcription factors controls stem cell proliferationand survival in hematopoietic stem cells [113] and PTENsignaling is a critical modulator of FOXO activity FOXO3A-deficient HSCs exhibit increased proliferation rate decreasedquiescence and a reduced ability to repopulate bone marrowafter transplantation into recipient mice Additionally thepreviously mentioned Wnt120573-catenin signaling pathway iscritical for HSC self-renewal and its activation is well knownto be modulated by PTEN Interestingly PTEN loss and AKTactivation in HSCs lead to a moderate increase in the levelof unphosphorylated 120573-catenin but this is not sufficient tomaintain Pten-null HSC self-renewal [114] Finally NOTCHsignaling plays a key role in regulating neural stem cellexpansion [115] and as stated previously NOTCH pathwayactivation leads to reduced PTEN expression in neural andhematopoietic stem cells

4 Conclusions

PTEN acts as the key endogenous negative modulatorof phosphoinositide signaling in mammalian cells and

Journal of Signal Transduction 9

therefore its role in normal cell homeostasis proliferationapoptosis and many additional components of cell biologyis extensive Because PTEN regulates cancer progressionmuch of what has been studied regarding PTEN relates totumorigenesis and tumor growth While this is warrantedbecause of the relevance of cancer to humanhealth PTENhassubstantial but underappreciated effects in normal tissue andorgan development immune system development and reg-ulation axonal regeneration glucose regulation and benigngrowth disorders PTEN is often dogmatically thought ofas a constitutive protein that exhibits lost activity duringdiseases butwhat is underappreciated is that PTENhas a verycomplex regulation network that involves signaling path-ways that regulate PTEN transcription transcript stabilityposttranslationalmodifications protein-protein interactionsand cellular location PTEN then in turn regulates numerousdevelopmental signaling networks that are critical to devel-opment and adult tissue maintenance

Abbreviations

Bcl2 B-cell lymphoma 2Bim BCL-2-interacting mediatorCK2 Casein Kinase 2CREB Cyclic AMP response element binding

proteinDLG Disks large homolog 1Egr-1 Early growth response protein 1Erk Extracellular regulated kinaseFOX Forkhead transcription factorsGSK3120573 Glycogen synthase kinase 3JNK Jun-terminal kinaseMAGI2 Membrane-associated guanylate kinase

inverted 2MAN2C1 Mannosidase alpha class 2C member 1MDM2 Mouse double minute 2 homologmTOR Mechanistic target of rapamycinNHERF Sodium-hydrogen antiporter 3

regulator 1NRG1 Neuregulin 1PCAF P300CBP-associated factorPDZ Postsynaptic density proteinmdashDisc

large tumor suppressormdashZonulaoccludens-1 protein

PIP3 Phosphoinositide triphosphatePPAR120574 Peroxisome proliferating antigen

receptorPREX2a Phosphatidylinositol-345-

trisphosphate-dependent Rac exchangefactor A

PTEN Phosphatase and Tensin homologueROCK Rho-associated coiled-coil-containing

protein kinaseSALL Spalt-like transcription factor-1SIPL1 Shank-interacting protein-like 1SIRT1 Sirtuin 1SMAD Small mothers against decapentaplegicSOCS Suppressor of cytokine signalingTGF120573 Transforming growth factor-beta

Disclosure

Travis J Jerde carried out the extensive literature reviewrequired to write this paper and have written the entirepaper The author has therefore read and approved the papersubmitted

Conflict of Interests

The author has no financial or nonfinancial conflict ofinterests with the submission of this paper

Acknowledgments

The author gratefully acknowledges the financial supportof the Indiana University School of Medicine Departmentof Pharmacology and Toxicology and the Melvin and BrynSimon Cancer Center The author also gratefully acknowl-edges this paper as part of his training made possible byNational Institutes of Health-NIDDK (DK092366-01A1)

References

[1] M Milella I Falcone F Conciatori et al ldquoPTEN multiplefunctions in human malignant tumorsrdquo Frontiers in Oncologyvol 5 article 24 2015

[2] J-O Lee H Yang M-M Georgescu et al ldquoCrystal structure ofthe PTEN tumor suppressor implications for its phosphoinosi-tide phosphatase activity and membrane associationrdquo Cell vol99 no 3 pp 323ndash334 1999

[3] W-L Yang G Jin C-F Li et al ldquoCycles of ubiquitinationand deubiquitination critically regulate growth factor-mediatedactivation of Akt signalingrdquo Science Signaling vol 6 no 257article ra3 2013

[4] J Gu S Nada M Okada and K Sekiguchi ldquoCsk regulatesintegrin-mediated signals involvement of differential activa-tion of ERK and Aktrdquo Biochemical and Biophysical ResearchCommunications vol 303 no 3 pp 973ndash977 2003

[5] A Clerk and P H Sugden ldquoActivation of protein kinase cas-cades in the heart by hypertrophic G protein-coupled receptoragonistsrdquoTheAmerican Journal of Cardiology vol 83 no 12 pp64Hndash69H 1999

[6] I Tonic W-N Yu Y Park C-C Chen and N Hay ldquoAktactivation emulates Chk1 inhibition and Bcl2 overexpressionand abrogates G2 cell cycle checkpoint by inhibiting BRCA1focirdquo The Journal of Biological Chemistry vol 285 no 31 pp23790ndash23798 2010

[7] S Fatrai L Elghazi N Balcazar et al ldquoAkt induces 120573-cellproliferation by regulating cyclin D1 cyclin D2 and p21 levelsand cyclin-dependent kinase-4 activityrdquo Diabetes vol 55 no 2pp 318ndash325 2006

[8] M Aoki E Blazek and P K Vogt ldquoA role of the kinase mTORin cellular transformation induced by the oncoproteins P3k andAktrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 98 no 1 pp 136ndash141 2001

[9] H Guan L Song J Cai et al ldquoSphingosine kinase 1 regulatesthe AktFOXO3aBim pathway and contributes to apoptosisresistance in glioma cellsrdquo PLoS ONE vol 6 no 5 Article IDe19946 2011

[10] T D Dung C H Day T V Binh et al ldquoPP2Amediates diosminp53 activation to block HA22T cell proliferation and tumor

10 Journal of Signal Transduction

growth in xenografted nude mice through PI3K-Akt-MDM2signaling suppressionrdquo Food and Chemical Toxicology vol 50no 5 pp 1802ndash1810 2012

[11] K Shanmugasundaram K Block B K Nayak C B Livi MA Venkatachalam and S Sudarshan ldquoPI3K regulation of theSKP-2p27 axis through mTORC2rdquo Oncogene vol 32 no 16pp 2027ndash2036 2013

[12] J-C Chang H-H Chang C-T Lin and S J Lo ldquoThe integrin12057261205731modulation of PI3K andCdc42 activities induces dynamicfilopodium formation in humanplateletsrdquo Journal of BiomedicalScience vol 12 no 6 pp 881ndash898 2005

[13] E Hajduch G J Litherland and H S Hundal ldquoProtein kinaseB (PKBAkt)mdasha key regulator of glucose transportrdquo FEBSLetters vol 492 no 3 pp 199ndash203 2001

[14] M M Martin J A Buckenberger J Jiang et al ldquoTGF-beta1stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[15] M M Martin J A Buckenberger J Jiang et al ldquoTGF-1205731stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[16] K Abell and C J Watson ldquoThe JakStat pathway a novel wayto regulate PI3K activityrdquo Cell Cycle vol 4 no 7 pp 897ndash9002005

[17] J-Y Hwang R S Duncan C Madry M Singh and P KoulenldquoProgesterone potentiates calcium release through IP3 recep-tors by an Akt-mediated mechanism in hippocampal neuronsrdquoCell Calcium vol 45 no 3 pp 233ndash242 2009

[18] G Pappas L A Zumstein A Munshi M Hobbs and R EMeyn ldquoAdenoviral-mediated PTEN expression radiosensitizesnon-small cell lung cancer cells by suppressing DNA repaircapacityrdquoCancer GeneTherapy vol 14 no 6 pp 543ndash549 2007

[19] A Di Cristofano B Pesce C Cordon-Cardo and P P PandolfildquoPten is essential for embryonic development and tumoursuppressionrdquo Nature Genetics vol 19 no 4 pp 348ndash355 1998

[20] J Bloomekatz J Grego-Bessa I Migeotte and K V AndersonldquoPten regulates collective cell migration during specification ofthe anterior-posterior axis of the mouse embryordquo Developmen-tal Biology vol 364 no 2 pp 192ndash201 2012

[21] S Ueno R Kono andY Iwao ldquoPTEN is required for the normalprogression of gastrulation by repressing cell proliferation afterMBT in Xenopus embryosrdquoDevelopmental Biology vol 297 no1 pp 274ndash283 2006

[22] C B Knobbe A Merlo and G Reifenberger ldquoPten signaling ingliomasrdquo Neuro Oncology vol 4 pp 196ndash211 2002

[23] E Kirches J Steiner T Schneider et al ldquoLhermitte-Duclosdisease caused by a novel germline PTEN mutation R173P in apatient presenting with psychosisrdquoNeuropathology and AppliedNeurobiology vol 36 no 1 pp 86ndash89 2010

[24] J-I Murata M Tada Y Sawamura K Mitsumori H Abe andK Nagashima ldquoDysplastic gangliocytoma (Lhermitte-Duclosdisease) associated with Cowden disease report of a case andreview of the literature for the genetic relationship between thetwo diseasesrdquo Journal of Neuro-Oncology vol 41 no 2 pp 129ndash136 1999

[25] G Zhu L M L Chow I T Bayazitov et al ldquoPten deletioncauses mTorc1-dependent ectopic neuroblast differentiation

without causing uniform migration defectsrdquo Development vol139 no 18 pp 3422ndash3431 2012

[26] K L McBride E A Varga M T Pastore et al ldquoConfirmationstudy of PTEN mutations among individuals with autism ordevelopmental delaysmental retardation and macrocephalyrdquoAutism Research vol 3 no 3 pp 137ndash141 2010

[27] J Zhou and L F Parada ldquoPTEN signaling in autism spectrumdisordersrdquo Current Opinion in Neurobiology vol 22 no 5 pp873ndash879 2012

[28] S A Backman V Stambolic A Suzuki et al ldquoDeletion of Ptenin mouse brain causes seizures ataxia and defects in soma sizeresembling Lhermitte-Duclos diseaserdquo Nature Genetics vol 29no 4 pp 396ndash403 2001

[29] L Cotter M Ozcelik C Jacob et al ldquoDlg1-PTEN interactionregulates myelin thickness to prevent damaging peripheralnerve overmyelinationrdquo Science vol 328 no 5984 pp 1415ndash1418 2010

[30] S Ogawa C-H Kwon J Zhou D Koovakkattu L F Paradaand C M Sinton ldquoA seizure-prone phenotype is associatedwith altered free-running rhythm in Pten mutant micerdquo BrainResearch vol 1168 no 1 pp 112ndash123 2007

[31] C-H Kwon X Zhu J Zhang and S J Baker ldquomTor isrequired for hypertrophy of Pten-deficient neuronal soma invivordquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 22 pp 12923ndash12928 2003

[32] C-H Kwon B W Luikart C M Powell et al ldquoPten regulatesneuronal arborization and social interaction in micerdquo Neuronvol 50 no 3 pp 377ndash388 2006

[33] A Suzuki S Itami M Ohishi et al ldquoKeratinocyte-specific Ptendeficiency results in epidermal hyperplasia accelerated hairfollicle morphogenesis and tumor formationrdquo Cancer Researchvol 63 no 3 pp 674ndash681 2003

[34] T Inoue-Narita K Hamada T Sasaki et al ldquoPten deficiency inmelanocytes results in resistance to hair graying and susceptibil-ity to carcinogen-induced melanomagenesisrdquo Cancer Researchvol 68 no 14 pp 5760ndash5768 2008

[35] R K Patel and C Mohan ldquoPI3KAKT signaling and systemicautoimmunityrdquo Immunologic Research vol 31 no 1 pp 47ndash552005

[36] K Podsypanina L H Ellenson A Nemes et al ldquoMutationof PtenMmac1 in mice causes neoplasia in multiple organsystemsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 4 pp 1563ndash1568 1999

[37] M Kashiwada P Lu and P B Rothman ldquoPIP3 pathway inregulatory T cells and autoimmunityrdquo Immunologic Researchvol 39 no 1ndash3 pp 194ndash224 2007

[38] A Suzuki M T Yamaguchi T Ohteki et al ldquoT cell-specificloss of Pten leads to defects in central and peripheral tolerancerdquoImmunity vol 14 no 5 pp 523ndash534 2001

[39] Y Yamanaka H Tagawa N Takahashi et al ldquoAberrant over-expression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lym-phomaleukemiardquo Blood vol 114 no 15 pp 3265ndash3275 2009

[40] H Kishimoto T Ohteki N Yajima et al ldquoThe PtenPI3Kpathway governs the homeostasis of V12057214iNKT cellsrdquo Bloodvol 109 no 8 pp 3316ndash3324 2007

[41] A Suzuki T Kaisho M Ohishi et al ldquoCritical roles ofPten in B cell homeostasis and immunoglobulin class switchrecombinationrdquo Journal of Experimental Medicine vol 197 no5 pp 657ndash667 2003

Journal of Signal Transduction 11

[42] M Nishio K-IWatanabe J Sasaki et al ldquoControl of cell polar-ity and motility by the PtdIns(345)P

3phosphatase SHIP1rdquo

Nature Cell Biology vol 9 no 1 pp 36ndash44 2007[43] S Kuroda M Nishio T Sasaki et al ldquoEffective clearance

of intracellular Leishmania major in vivo requires Pten inmacrophagesrdquo European Journal of Immunology vol 38 no 5pp 1331ndash1340 2008

[44] O H Yilmaz R Valdez B K Theisen et al ldquoPten depen-dence distinguishes haematopoietic stem cells from leukaemia-initiating cellsrdquo Nature vol 441 no 7092 pp 475ndash482 2006

[45] Y Li K Podsypanina X Liu et al ldquoDeficiency of Ptenaccelerates mammary oncogenesis in MMTV-Wnt-1 transgenicmicerdquo BMCMolecular Biology vol 2 article 2 2001

[46] P Reddy L Liu D Adhikari et al ldquoOocyte-specific deletion ofpten causes premature activation of the primordial follicle poolrdquoScience vol 319 no 5863 pp 611ndash613 2008

[47] H Tsuruta H Kishimoto T Sasaki et al ldquoHyperplasia andcarcinomas in Pten-deficient mice and reduced PTEN proteinin human bladder cancer patientsrdquoCancer Research vol 66 no17 pp 8389ndash8396 2006

[48] L I Yoo D W Liu S Le Vu R T Bronson H Wu and JYuan ldquoPten deficiency activates distinct downstream signalingpathways in a tissue-specific mannerrdquo Cancer Research vol 66no 4 pp 1929ndash1939 2006

[49] J Li C Yen D Liaw et al ldquoPTEN a putative protein tyrosinephosphatase gene mutated in human brain breast and prostatecancerrdquo Science vol 275 no 5308 pp 1943ndash1947 1997

[50] N D Deocampo H Huang and D J Tindall ldquoThe role ofPTEN in the progression and survival of prostate cancerrdquoMinerva Endocrinologica vol 28 no 2 pp 145ndash153 2003

[51] S A Backman D Ghazarian K So et al ldquoEarly onset ofneoplasia in the prostate and skin of mice with tissue-specificdeletion of Ptenrdquo Proceedings of the National Academy ofSciences of the United States of America vol 101 no 6 pp 1725ndash1730 2004

[52] X Wu K Xu L Zhang et al ldquoDifferentiation of the ductalepithelium and smooth muscle in the prostate gland areregulated by the NotchPTEN-dependent mechanismrdquo Devel-opmental Biology vol 356 no 2 pp 337ndash349 2011

[53] D Kim and G R Dressler ldquoPTEN modulates GDNFRETmediated chemotaxis and branching morphogenesis in thedeveloping kidneyrdquo Developmental Biology vol 307 no 2 pp290ndash299 2007

[54] N O Lindstrom M L Lawrence S F Burn et al ldquoIntegrated120573-catenin BMP PTEN and notch signalling patterns thenephronrdquo eLife no 4 Article ID e04000 2015

[55] V Marsh D J Winton G T Williams et al ldquoEpithelialPten is dispensable for intestinal homeostasis but suppressesadenoma development and progression after Apc mutationrdquoNature Genetics vol 40 no 12 pp 1436ndash1444 2008

[56] S Matsuda M Kobayashi and Y Kitagishi ldquoRoles forPI3KAKTPTEN pathway in cell signaling of nonalcoholicfatty liver diseaserdquo ISRN Endocrinology vol 2013 Article ID472432 7 pages 2013

[57] X Qi J Xu P Gu X Yang and X Gao ldquoPTEN in smoothmuscle cells is essential for colonic immune homeostasisrdquoInternational Journal of Biochemistry and Cell Biology vol 53pp 108ndash114 2014

[58] A Pal T M Barber M Van de Bunt et al ldquoPTENmutations asa cause of constitutive insulin sensitivity and obesityrdquoThe NewEngland Journal of Medicine vol 367 no 11 pp 1002ndash1011 2012

[59] B L Stiles C Kuralwalla-Martinez W Guo et al ldquoSelectivedeletion of Pten in pancreatic 120573 cells leads to increased isletmass and resistance to STZ-induced diabetesrdquo Molecular andCellular Biology vol 26 no 7 pp 2772ndash2781 2006

[60] LWang C T Luk E P Cai et al ldquoPTEN deletion in pancreatic120572-cells protects against high-fat diet-induced hyperglucagone-mia and insulin resistancerdquo Diabetes vol 64 no 1 pp 147ndash1572015

[61] C Kurlawalla-Martinez B Stiles Y Wang S U Devaskar BB Kahn and H Wu ldquoInsulin hypersensitivity and resistanceto streptozotocin-induced diabetes in mice lacking PTEN inadipose tissuerdquo Molecular and Cellular Biology vol 25 no 6pp 2498ndash2510 2005

[62] N Wijesekara D Konrad M Eweida et al ldquoMuscle-specificPten deletion protects against insulin resistance and diabetesrdquoMolecular and Cellular Biology vol 25 no 3 pp 1135ndash11452005

[63] K Hamada T Sasaki P A Koni et al ldquoThe PTENPI3Kpathway governs normal vascular development and tumorangiogenesisrdquo Genes and Development vol 19 no 17 pp 2054ndash2065 2005

[64] N D Roe X Xu M R Kandadi et al ldquoTargeted deletionof PTEN in cardiomyocytes renders cardiac contractile dys-function through interruption of Pink1-AMPK signaling andautophagyrdquo Biochimica et Biophysica Acta Molecular Basis ofDisease vol 1852 no 2 pp 290ndash298 2015

[65] A F Ford-Hutchinson Z Ali S E Lines B HallgrımssonS K Boyd and F R Jirik ldquoInactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnor-malities and skeletal overgrowthrdquo Journal of Bone and MineralResearch vol 22 no 8 pp 1245ndash1259 2007

[66] T A Burgers M F Hoffmann C J Collins et al ldquoMice lackingpten in osteoblasts have improved intramembranous and lateendochondral fracture healingrdquo PLoS ONE vol 8 no 5 ArticleID e63857 2013

[67] N R Leslie L Spinelli P Tibarewal et al ldquoIndirect mecha-nisms of carcinogenesis via downregulation of PTEN functionrdquoAdvances in Enzyme Regulation vol 50 no 1 pp 112ndash118 2010

[68] L He ldquoPosttranscriptional regulation of PTEN dosage bynoncoding RNAsrdquo Science Signaling vol 3 no 146 article pe392010

[69] F Vazquez S R Grossman Y Takahashi M V Rokas NNakamura andWR Sellers ldquoPhosphorylation of the PTEN tailacts as an inhibitory switch by preventing its recruitment into aprotein complexrdquo The Journal of Biological Chemistry vol 276no 52 pp 48627ndash48630 2001

[70] X Wang L C Trotman T Koppie et al ldquoNEDD4-1 is a proto-oncogenic ubiquitin ligase for PTENrdquo Cell vol 128 no 1 pp129ndash139 2007

[71] N R Leslie and M Foti ldquoNon-genomic loss of PTEN functionin cancer not in my genesrdquo Trends in Pharmacological Sciencesvol 32 no 3 pp 131ndash140 2011

[72] Y Xing C Li L Hu et al ldquoMechanisms of TGF120573 inhibition ofLUNG endodermal morphogenesis the role of T120573RII SmadsNkx21 and Ptenrdquo Developmental Biology vol 320 no 2 pp340ndash350 2008

[73] J P Luyendyk G A Schabbauer M Tencati T Holscher RPawlinski and N Mackman ldquoGenetic analysis of the role ofthe PI3K-Akt pathway in lipopolysaccharide-induced cytokineand tissue factor gene expression in monocytesmacrophagesrdquoJournal of Immunology vol 180 no 6 pp 4218ndash4226 2008

12 Journal of Signal Transduction

[74] F Sun K K Park S Belin et al ldquoSustained axon regenerationinduced by co-deletion of PTEN and SOCS3rdquo Nature vol 480no 7377 pp 372ndash375 2011

[75] C B Knobbe V Lapin A Suzuki and T W Mak ldquoThe roles ofPTEN in development physiology and tumorigenesis in mousemodels a tissue-by-tissue surveyrdquo Oncogene vol 27 no 41 pp5398ndash5415 2008

[76] S J Assinder Q Dong Z Kovacevic and D R RichardsonldquoThe TGF-beta PI3KAkt and PTEN pathways establishedand proposed biochemical integration in prostate cancerrdquoBiochemical Journal vol 417 no 2 pp 411ndash421 2009

[77] K A Waite and C Eng ldquoFrom developmental disorder toheritable cancer itrsquos all in the BMPTGF-120573 familyrdquo NatureReviews Genetics vol 4 no 10 pp 763ndash773 2003

[78] H B Newton ldquoMolecular neuro-oncology and developmentof targeted therapeutic strategies for brain tumors Part2 PI3KAktPTEN mTOR SHHPTCH and angiogenesisrdquoExpert Review of Anticancer Therapy vol 4 no 1 pp 105ndash1282004

[79] R H KimM Peters Y Jang et al ldquoDJ-1 a novel regulator of thetumor suppressor PTENrdquo Cancer Cell vol 7 no 3 pp 263ndash2732005

[80] J Lu H W Jeong N Kong et al ldquoStem cell factor SALL4represses the transcriptions of PTEN and SALL1 through anepigenetic repressor complexrdquo PLoS ONE vol 4 no 5 ArticleID e5577 2009

[81] M M A Rizvi M S Alam A Ali S J Mehdi S Batra andA KMandal ldquoAberrant promotermethylation and inactivationof PTEN gene in cervical carcinoma from Indian populationrdquoJournal of Cancer Research and Clinical Oncology vol 137 no 8pp 1255ndash1262 2011

[82] J Liu ldquoControl of protein synthesis and mRNA degradation bymicroRNAsrdquo Current Opinion in Cell Biology vol 20 no 2 pp214ndash221 2008

[83] S W Shan L Fang T Shatseva et al ldquoMature miR-17-5pand passenger miR-17-3p induce hepatocellular carcinoma bytargeting PTEN GalNT7 and vimentin in different signalpathwaysrdquo Journal of Cell Science vol 126 part 6 pp 1517ndash15302013

[84] Z Liang Y Li K Huang N Wagar and H Shim ldquoRegulationof miR-19 to breast cancer chemoresistance through targetingPTENrdquo Pharmaceutical Research vol 28 no 12 pp 3091ndash31002011

[85] X Lu Q Fan L Xu et al ldquoUrsolic acid attenuates diabeticmesangial cell injury through the up-regulation of autophagyvia miRNA-21PTENAktmTOR suppressionrdquo PLoS ONE vol10 no 2 Article ID e0117400 2015

[86] L Poliseno L Salmena J Zhang B Carver W J Havemanand P P Pandolfi ldquoA coding-independent function of geneand pseudogenemRNAs regulates tumour biologyrdquoNature vol465 no 7301 pp 1033ndash1038 2010

[87] Y Tay L Kats L Salmena et al ldquoCoding-independent regula-tion of the tumor suppressor PTEN by competing endogenousmRNAsrdquo Cell vol 147 no 2 pp 344ndash357 2011

[88] L Odriozola G Singh T Hoang and A M Chan ldquoRegula-tion of PTEN activity by its carboxyl-terminal autoinhibitorydomainrdquo The Journal of Biological Chemistry vol 282 no 32pp 23306ndash23315 2007

[89] Z Li X Dong Z Wang et al ldquoRegulation of PTEN by Rhosmall GTPasesrdquo Nature Cell Biology vol 7 no 4 pp 399ndash4042005

[90] E-K Yim G Peng H Dai et al ldquoRak functions as a tumorsuppressor by regulating PTEN protein stability and functionrdquoCancer Cell vol 15 no 4 pp 304ndash314 2009

[91] AMAl-Khouri YMa SH Togo SWilliams andTMustelinldquoCooperative phosphorylation of the tumor suppressor phos-phatase and tensin homologue (PTEN) by casein kinasesand glycogen synthase kinase 3120573rdquo The Journal of BiologicalChemistry vol 280 no 42 pp 35195ndash35202 2005

[92] H Maccario N M Perera L Davidson C P Downes and NR Leslie ldquoPTEN is destabilized by phosphorylation onThr366rdquoBiochemical Journal vol 405 no 3 pp 439ndash444 2007

[93] K A Waite and C Eng ldquoBMP2 exposure results in decreasedPTEN protein degradation and increased PTEN levelsrdquoHumanMolecular Genetics vol 12 no 6 pp 679ndash684 2003

[94] T J Jerde Z Wu D Theodorescu and W Bushman ldquoRegu-lation of phosphatase homologue of tensin protein expressionby bone morphogenetic proteins in prostate epithelial cellsrdquoProstate vol 71 no 8 pp 791ndash800 2011

[95] G Singh and A M Chan ldquoPost-translational modificationsof PTEN and their potential therapeutic implicationsrdquo CurrentCancer Drug Targets vol 11 no 5 pp 536ndash547 2011

[96] T Ikenoue K Inoki B Zhao and K-L Guan ldquoPTEN acety-lation modulates its interaction with PDZ domainrdquo CancerResearch vol 68 no 17 pp 6908ndash6912 2008

[97] L C Trotman X Wang A Alimonti et al ldquoUbiquitinationregulates PTEN nuclear import and tumor suppressionrdquo Cellvol 128 no 1 pp 141ndash156 2007

[98] T Tolkacheva M Boddapati A Sanfiz K Tsuchida A CKimmelman and AM-L Chan ldquoRegulation of PTEN bindingto MAGI-2 by two putative phosphorylation sites at threonine382 and 383rdquo Cancer Research vol 61 no 13 pp 4985ndash49892001

[99] E Lima-Fernandes H Enslen E Camand et al ldquoDistinct func-tional outputs of PTEN signalling are controlled by dynamicassociation with 120573-arrestinsrdquoThe EMBO Journal vol 30 no 13pp 2557ndash2568 2011

[100] M T van Diepen M Parsons C P Downes N R Leslie RHindges and B J Eickholt ldquoMyosinV controls PTEN functionand neuronal cell sizerdquo Nature Cell Biology vol 11 no 10 pp1191ndash1196 2009

[101] R B Chagpar P H Links M C Pastor et al ldquoDirect positiveregulation of PTEN by the p85 subunit of phosphatidylinositol3-kinaserdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 107 no 12 pp 5471ndash5476 2010

[102] Y Takahashi F C Morales E L Kreimann and M-MGeorgescu ldquoPTEN tumor suppressor associates with NHERFproteins to attenuate PDGF receptor signalingrdquo The EMBOJournal vol 25 no 4 pp 910ndash920 2006

[103] M Valiente A Andres-Pons B Gomar et al ldquoBinding ofPTEN to specific PDZ domains contributes to PTEN proteinstability and phosphorylation by microtubule-associated ser-inethreonine kinasesrdquoThe Journal of Biological Chemistry vol280 no 32 pp 28936ndash28943 2005

[104] SQuintes SGoebbels G SaherMH Schwab andK-ANaveldquoNeuron-glia signaling and the protection of axon function bySchwann cellsrdquo Journal of the Peripheral Nervous System vol 15no 1 pp 10ndash16 2010

[105] B Fine C Hodakoski S Koujak et al ldquoActivation of the PI3Kpathway in cancer through inhibition of PTEN by exchangefactor P-REX2ardquo Science vol 325 no 5945 pp 1261ndash1265 2009

Journal of Signal Transduction 13

[106] L He A Ingram A P Rybak and D Tang ldquoShank-interactingprotein-like 1 promotes tumorigenesis via PTEN inhibition inhuman tumor cellsrdquo The Journal of Clinical Investigation vol120 no 6 pp 2094ndash2108 2010

[107] L He C Fan A Kapoor et al ldquo120572-Mannosidase 2C1 attenuatesPTEN function in prostate cancer cellsrdquo Nature Communica-tions vol 2 no 1 article 307 2011

[108] Z Radisavljevic ldquoAKT as locus of cancer positive feedbackloops and extreme robustnessrdquo Journal of Cellular Physiologyvol 228 no 3 pp 522ndash524 2013

[109] M Y Lee HW Lim S H Lee andH J Han ldquoSmad PI3KAktand wnt-dependent signaling pathways are involved in BMP-4-induced ESC self-renewalrdquo Stem Cells vol 27 no 8 pp 1858ndash1868 2009

[110] K Song S C Cornelius M Reiss and D Danielpour ldquoInsulin-like growth factor-I inhibits transcriptional responses of trans-forming growth factor-120573 by phosphatidylinositol 3-kinaseAkt-dependent suppression of the activation of Smad3 but notSmad2rdquoThe Journal of Biological Chemistry vol 278 no 40 pp38342ndash38351 2003

[111] D Fang D Hawke Y Zheng et al ldquoPhosphorylation of 120573-catenin by AKT promotes 120573-catenin transcriptional activityrdquoThe Journal of Biological Chemistry vol 282 no 15 pp 11221ndash11229 2007

[112] Q Lei J Jiao L Xin et al ldquoNKX31 stabilizes p53 inhibitsAKT activation and blocks prostate cancer initiation caused byPTEN lossrdquo Cancer Cell vol 9 no 5 pp 367ndash378 2006

[113] A Sengupta J D Molkentin J-H Paik R A DePinho and KE Yutzey ldquoFoxO transcription factors promote cardiomyocytesurvival upon induction of oxidative stressrdquo The Journal ofBiological Chemistry vol 286 no 9 pp 7468ndash7478 2011

[114] C H M Jamieson L E Ailles S J Dylla et al ldquoGranulocyte-macrophage progenitors as candidate leukemic stem cells inblast-crisis CMLrdquoTheNewEngland Journal ofMedicine vol 351no 7 pp 657ndash667 2004

[115] A Androutsellis-Theotokis R R Leker F Soldner et al ldquoNotchsignalling regulates stem cell numbers in vitro and in vivordquoNature vol 442 no 7104 pp 823ndash826 2006

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

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BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

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Nucleic AcidsJournal of

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Stem CellsInternational

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Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

Page 9: Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling TravisJ.Jerde Department of Pharmacology

Journal of Signal Transduction 9

therefore its role in normal cell homeostasis proliferationapoptosis and many additional components of cell biologyis extensive Because PTEN regulates cancer progressionmuch of what has been studied regarding PTEN relates totumorigenesis and tumor growth While this is warrantedbecause of the relevance of cancer to humanhealth PTENhassubstantial but underappreciated effects in normal tissue andorgan development immune system development and reg-ulation axonal regeneration glucose regulation and benigngrowth disorders PTEN is often dogmatically thought ofas a constitutive protein that exhibits lost activity duringdiseases butwhat is underappreciated is that PTENhas a verycomplex regulation network that involves signaling path-ways that regulate PTEN transcription transcript stabilityposttranslationalmodifications protein-protein interactionsand cellular location PTEN then in turn regulates numerousdevelopmental signaling networks that are critical to devel-opment and adult tissue maintenance

Abbreviations

Bcl2 B-cell lymphoma 2Bim BCL-2-interacting mediatorCK2 Casein Kinase 2CREB Cyclic AMP response element binding

proteinDLG Disks large homolog 1Egr-1 Early growth response protein 1Erk Extracellular regulated kinaseFOX Forkhead transcription factorsGSK3120573 Glycogen synthase kinase 3JNK Jun-terminal kinaseMAGI2 Membrane-associated guanylate kinase

inverted 2MAN2C1 Mannosidase alpha class 2C member 1MDM2 Mouse double minute 2 homologmTOR Mechanistic target of rapamycinNHERF Sodium-hydrogen antiporter 3

regulator 1NRG1 Neuregulin 1PCAF P300CBP-associated factorPDZ Postsynaptic density proteinmdashDisc

large tumor suppressormdashZonulaoccludens-1 protein

PIP3 Phosphoinositide triphosphatePPAR120574 Peroxisome proliferating antigen

receptorPREX2a Phosphatidylinositol-345-

trisphosphate-dependent Rac exchangefactor A

PTEN Phosphatase and Tensin homologueROCK Rho-associated coiled-coil-containing

protein kinaseSALL Spalt-like transcription factor-1SIPL1 Shank-interacting protein-like 1SIRT1 Sirtuin 1SMAD Small mothers against decapentaplegicSOCS Suppressor of cytokine signalingTGF120573 Transforming growth factor-beta

Disclosure

Travis J Jerde carried out the extensive literature reviewrequired to write this paper and have written the entirepaper The author has therefore read and approved the papersubmitted

Conflict of Interests

The author has no financial or nonfinancial conflict ofinterests with the submission of this paper

Acknowledgments

The author gratefully acknowledges the financial supportof the Indiana University School of Medicine Departmentof Pharmacology and Toxicology and the Melvin and BrynSimon Cancer Center The author also gratefully acknowl-edges this paper as part of his training made possible byNational Institutes of Health-NIDDK (DK092366-01A1)

References

[1] M Milella I Falcone F Conciatori et al ldquoPTEN multiplefunctions in human malignant tumorsrdquo Frontiers in Oncologyvol 5 article 24 2015

[2] J-O Lee H Yang M-M Georgescu et al ldquoCrystal structure ofthe PTEN tumor suppressor implications for its phosphoinosi-tide phosphatase activity and membrane associationrdquo Cell vol99 no 3 pp 323ndash334 1999

[3] W-L Yang G Jin C-F Li et al ldquoCycles of ubiquitinationand deubiquitination critically regulate growth factor-mediatedactivation of Akt signalingrdquo Science Signaling vol 6 no 257article ra3 2013

[4] J Gu S Nada M Okada and K Sekiguchi ldquoCsk regulatesintegrin-mediated signals involvement of differential activa-tion of ERK and Aktrdquo Biochemical and Biophysical ResearchCommunications vol 303 no 3 pp 973ndash977 2003

[5] A Clerk and P H Sugden ldquoActivation of protein kinase cas-cades in the heart by hypertrophic G protein-coupled receptoragonistsrdquoTheAmerican Journal of Cardiology vol 83 no 12 pp64Hndash69H 1999

[6] I Tonic W-N Yu Y Park C-C Chen and N Hay ldquoAktactivation emulates Chk1 inhibition and Bcl2 overexpressionand abrogates G2 cell cycle checkpoint by inhibiting BRCA1focirdquo The Journal of Biological Chemistry vol 285 no 31 pp23790ndash23798 2010

[7] S Fatrai L Elghazi N Balcazar et al ldquoAkt induces 120573-cellproliferation by regulating cyclin D1 cyclin D2 and p21 levelsand cyclin-dependent kinase-4 activityrdquo Diabetes vol 55 no 2pp 318ndash325 2006

[8] M Aoki E Blazek and P K Vogt ldquoA role of the kinase mTORin cellular transformation induced by the oncoproteins P3k andAktrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 98 no 1 pp 136ndash141 2001

[9] H Guan L Song J Cai et al ldquoSphingosine kinase 1 regulatesthe AktFOXO3aBim pathway and contributes to apoptosisresistance in glioma cellsrdquo PLoS ONE vol 6 no 5 Article IDe19946 2011

[10] T D Dung C H Day T V Binh et al ldquoPP2Amediates diosminp53 activation to block HA22T cell proliferation and tumor

10 Journal of Signal Transduction

growth in xenografted nude mice through PI3K-Akt-MDM2signaling suppressionrdquo Food and Chemical Toxicology vol 50no 5 pp 1802ndash1810 2012

[11] K Shanmugasundaram K Block B K Nayak C B Livi MA Venkatachalam and S Sudarshan ldquoPI3K regulation of theSKP-2p27 axis through mTORC2rdquo Oncogene vol 32 no 16pp 2027ndash2036 2013

[12] J-C Chang H-H Chang C-T Lin and S J Lo ldquoThe integrin12057261205731modulation of PI3K andCdc42 activities induces dynamicfilopodium formation in humanplateletsrdquo Journal of BiomedicalScience vol 12 no 6 pp 881ndash898 2005

[13] E Hajduch G J Litherland and H S Hundal ldquoProtein kinaseB (PKBAkt)mdasha key regulator of glucose transportrdquo FEBSLetters vol 492 no 3 pp 199ndash203 2001

[14] M M Martin J A Buckenberger J Jiang et al ldquoTGF-beta1stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[15] M M Martin J A Buckenberger J Jiang et al ldquoTGF-1205731stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[16] K Abell and C J Watson ldquoThe JakStat pathway a novel wayto regulate PI3K activityrdquo Cell Cycle vol 4 no 7 pp 897ndash9002005

[17] J-Y Hwang R S Duncan C Madry M Singh and P KoulenldquoProgesterone potentiates calcium release through IP3 recep-tors by an Akt-mediated mechanism in hippocampal neuronsrdquoCell Calcium vol 45 no 3 pp 233ndash242 2009

[18] G Pappas L A Zumstein A Munshi M Hobbs and R EMeyn ldquoAdenoviral-mediated PTEN expression radiosensitizesnon-small cell lung cancer cells by suppressing DNA repaircapacityrdquoCancer GeneTherapy vol 14 no 6 pp 543ndash549 2007

[19] A Di Cristofano B Pesce C Cordon-Cardo and P P PandolfildquoPten is essential for embryonic development and tumoursuppressionrdquo Nature Genetics vol 19 no 4 pp 348ndash355 1998

[20] J Bloomekatz J Grego-Bessa I Migeotte and K V AndersonldquoPten regulates collective cell migration during specification ofthe anterior-posterior axis of the mouse embryordquo Developmen-tal Biology vol 364 no 2 pp 192ndash201 2012

[21] S Ueno R Kono andY Iwao ldquoPTEN is required for the normalprogression of gastrulation by repressing cell proliferation afterMBT in Xenopus embryosrdquoDevelopmental Biology vol 297 no1 pp 274ndash283 2006

[22] C B Knobbe A Merlo and G Reifenberger ldquoPten signaling ingliomasrdquo Neuro Oncology vol 4 pp 196ndash211 2002

[23] E Kirches J Steiner T Schneider et al ldquoLhermitte-Duclosdisease caused by a novel germline PTEN mutation R173P in apatient presenting with psychosisrdquoNeuropathology and AppliedNeurobiology vol 36 no 1 pp 86ndash89 2010

[24] J-I Murata M Tada Y Sawamura K Mitsumori H Abe andK Nagashima ldquoDysplastic gangliocytoma (Lhermitte-Duclosdisease) associated with Cowden disease report of a case andreview of the literature for the genetic relationship between thetwo diseasesrdquo Journal of Neuro-Oncology vol 41 no 2 pp 129ndash136 1999

[25] G Zhu L M L Chow I T Bayazitov et al ldquoPten deletioncauses mTorc1-dependent ectopic neuroblast differentiation

without causing uniform migration defectsrdquo Development vol139 no 18 pp 3422ndash3431 2012

[26] K L McBride E A Varga M T Pastore et al ldquoConfirmationstudy of PTEN mutations among individuals with autism ordevelopmental delaysmental retardation and macrocephalyrdquoAutism Research vol 3 no 3 pp 137ndash141 2010

[27] J Zhou and L F Parada ldquoPTEN signaling in autism spectrumdisordersrdquo Current Opinion in Neurobiology vol 22 no 5 pp873ndash879 2012

[28] S A Backman V Stambolic A Suzuki et al ldquoDeletion of Ptenin mouse brain causes seizures ataxia and defects in soma sizeresembling Lhermitte-Duclos diseaserdquo Nature Genetics vol 29no 4 pp 396ndash403 2001

[29] L Cotter M Ozcelik C Jacob et al ldquoDlg1-PTEN interactionregulates myelin thickness to prevent damaging peripheralnerve overmyelinationrdquo Science vol 328 no 5984 pp 1415ndash1418 2010

[30] S Ogawa C-H Kwon J Zhou D Koovakkattu L F Paradaand C M Sinton ldquoA seizure-prone phenotype is associatedwith altered free-running rhythm in Pten mutant micerdquo BrainResearch vol 1168 no 1 pp 112ndash123 2007

[31] C-H Kwon X Zhu J Zhang and S J Baker ldquomTor isrequired for hypertrophy of Pten-deficient neuronal soma invivordquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 22 pp 12923ndash12928 2003

[32] C-H Kwon B W Luikart C M Powell et al ldquoPten regulatesneuronal arborization and social interaction in micerdquo Neuronvol 50 no 3 pp 377ndash388 2006

[33] A Suzuki S Itami M Ohishi et al ldquoKeratinocyte-specific Ptendeficiency results in epidermal hyperplasia accelerated hairfollicle morphogenesis and tumor formationrdquo Cancer Researchvol 63 no 3 pp 674ndash681 2003

[34] T Inoue-Narita K Hamada T Sasaki et al ldquoPten deficiency inmelanocytes results in resistance to hair graying and susceptibil-ity to carcinogen-induced melanomagenesisrdquo Cancer Researchvol 68 no 14 pp 5760ndash5768 2008

[35] R K Patel and C Mohan ldquoPI3KAKT signaling and systemicautoimmunityrdquo Immunologic Research vol 31 no 1 pp 47ndash552005

[36] K Podsypanina L H Ellenson A Nemes et al ldquoMutationof PtenMmac1 in mice causes neoplasia in multiple organsystemsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 4 pp 1563ndash1568 1999

[37] M Kashiwada P Lu and P B Rothman ldquoPIP3 pathway inregulatory T cells and autoimmunityrdquo Immunologic Researchvol 39 no 1ndash3 pp 194ndash224 2007

[38] A Suzuki M T Yamaguchi T Ohteki et al ldquoT cell-specificloss of Pten leads to defects in central and peripheral tolerancerdquoImmunity vol 14 no 5 pp 523ndash534 2001

[39] Y Yamanaka H Tagawa N Takahashi et al ldquoAberrant over-expression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lym-phomaleukemiardquo Blood vol 114 no 15 pp 3265ndash3275 2009

[40] H Kishimoto T Ohteki N Yajima et al ldquoThe PtenPI3Kpathway governs the homeostasis of V12057214iNKT cellsrdquo Bloodvol 109 no 8 pp 3316ndash3324 2007

[41] A Suzuki T Kaisho M Ohishi et al ldquoCritical roles ofPten in B cell homeostasis and immunoglobulin class switchrecombinationrdquo Journal of Experimental Medicine vol 197 no5 pp 657ndash667 2003

Journal of Signal Transduction 11

[42] M Nishio K-IWatanabe J Sasaki et al ldquoControl of cell polar-ity and motility by the PtdIns(345)P

3phosphatase SHIP1rdquo

Nature Cell Biology vol 9 no 1 pp 36ndash44 2007[43] S Kuroda M Nishio T Sasaki et al ldquoEffective clearance

of intracellular Leishmania major in vivo requires Pten inmacrophagesrdquo European Journal of Immunology vol 38 no 5pp 1331ndash1340 2008

[44] O H Yilmaz R Valdez B K Theisen et al ldquoPten depen-dence distinguishes haematopoietic stem cells from leukaemia-initiating cellsrdquo Nature vol 441 no 7092 pp 475ndash482 2006

[45] Y Li K Podsypanina X Liu et al ldquoDeficiency of Ptenaccelerates mammary oncogenesis in MMTV-Wnt-1 transgenicmicerdquo BMCMolecular Biology vol 2 article 2 2001

[46] P Reddy L Liu D Adhikari et al ldquoOocyte-specific deletion ofpten causes premature activation of the primordial follicle poolrdquoScience vol 319 no 5863 pp 611ndash613 2008

[47] H Tsuruta H Kishimoto T Sasaki et al ldquoHyperplasia andcarcinomas in Pten-deficient mice and reduced PTEN proteinin human bladder cancer patientsrdquoCancer Research vol 66 no17 pp 8389ndash8396 2006

[48] L I Yoo D W Liu S Le Vu R T Bronson H Wu and JYuan ldquoPten deficiency activates distinct downstream signalingpathways in a tissue-specific mannerrdquo Cancer Research vol 66no 4 pp 1929ndash1939 2006

[49] J Li C Yen D Liaw et al ldquoPTEN a putative protein tyrosinephosphatase gene mutated in human brain breast and prostatecancerrdquo Science vol 275 no 5308 pp 1943ndash1947 1997

[50] N D Deocampo H Huang and D J Tindall ldquoThe role ofPTEN in the progression and survival of prostate cancerrdquoMinerva Endocrinologica vol 28 no 2 pp 145ndash153 2003

[51] S A Backman D Ghazarian K So et al ldquoEarly onset ofneoplasia in the prostate and skin of mice with tissue-specificdeletion of Ptenrdquo Proceedings of the National Academy ofSciences of the United States of America vol 101 no 6 pp 1725ndash1730 2004

[52] X Wu K Xu L Zhang et al ldquoDifferentiation of the ductalepithelium and smooth muscle in the prostate gland areregulated by the NotchPTEN-dependent mechanismrdquo Devel-opmental Biology vol 356 no 2 pp 337ndash349 2011

[53] D Kim and G R Dressler ldquoPTEN modulates GDNFRETmediated chemotaxis and branching morphogenesis in thedeveloping kidneyrdquo Developmental Biology vol 307 no 2 pp290ndash299 2007

[54] N O Lindstrom M L Lawrence S F Burn et al ldquoIntegrated120573-catenin BMP PTEN and notch signalling patterns thenephronrdquo eLife no 4 Article ID e04000 2015

[55] V Marsh D J Winton G T Williams et al ldquoEpithelialPten is dispensable for intestinal homeostasis but suppressesadenoma development and progression after Apc mutationrdquoNature Genetics vol 40 no 12 pp 1436ndash1444 2008

[56] S Matsuda M Kobayashi and Y Kitagishi ldquoRoles forPI3KAKTPTEN pathway in cell signaling of nonalcoholicfatty liver diseaserdquo ISRN Endocrinology vol 2013 Article ID472432 7 pages 2013

[57] X Qi J Xu P Gu X Yang and X Gao ldquoPTEN in smoothmuscle cells is essential for colonic immune homeostasisrdquoInternational Journal of Biochemistry and Cell Biology vol 53pp 108ndash114 2014

[58] A Pal T M Barber M Van de Bunt et al ldquoPTENmutations asa cause of constitutive insulin sensitivity and obesityrdquoThe NewEngland Journal of Medicine vol 367 no 11 pp 1002ndash1011 2012

[59] B L Stiles C Kuralwalla-Martinez W Guo et al ldquoSelectivedeletion of Pten in pancreatic 120573 cells leads to increased isletmass and resistance to STZ-induced diabetesrdquo Molecular andCellular Biology vol 26 no 7 pp 2772ndash2781 2006

[60] LWang C T Luk E P Cai et al ldquoPTEN deletion in pancreatic120572-cells protects against high-fat diet-induced hyperglucagone-mia and insulin resistancerdquo Diabetes vol 64 no 1 pp 147ndash1572015

[61] C Kurlawalla-Martinez B Stiles Y Wang S U Devaskar BB Kahn and H Wu ldquoInsulin hypersensitivity and resistanceto streptozotocin-induced diabetes in mice lacking PTEN inadipose tissuerdquo Molecular and Cellular Biology vol 25 no 6pp 2498ndash2510 2005

[62] N Wijesekara D Konrad M Eweida et al ldquoMuscle-specificPten deletion protects against insulin resistance and diabetesrdquoMolecular and Cellular Biology vol 25 no 3 pp 1135ndash11452005

[63] K Hamada T Sasaki P A Koni et al ldquoThe PTENPI3Kpathway governs normal vascular development and tumorangiogenesisrdquo Genes and Development vol 19 no 17 pp 2054ndash2065 2005

[64] N D Roe X Xu M R Kandadi et al ldquoTargeted deletionof PTEN in cardiomyocytes renders cardiac contractile dys-function through interruption of Pink1-AMPK signaling andautophagyrdquo Biochimica et Biophysica Acta Molecular Basis ofDisease vol 1852 no 2 pp 290ndash298 2015

[65] A F Ford-Hutchinson Z Ali S E Lines B HallgrımssonS K Boyd and F R Jirik ldquoInactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnor-malities and skeletal overgrowthrdquo Journal of Bone and MineralResearch vol 22 no 8 pp 1245ndash1259 2007

[66] T A Burgers M F Hoffmann C J Collins et al ldquoMice lackingpten in osteoblasts have improved intramembranous and lateendochondral fracture healingrdquo PLoS ONE vol 8 no 5 ArticleID e63857 2013

[67] N R Leslie L Spinelli P Tibarewal et al ldquoIndirect mecha-nisms of carcinogenesis via downregulation of PTEN functionrdquoAdvances in Enzyme Regulation vol 50 no 1 pp 112ndash118 2010

[68] L He ldquoPosttranscriptional regulation of PTEN dosage bynoncoding RNAsrdquo Science Signaling vol 3 no 146 article pe392010

[69] F Vazquez S R Grossman Y Takahashi M V Rokas NNakamura andWR Sellers ldquoPhosphorylation of the PTEN tailacts as an inhibitory switch by preventing its recruitment into aprotein complexrdquo The Journal of Biological Chemistry vol 276no 52 pp 48627ndash48630 2001

[70] X Wang L C Trotman T Koppie et al ldquoNEDD4-1 is a proto-oncogenic ubiquitin ligase for PTENrdquo Cell vol 128 no 1 pp129ndash139 2007

[71] N R Leslie and M Foti ldquoNon-genomic loss of PTEN functionin cancer not in my genesrdquo Trends in Pharmacological Sciencesvol 32 no 3 pp 131ndash140 2011

[72] Y Xing C Li L Hu et al ldquoMechanisms of TGF120573 inhibition ofLUNG endodermal morphogenesis the role of T120573RII SmadsNkx21 and Ptenrdquo Developmental Biology vol 320 no 2 pp340ndash350 2008

[73] J P Luyendyk G A Schabbauer M Tencati T Holscher RPawlinski and N Mackman ldquoGenetic analysis of the role ofthe PI3K-Akt pathway in lipopolysaccharide-induced cytokineand tissue factor gene expression in monocytesmacrophagesrdquoJournal of Immunology vol 180 no 6 pp 4218ndash4226 2008

12 Journal of Signal Transduction

[74] F Sun K K Park S Belin et al ldquoSustained axon regenerationinduced by co-deletion of PTEN and SOCS3rdquo Nature vol 480no 7377 pp 372ndash375 2011

[75] C B Knobbe V Lapin A Suzuki and T W Mak ldquoThe roles ofPTEN in development physiology and tumorigenesis in mousemodels a tissue-by-tissue surveyrdquo Oncogene vol 27 no 41 pp5398ndash5415 2008

[76] S J Assinder Q Dong Z Kovacevic and D R RichardsonldquoThe TGF-beta PI3KAkt and PTEN pathways establishedand proposed biochemical integration in prostate cancerrdquoBiochemical Journal vol 417 no 2 pp 411ndash421 2009

[77] K A Waite and C Eng ldquoFrom developmental disorder toheritable cancer itrsquos all in the BMPTGF-120573 familyrdquo NatureReviews Genetics vol 4 no 10 pp 763ndash773 2003

[78] H B Newton ldquoMolecular neuro-oncology and developmentof targeted therapeutic strategies for brain tumors Part2 PI3KAktPTEN mTOR SHHPTCH and angiogenesisrdquoExpert Review of Anticancer Therapy vol 4 no 1 pp 105ndash1282004

[79] R H KimM Peters Y Jang et al ldquoDJ-1 a novel regulator of thetumor suppressor PTENrdquo Cancer Cell vol 7 no 3 pp 263ndash2732005

[80] J Lu H W Jeong N Kong et al ldquoStem cell factor SALL4represses the transcriptions of PTEN and SALL1 through anepigenetic repressor complexrdquo PLoS ONE vol 4 no 5 ArticleID e5577 2009

[81] M M A Rizvi M S Alam A Ali S J Mehdi S Batra andA KMandal ldquoAberrant promotermethylation and inactivationof PTEN gene in cervical carcinoma from Indian populationrdquoJournal of Cancer Research and Clinical Oncology vol 137 no 8pp 1255ndash1262 2011

[82] J Liu ldquoControl of protein synthesis and mRNA degradation bymicroRNAsrdquo Current Opinion in Cell Biology vol 20 no 2 pp214ndash221 2008

[83] S W Shan L Fang T Shatseva et al ldquoMature miR-17-5pand passenger miR-17-3p induce hepatocellular carcinoma bytargeting PTEN GalNT7 and vimentin in different signalpathwaysrdquo Journal of Cell Science vol 126 part 6 pp 1517ndash15302013

[84] Z Liang Y Li K Huang N Wagar and H Shim ldquoRegulationof miR-19 to breast cancer chemoresistance through targetingPTENrdquo Pharmaceutical Research vol 28 no 12 pp 3091ndash31002011

[85] X Lu Q Fan L Xu et al ldquoUrsolic acid attenuates diabeticmesangial cell injury through the up-regulation of autophagyvia miRNA-21PTENAktmTOR suppressionrdquo PLoS ONE vol10 no 2 Article ID e0117400 2015

[86] L Poliseno L Salmena J Zhang B Carver W J Havemanand P P Pandolfi ldquoA coding-independent function of geneand pseudogenemRNAs regulates tumour biologyrdquoNature vol465 no 7301 pp 1033ndash1038 2010

[87] Y Tay L Kats L Salmena et al ldquoCoding-independent regula-tion of the tumor suppressor PTEN by competing endogenousmRNAsrdquo Cell vol 147 no 2 pp 344ndash357 2011

[88] L Odriozola G Singh T Hoang and A M Chan ldquoRegula-tion of PTEN activity by its carboxyl-terminal autoinhibitorydomainrdquo The Journal of Biological Chemistry vol 282 no 32pp 23306ndash23315 2007

[89] Z Li X Dong Z Wang et al ldquoRegulation of PTEN by Rhosmall GTPasesrdquo Nature Cell Biology vol 7 no 4 pp 399ndash4042005

[90] E-K Yim G Peng H Dai et al ldquoRak functions as a tumorsuppressor by regulating PTEN protein stability and functionrdquoCancer Cell vol 15 no 4 pp 304ndash314 2009

[91] AMAl-Khouri YMa SH Togo SWilliams andTMustelinldquoCooperative phosphorylation of the tumor suppressor phos-phatase and tensin homologue (PTEN) by casein kinasesand glycogen synthase kinase 3120573rdquo The Journal of BiologicalChemistry vol 280 no 42 pp 35195ndash35202 2005

[92] H Maccario N M Perera L Davidson C P Downes and NR Leslie ldquoPTEN is destabilized by phosphorylation onThr366rdquoBiochemical Journal vol 405 no 3 pp 439ndash444 2007

[93] K A Waite and C Eng ldquoBMP2 exposure results in decreasedPTEN protein degradation and increased PTEN levelsrdquoHumanMolecular Genetics vol 12 no 6 pp 679ndash684 2003

[94] T J Jerde Z Wu D Theodorescu and W Bushman ldquoRegu-lation of phosphatase homologue of tensin protein expressionby bone morphogenetic proteins in prostate epithelial cellsrdquoProstate vol 71 no 8 pp 791ndash800 2011

[95] G Singh and A M Chan ldquoPost-translational modificationsof PTEN and their potential therapeutic implicationsrdquo CurrentCancer Drug Targets vol 11 no 5 pp 536ndash547 2011

[96] T Ikenoue K Inoki B Zhao and K-L Guan ldquoPTEN acety-lation modulates its interaction with PDZ domainrdquo CancerResearch vol 68 no 17 pp 6908ndash6912 2008

[97] L C Trotman X Wang A Alimonti et al ldquoUbiquitinationregulates PTEN nuclear import and tumor suppressionrdquo Cellvol 128 no 1 pp 141ndash156 2007

[98] T Tolkacheva M Boddapati A Sanfiz K Tsuchida A CKimmelman and AM-L Chan ldquoRegulation of PTEN bindingto MAGI-2 by two putative phosphorylation sites at threonine382 and 383rdquo Cancer Research vol 61 no 13 pp 4985ndash49892001

[99] E Lima-Fernandes H Enslen E Camand et al ldquoDistinct func-tional outputs of PTEN signalling are controlled by dynamicassociation with 120573-arrestinsrdquoThe EMBO Journal vol 30 no 13pp 2557ndash2568 2011

[100] M T van Diepen M Parsons C P Downes N R Leslie RHindges and B J Eickholt ldquoMyosinV controls PTEN functionand neuronal cell sizerdquo Nature Cell Biology vol 11 no 10 pp1191ndash1196 2009

[101] R B Chagpar P H Links M C Pastor et al ldquoDirect positiveregulation of PTEN by the p85 subunit of phosphatidylinositol3-kinaserdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 107 no 12 pp 5471ndash5476 2010

[102] Y Takahashi F C Morales E L Kreimann and M-MGeorgescu ldquoPTEN tumor suppressor associates with NHERFproteins to attenuate PDGF receptor signalingrdquo The EMBOJournal vol 25 no 4 pp 910ndash920 2006

[103] M Valiente A Andres-Pons B Gomar et al ldquoBinding ofPTEN to specific PDZ domains contributes to PTEN proteinstability and phosphorylation by microtubule-associated ser-inethreonine kinasesrdquoThe Journal of Biological Chemistry vol280 no 32 pp 28936ndash28943 2005

[104] SQuintes SGoebbels G SaherMH Schwab andK-ANaveldquoNeuron-glia signaling and the protection of axon function bySchwann cellsrdquo Journal of the Peripheral Nervous System vol 15no 1 pp 10ndash16 2010

[105] B Fine C Hodakoski S Koujak et al ldquoActivation of the PI3Kpathway in cancer through inhibition of PTEN by exchangefactor P-REX2ardquo Science vol 325 no 5945 pp 1261ndash1265 2009

Journal of Signal Transduction 13

[106] L He A Ingram A P Rybak and D Tang ldquoShank-interactingprotein-like 1 promotes tumorigenesis via PTEN inhibition inhuman tumor cellsrdquo The Journal of Clinical Investigation vol120 no 6 pp 2094ndash2108 2010

[107] L He C Fan A Kapoor et al ldquo120572-Mannosidase 2C1 attenuatesPTEN function in prostate cancer cellsrdquo Nature Communica-tions vol 2 no 1 article 307 2011

[108] Z Radisavljevic ldquoAKT as locus of cancer positive feedbackloops and extreme robustnessrdquo Journal of Cellular Physiologyvol 228 no 3 pp 522ndash524 2013

[109] M Y Lee HW Lim S H Lee andH J Han ldquoSmad PI3KAktand wnt-dependent signaling pathways are involved in BMP-4-induced ESC self-renewalrdquo Stem Cells vol 27 no 8 pp 1858ndash1868 2009

[110] K Song S C Cornelius M Reiss and D Danielpour ldquoInsulin-like growth factor-I inhibits transcriptional responses of trans-forming growth factor-120573 by phosphatidylinositol 3-kinaseAkt-dependent suppression of the activation of Smad3 but notSmad2rdquoThe Journal of Biological Chemistry vol 278 no 40 pp38342ndash38351 2003

[111] D Fang D Hawke Y Zheng et al ldquoPhosphorylation of 120573-catenin by AKT promotes 120573-catenin transcriptional activityrdquoThe Journal of Biological Chemistry vol 282 no 15 pp 11221ndash11229 2007

[112] Q Lei J Jiao L Xin et al ldquoNKX31 stabilizes p53 inhibitsAKT activation and blocks prostate cancer initiation caused byPTEN lossrdquo Cancer Cell vol 9 no 5 pp 367ndash378 2006

[113] A Sengupta J D Molkentin J-H Paik R A DePinho and KE Yutzey ldquoFoxO transcription factors promote cardiomyocytesurvival upon induction of oxidative stressrdquo The Journal ofBiological Chemistry vol 286 no 9 pp 7468ndash7478 2011

[114] C H M Jamieson L E Ailles S J Dylla et al ldquoGranulocyte-macrophage progenitors as candidate leukemic stem cells inblast-crisis CMLrdquoTheNewEngland Journal ofMedicine vol 351no 7 pp 657ndash667 2004

[115] A Androutsellis-Theotokis R R Leker F Soldner et al ldquoNotchsignalling regulates stem cell numbers in vitro and in vivordquoNature vol 442 no 7104 pp 823ndash826 2006

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

Page 10: Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling TravisJ.Jerde Department of Pharmacology

10 Journal of Signal Transduction

growth in xenografted nude mice through PI3K-Akt-MDM2signaling suppressionrdquo Food and Chemical Toxicology vol 50no 5 pp 1802ndash1810 2012

[11] K Shanmugasundaram K Block B K Nayak C B Livi MA Venkatachalam and S Sudarshan ldquoPI3K regulation of theSKP-2p27 axis through mTORC2rdquo Oncogene vol 32 no 16pp 2027ndash2036 2013

[12] J-C Chang H-H Chang C-T Lin and S J Lo ldquoThe integrin12057261205731modulation of PI3K andCdc42 activities induces dynamicfilopodium formation in humanplateletsrdquo Journal of BiomedicalScience vol 12 no 6 pp 881ndash898 2005

[13] E Hajduch G J Litherland and H S Hundal ldquoProtein kinaseB (PKBAkt)mdasha key regulator of glucose transportrdquo FEBSLetters vol 492 no 3 pp 199ndash203 2001

[14] M M Martin J A Buckenberger J Jiang et al ldquoTGF-beta1stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[15] M M Martin J A Buckenberger J Jiang et al ldquoTGF-1205731stimulates human at1 receptor expression in lung fibroblastsby cross talk between the Smad p38 MAPK JNK and PI3Ksignaling pathwaysrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 293 no 3 pp L790ndashL799 2007

[16] K Abell and C J Watson ldquoThe JakStat pathway a novel wayto regulate PI3K activityrdquo Cell Cycle vol 4 no 7 pp 897ndash9002005

[17] J-Y Hwang R S Duncan C Madry M Singh and P KoulenldquoProgesterone potentiates calcium release through IP3 recep-tors by an Akt-mediated mechanism in hippocampal neuronsrdquoCell Calcium vol 45 no 3 pp 233ndash242 2009

[18] G Pappas L A Zumstein A Munshi M Hobbs and R EMeyn ldquoAdenoviral-mediated PTEN expression radiosensitizesnon-small cell lung cancer cells by suppressing DNA repaircapacityrdquoCancer GeneTherapy vol 14 no 6 pp 543ndash549 2007

[19] A Di Cristofano B Pesce C Cordon-Cardo and P P PandolfildquoPten is essential for embryonic development and tumoursuppressionrdquo Nature Genetics vol 19 no 4 pp 348ndash355 1998

[20] J Bloomekatz J Grego-Bessa I Migeotte and K V AndersonldquoPten regulates collective cell migration during specification ofthe anterior-posterior axis of the mouse embryordquo Developmen-tal Biology vol 364 no 2 pp 192ndash201 2012

[21] S Ueno R Kono andY Iwao ldquoPTEN is required for the normalprogression of gastrulation by repressing cell proliferation afterMBT in Xenopus embryosrdquoDevelopmental Biology vol 297 no1 pp 274ndash283 2006

[22] C B Knobbe A Merlo and G Reifenberger ldquoPten signaling ingliomasrdquo Neuro Oncology vol 4 pp 196ndash211 2002

[23] E Kirches J Steiner T Schneider et al ldquoLhermitte-Duclosdisease caused by a novel germline PTEN mutation R173P in apatient presenting with psychosisrdquoNeuropathology and AppliedNeurobiology vol 36 no 1 pp 86ndash89 2010

[24] J-I Murata M Tada Y Sawamura K Mitsumori H Abe andK Nagashima ldquoDysplastic gangliocytoma (Lhermitte-Duclosdisease) associated with Cowden disease report of a case andreview of the literature for the genetic relationship between thetwo diseasesrdquo Journal of Neuro-Oncology vol 41 no 2 pp 129ndash136 1999

[25] G Zhu L M L Chow I T Bayazitov et al ldquoPten deletioncauses mTorc1-dependent ectopic neuroblast differentiation

without causing uniform migration defectsrdquo Development vol139 no 18 pp 3422ndash3431 2012

[26] K L McBride E A Varga M T Pastore et al ldquoConfirmationstudy of PTEN mutations among individuals with autism ordevelopmental delaysmental retardation and macrocephalyrdquoAutism Research vol 3 no 3 pp 137ndash141 2010

[27] J Zhou and L F Parada ldquoPTEN signaling in autism spectrumdisordersrdquo Current Opinion in Neurobiology vol 22 no 5 pp873ndash879 2012

[28] S A Backman V Stambolic A Suzuki et al ldquoDeletion of Ptenin mouse brain causes seizures ataxia and defects in soma sizeresembling Lhermitte-Duclos diseaserdquo Nature Genetics vol 29no 4 pp 396ndash403 2001

[29] L Cotter M Ozcelik C Jacob et al ldquoDlg1-PTEN interactionregulates myelin thickness to prevent damaging peripheralnerve overmyelinationrdquo Science vol 328 no 5984 pp 1415ndash1418 2010

[30] S Ogawa C-H Kwon J Zhou D Koovakkattu L F Paradaand C M Sinton ldquoA seizure-prone phenotype is associatedwith altered free-running rhythm in Pten mutant micerdquo BrainResearch vol 1168 no 1 pp 112ndash123 2007

[31] C-H Kwon X Zhu J Zhang and S J Baker ldquomTor isrequired for hypertrophy of Pten-deficient neuronal soma invivordquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 22 pp 12923ndash12928 2003

[32] C-H Kwon B W Luikart C M Powell et al ldquoPten regulatesneuronal arborization and social interaction in micerdquo Neuronvol 50 no 3 pp 377ndash388 2006

[33] A Suzuki S Itami M Ohishi et al ldquoKeratinocyte-specific Ptendeficiency results in epidermal hyperplasia accelerated hairfollicle morphogenesis and tumor formationrdquo Cancer Researchvol 63 no 3 pp 674ndash681 2003

[34] T Inoue-Narita K Hamada T Sasaki et al ldquoPten deficiency inmelanocytes results in resistance to hair graying and susceptibil-ity to carcinogen-induced melanomagenesisrdquo Cancer Researchvol 68 no 14 pp 5760ndash5768 2008

[35] R K Patel and C Mohan ldquoPI3KAKT signaling and systemicautoimmunityrdquo Immunologic Research vol 31 no 1 pp 47ndash552005

[36] K Podsypanina L H Ellenson A Nemes et al ldquoMutationof PtenMmac1 in mice causes neoplasia in multiple organsystemsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 4 pp 1563ndash1568 1999

[37] M Kashiwada P Lu and P B Rothman ldquoPIP3 pathway inregulatory T cells and autoimmunityrdquo Immunologic Researchvol 39 no 1ndash3 pp 194ndash224 2007

[38] A Suzuki M T Yamaguchi T Ohteki et al ldquoT cell-specificloss of Pten leads to defects in central and peripheral tolerancerdquoImmunity vol 14 no 5 pp 523ndash534 2001

[39] Y Yamanaka H Tagawa N Takahashi et al ldquoAberrant over-expression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lym-phomaleukemiardquo Blood vol 114 no 15 pp 3265ndash3275 2009

[40] H Kishimoto T Ohteki N Yajima et al ldquoThe PtenPI3Kpathway governs the homeostasis of V12057214iNKT cellsrdquo Bloodvol 109 no 8 pp 3316ndash3324 2007

[41] A Suzuki T Kaisho M Ohishi et al ldquoCritical roles ofPten in B cell homeostasis and immunoglobulin class switchrecombinationrdquo Journal of Experimental Medicine vol 197 no5 pp 657ndash667 2003

Journal of Signal Transduction 11

[42] M Nishio K-IWatanabe J Sasaki et al ldquoControl of cell polar-ity and motility by the PtdIns(345)P

3phosphatase SHIP1rdquo

Nature Cell Biology vol 9 no 1 pp 36ndash44 2007[43] S Kuroda M Nishio T Sasaki et al ldquoEffective clearance

of intracellular Leishmania major in vivo requires Pten inmacrophagesrdquo European Journal of Immunology vol 38 no 5pp 1331ndash1340 2008

[44] O H Yilmaz R Valdez B K Theisen et al ldquoPten depen-dence distinguishes haematopoietic stem cells from leukaemia-initiating cellsrdquo Nature vol 441 no 7092 pp 475ndash482 2006

[45] Y Li K Podsypanina X Liu et al ldquoDeficiency of Ptenaccelerates mammary oncogenesis in MMTV-Wnt-1 transgenicmicerdquo BMCMolecular Biology vol 2 article 2 2001

[46] P Reddy L Liu D Adhikari et al ldquoOocyte-specific deletion ofpten causes premature activation of the primordial follicle poolrdquoScience vol 319 no 5863 pp 611ndash613 2008

[47] H Tsuruta H Kishimoto T Sasaki et al ldquoHyperplasia andcarcinomas in Pten-deficient mice and reduced PTEN proteinin human bladder cancer patientsrdquoCancer Research vol 66 no17 pp 8389ndash8396 2006

[48] L I Yoo D W Liu S Le Vu R T Bronson H Wu and JYuan ldquoPten deficiency activates distinct downstream signalingpathways in a tissue-specific mannerrdquo Cancer Research vol 66no 4 pp 1929ndash1939 2006

[49] J Li C Yen D Liaw et al ldquoPTEN a putative protein tyrosinephosphatase gene mutated in human brain breast and prostatecancerrdquo Science vol 275 no 5308 pp 1943ndash1947 1997

[50] N D Deocampo H Huang and D J Tindall ldquoThe role ofPTEN in the progression and survival of prostate cancerrdquoMinerva Endocrinologica vol 28 no 2 pp 145ndash153 2003

[51] S A Backman D Ghazarian K So et al ldquoEarly onset ofneoplasia in the prostate and skin of mice with tissue-specificdeletion of Ptenrdquo Proceedings of the National Academy ofSciences of the United States of America vol 101 no 6 pp 1725ndash1730 2004

[52] X Wu K Xu L Zhang et al ldquoDifferentiation of the ductalepithelium and smooth muscle in the prostate gland areregulated by the NotchPTEN-dependent mechanismrdquo Devel-opmental Biology vol 356 no 2 pp 337ndash349 2011

[53] D Kim and G R Dressler ldquoPTEN modulates GDNFRETmediated chemotaxis and branching morphogenesis in thedeveloping kidneyrdquo Developmental Biology vol 307 no 2 pp290ndash299 2007

[54] N O Lindstrom M L Lawrence S F Burn et al ldquoIntegrated120573-catenin BMP PTEN and notch signalling patterns thenephronrdquo eLife no 4 Article ID e04000 2015

[55] V Marsh D J Winton G T Williams et al ldquoEpithelialPten is dispensable for intestinal homeostasis but suppressesadenoma development and progression after Apc mutationrdquoNature Genetics vol 40 no 12 pp 1436ndash1444 2008

[56] S Matsuda M Kobayashi and Y Kitagishi ldquoRoles forPI3KAKTPTEN pathway in cell signaling of nonalcoholicfatty liver diseaserdquo ISRN Endocrinology vol 2013 Article ID472432 7 pages 2013

[57] X Qi J Xu P Gu X Yang and X Gao ldquoPTEN in smoothmuscle cells is essential for colonic immune homeostasisrdquoInternational Journal of Biochemistry and Cell Biology vol 53pp 108ndash114 2014

[58] A Pal T M Barber M Van de Bunt et al ldquoPTENmutations asa cause of constitutive insulin sensitivity and obesityrdquoThe NewEngland Journal of Medicine vol 367 no 11 pp 1002ndash1011 2012

[59] B L Stiles C Kuralwalla-Martinez W Guo et al ldquoSelectivedeletion of Pten in pancreatic 120573 cells leads to increased isletmass and resistance to STZ-induced diabetesrdquo Molecular andCellular Biology vol 26 no 7 pp 2772ndash2781 2006

[60] LWang C T Luk E P Cai et al ldquoPTEN deletion in pancreatic120572-cells protects against high-fat diet-induced hyperglucagone-mia and insulin resistancerdquo Diabetes vol 64 no 1 pp 147ndash1572015

[61] C Kurlawalla-Martinez B Stiles Y Wang S U Devaskar BB Kahn and H Wu ldquoInsulin hypersensitivity and resistanceto streptozotocin-induced diabetes in mice lacking PTEN inadipose tissuerdquo Molecular and Cellular Biology vol 25 no 6pp 2498ndash2510 2005

[62] N Wijesekara D Konrad M Eweida et al ldquoMuscle-specificPten deletion protects against insulin resistance and diabetesrdquoMolecular and Cellular Biology vol 25 no 3 pp 1135ndash11452005

[63] K Hamada T Sasaki P A Koni et al ldquoThe PTENPI3Kpathway governs normal vascular development and tumorangiogenesisrdquo Genes and Development vol 19 no 17 pp 2054ndash2065 2005

[64] N D Roe X Xu M R Kandadi et al ldquoTargeted deletionof PTEN in cardiomyocytes renders cardiac contractile dys-function through interruption of Pink1-AMPK signaling andautophagyrdquo Biochimica et Biophysica Acta Molecular Basis ofDisease vol 1852 no 2 pp 290ndash298 2015

[65] A F Ford-Hutchinson Z Ali S E Lines B HallgrımssonS K Boyd and F R Jirik ldquoInactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnor-malities and skeletal overgrowthrdquo Journal of Bone and MineralResearch vol 22 no 8 pp 1245ndash1259 2007

[66] T A Burgers M F Hoffmann C J Collins et al ldquoMice lackingpten in osteoblasts have improved intramembranous and lateendochondral fracture healingrdquo PLoS ONE vol 8 no 5 ArticleID e63857 2013

[67] N R Leslie L Spinelli P Tibarewal et al ldquoIndirect mecha-nisms of carcinogenesis via downregulation of PTEN functionrdquoAdvances in Enzyme Regulation vol 50 no 1 pp 112ndash118 2010

[68] L He ldquoPosttranscriptional regulation of PTEN dosage bynoncoding RNAsrdquo Science Signaling vol 3 no 146 article pe392010

[69] F Vazquez S R Grossman Y Takahashi M V Rokas NNakamura andWR Sellers ldquoPhosphorylation of the PTEN tailacts as an inhibitory switch by preventing its recruitment into aprotein complexrdquo The Journal of Biological Chemistry vol 276no 52 pp 48627ndash48630 2001

[70] X Wang L C Trotman T Koppie et al ldquoNEDD4-1 is a proto-oncogenic ubiquitin ligase for PTENrdquo Cell vol 128 no 1 pp129ndash139 2007

[71] N R Leslie and M Foti ldquoNon-genomic loss of PTEN functionin cancer not in my genesrdquo Trends in Pharmacological Sciencesvol 32 no 3 pp 131ndash140 2011

[72] Y Xing C Li L Hu et al ldquoMechanisms of TGF120573 inhibition ofLUNG endodermal morphogenesis the role of T120573RII SmadsNkx21 and Ptenrdquo Developmental Biology vol 320 no 2 pp340ndash350 2008

[73] J P Luyendyk G A Schabbauer M Tencati T Holscher RPawlinski and N Mackman ldquoGenetic analysis of the role ofthe PI3K-Akt pathway in lipopolysaccharide-induced cytokineand tissue factor gene expression in monocytesmacrophagesrdquoJournal of Immunology vol 180 no 6 pp 4218ndash4226 2008

12 Journal of Signal Transduction

[74] F Sun K K Park S Belin et al ldquoSustained axon regenerationinduced by co-deletion of PTEN and SOCS3rdquo Nature vol 480no 7377 pp 372ndash375 2011

[75] C B Knobbe V Lapin A Suzuki and T W Mak ldquoThe roles ofPTEN in development physiology and tumorigenesis in mousemodels a tissue-by-tissue surveyrdquo Oncogene vol 27 no 41 pp5398ndash5415 2008

[76] S J Assinder Q Dong Z Kovacevic and D R RichardsonldquoThe TGF-beta PI3KAkt and PTEN pathways establishedand proposed biochemical integration in prostate cancerrdquoBiochemical Journal vol 417 no 2 pp 411ndash421 2009

[77] K A Waite and C Eng ldquoFrom developmental disorder toheritable cancer itrsquos all in the BMPTGF-120573 familyrdquo NatureReviews Genetics vol 4 no 10 pp 763ndash773 2003

[78] H B Newton ldquoMolecular neuro-oncology and developmentof targeted therapeutic strategies for brain tumors Part2 PI3KAktPTEN mTOR SHHPTCH and angiogenesisrdquoExpert Review of Anticancer Therapy vol 4 no 1 pp 105ndash1282004

[79] R H KimM Peters Y Jang et al ldquoDJ-1 a novel regulator of thetumor suppressor PTENrdquo Cancer Cell vol 7 no 3 pp 263ndash2732005

[80] J Lu H W Jeong N Kong et al ldquoStem cell factor SALL4represses the transcriptions of PTEN and SALL1 through anepigenetic repressor complexrdquo PLoS ONE vol 4 no 5 ArticleID e5577 2009

[81] M M A Rizvi M S Alam A Ali S J Mehdi S Batra andA KMandal ldquoAberrant promotermethylation and inactivationof PTEN gene in cervical carcinoma from Indian populationrdquoJournal of Cancer Research and Clinical Oncology vol 137 no 8pp 1255ndash1262 2011

[82] J Liu ldquoControl of protein synthesis and mRNA degradation bymicroRNAsrdquo Current Opinion in Cell Biology vol 20 no 2 pp214ndash221 2008

[83] S W Shan L Fang T Shatseva et al ldquoMature miR-17-5pand passenger miR-17-3p induce hepatocellular carcinoma bytargeting PTEN GalNT7 and vimentin in different signalpathwaysrdquo Journal of Cell Science vol 126 part 6 pp 1517ndash15302013

[84] Z Liang Y Li K Huang N Wagar and H Shim ldquoRegulationof miR-19 to breast cancer chemoresistance through targetingPTENrdquo Pharmaceutical Research vol 28 no 12 pp 3091ndash31002011

[85] X Lu Q Fan L Xu et al ldquoUrsolic acid attenuates diabeticmesangial cell injury through the up-regulation of autophagyvia miRNA-21PTENAktmTOR suppressionrdquo PLoS ONE vol10 no 2 Article ID e0117400 2015

[86] L Poliseno L Salmena J Zhang B Carver W J Havemanand P P Pandolfi ldquoA coding-independent function of geneand pseudogenemRNAs regulates tumour biologyrdquoNature vol465 no 7301 pp 1033ndash1038 2010

[87] Y Tay L Kats L Salmena et al ldquoCoding-independent regula-tion of the tumor suppressor PTEN by competing endogenousmRNAsrdquo Cell vol 147 no 2 pp 344ndash357 2011

[88] L Odriozola G Singh T Hoang and A M Chan ldquoRegula-tion of PTEN activity by its carboxyl-terminal autoinhibitorydomainrdquo The Journal of Biological Chemistry vol 282 no 32pp 23306ndash23315 2007

[89] Z Li X Dong Z Wang et al ldquoRegulation of PTEN by Rhosmall GTPasesrdquo Nature Cell Biology vol 7 no 4 pp 399ndash4042005

[90] E-K Yim G Peng H Dai et al ldquoRak functions as a tumorsuppressor by regulating PTEN protein stability and functionrdquoCancer Cell vol 15 no 4 pp 304ndash314 2009

[91] AMAl-Khouri YMa SH Togo SWilliams andTMustelinldquoCooperative phosphorylation of the tumor suppressor phos-phatase and tensin homologue (PTEN) by casein kinasesand glycogen synthase kinase 3120573rdquo The Journal of BiologicalChemistry vol 280 no 42 pp 35195ndash35202 2005

[92] H Maccario N M Perera L Davidson C P Downes and NR Leslie ldquoPTEN is destabilized by phosphorylation onThr366rdquoBiochemical Journal vol 405 no 3 pp 439ndash444 2007

[93] K A Waite and C Eng ldquoBMP2 exposure results in decreasedPTEN protein degradation and increased PTEN levelsrdquoHumanMolecular Genetics vol 12 no 6 pp 679ndash684 2003

[94] T J Jerde Z Wu D Theodorescu and W Bushman ldquoRegu-lation of phosphatase homologue of tensin protein expressionby bone morphogenetic proteins in prostate epithelial cellsrdquoProstate vol 71 no 8 pp 791ndash800 2011

[95] G Singh and A M Chan ldquoPost-translational modificationsof PTEN and their potential therapeutic implicationsrdquo CurrentCancer Drug Targets vol 11 no 5 pp 536ndash547 2011

[96] T Ikenoue K Inoki B Zhao and K-L Guan ldquoPTEN acety-lation modulates its interaction with PDZ domainrdquo CancerResearch vol 68 no 17 pp 6908ndash6912 2008

[97] L C Trotman X Wang A Alimonti et al ldquoUbiquitinationregulates PTEN nuclear import and tumor suppressionrdquo Cellvol 128 no 1 pp 141ndash156 2007

[98] T Tolkacheva M Boddapati A Sanfiz K Tsuchida A CKimmelman and AM-L Chan ldquoRegulation of PTEN bindingto MAGI-2 by two putative phosphorylation sites at threonine382 and 383rdquo Cancer Research vol 61 no 13 pp 4985ndash49892001

[99] E Lima-Fernandes H Enslen E Camand et al ldquoDistinct func-tional outputs of PTEN signalling are controlled by dynamicassociation with 120573-arrestinsrdquoThe EMBO Journal vol 30 no 13pp 2557ndash2568 2011

[100] M T van Diepen M Parsons C P Downes N R Leslie RHindges and B J Eickholt ldquoMyosinV controls PTEN functionand neuronal cell sizerdquo Nature Cell Biology vol 11 no 10 pp1191ndash1196 2009

[101] R B Chagpar P H Links M C Pastor et al ldquoDirect positiveregulation of PTEN by the p85 subunit of phosphatidylinositol3-kinaserdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 107 no 12 pp 5471ndash5476 2010

[102] Y Takahashi F C Morales E L Kreimann and M-MGeorgescu ldquoPTEN tumor suppressor associates with NHERFproteins to attenuate PDGF receptor signalingrdquo The EMBOJournal vol 25 no 4 pp 910ndash920 2006

[103] M Valiente A Andres-Pons B Gomar et al ldquoBinding ofPTEN to specific PDZ domains contributes to PTEN proteinstability and phosphorylation by microtubule-associated ser-inethreonine kinasesrdquoThe Journal of Biological Chemistry vol280 no 32 pp 28936ndash28943 2005

[104] SQuintes SGoebbels G SaherMH Schwab andK-ANaveldquoNeuron-glia signaling and the protection of axon function bySchwann cellsrdquo Journal of the Peripheral Nervous System vol 15no 1 pp 10ndash16 2010

[105] B Fine C Hodakoski S Koujak et al ldquoActivation of the PI3Kpathway in cancer through inhibition of PTEN by exchangefactor P-REX2ardquo Science vol 325 no 5945 pp 1261ndash1265 2009

Journal of Signal Transduction 13

[106] L He A Ingram A P Rybak and D Tang ldquoShank-interactingprotein-like 1 promotes tumorigenesis via PTEN inhibition inhuman tumor cellsrdquo The Journal of Clinical Investigation vol120 no 6 pp 2094ndash2108 2010

[107] L He C Fan A Kapoor et al ldquo120572-Mannosidase 2C1 attenuatesPTEN function in prostate cancer cellsrdquo Nature Communica-tions vol 2 no 1 article 307 2011

[108] Z Radisavljevic ldquoAKT as locus of cancer positive feedbackloops and extreme robustnessrdquo Journal of Cellular Physiologyvol 228 no 3 pp 522ndash524 2013

[109] M Y Lee HW Lim S H Lee andH J Han ldquoSmad PI3KAktand wnt-dependent signaling pathways are involved in BMP-4-induced ESC self-renewalrdquo Stem Cells vol 27 no 8 pp 1858ndash1868 2009

[110] K Song S C Cornelius M Reiss and D Danielpour ldquoInsulin-like growth factor-I inhibits transcriptional responses of trans-forming growth factor-120573 by phosphatidylinositol 3-kinaseAkt-dependent suppression of the activation of Smad3 but notSmad2rdquoThe Journal of Biological Chemistry vol 278 no 40 pp38342ndash38351 2003

[111] D Fang D Hawke Y Zheng et al ldquoPhosphorylation of 120573-catenin by AKT promotes 120573-catenin transcriptional activityrdquoThe Journal of Biological Chemistry vol 282 no 15 pp 11221ndash11229 2007

[112] Q Lei J Jiao L Xin et al ldquoNKX31 stabilizes p53 inhibitsAKT activation and blocks prostate cancer initiation caused byPTEN lossrdquo Cancer Cell vol 9 no 5 pp 367ndash378 2006

[113] A Sengupta J D Molkentin J-H Paik R A DePinho and KE Yutzey ldquoFoxO transcription factors promote cardiomyocytesurvival upon induction of oxidative stressrdquo The Journal ofBiological Chemistry vol 286 no 9 pp 7468ndash7478 2011

[114] C H M Jamieson L E Ailles S J Dylla et al ldquoGranulocyte-macrophage progenitors as candidate leukemic stem cells inblast-crisis CMLrdquoTheNewEngland Journal ofMedicine vol 351no 7 pp 657ndash667 2004

[115] A Androutsellis-Theotokis R R Leker F Soldner et al ldquoNotchsignalling regulates stem cell numbers in vitro and in vivordquoNature vol 442 no 7104 pp 823ndash826 2006

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

Page 11: Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling TravisJ.Jerde Department of Pharmacology

Journal of Signal Transduction 11

[42] M Nishio K-IWatanabe J Sasaki et al ldquoControl of cell polar-ity and motility by the PtdIns(345)P

3phosphatase SHIP1rdquo

Nature Cell Biology vol 9 no 1 pp 36ndash44 2007[43] S Kuroda M Nishio T Sasaki et al ldquoEffective clearance

of intracellular Leishmania major in vivo requires Pten inmacrophagesrdquo European Journal of Immunology vol 38 no 5pp 1331ndash1340 2008

[44] O H Yilmaz R Valdez B K Theisen et al ldquoPten depen-dence distinguishes haematopoietic stem cells from leukaemia-initiating cellsrdquo Nature vol 441 no 7092 pp 475ndash482 2006

[45] Y Li K Podsypanina X Liu et al ldquoDeficiency of Ptenaccelerates mammary oncogenesis in MMTV-Wnt-1 transgenicmicerdquo BMCMolecular Biology vol 2 article 2 2001

[46] P Reddy L Liu D Adhikari et al ldquoOocyte-specific deletion ofpten causes premature activation of the primordial follicle poolrdquoScience vol 319 no 5863 pp 611ndash613 2008

[47] H Tsuruta H Kishimoto T Sasaki et al ldquoHyperplasia andcarcinomas in Pten-deficient mice and reduced PTEN proteinin human bladder cancer patientsrdquoCancer Research vol 66 no17 pp 8389ndash8396 2006

[48] L I Yoo D W Liu S Le Vu R T Bronson H Wu and JYuan ldquoPten deficiency activates distinct downstream signalingpathways in a tissue-specific mannerrdquo Cancer Research vol 66no 4 pp 1929ndash1939 2006

[49] J Li C Yen D Liaw et al ldquoPTEN a putative protein tyrosinephosphatase gene mutated in human brain breast and prostatecancerrdquo Science vol 275 no 5308 pp 1943ndash1947 1997

[50] N D Deocampo H Huang and D J Tindall ldquoThe role ofPTEN in the progression and survival of prostate cancerrdquoMinerva Endocrinologica vol 28 no 2 pp 145ndash153 2003

[51] S A Backman D Ghazarian K So et al ldquoEarly onset ofneoplasia in the prostate and skin of mice with tissue-specificdeletion of Ptenrdquo Proceedings of the National Academy ofSciences of the United States of America vol 101 no 6 pp 1725ndash1730 2004

[52] X Wu K Xu L Zhang et al ldquoDifferentiation of the ductalepithelium and smooth muscle in the prostate gland areregulated by the NotchPTEN-dependent mechanismrdquo Devel-opmental Biology vol 356 no 2 pp 337ndash349 2011

[53] D Kim and G R Dressler ldquoPTEN modulates GDNFRETmediated chemotaxis and branching morphogenesis in thedeveloping kidneyrdquo Developmental Biology vol 307 no 2 pp290ndash299 2007

[54] N O Lindstrom M L Lawrence S F Burn et al ldquoIntegrated120573-catenin BMP PTEN and notch signalling patterns thenephronrdquo eLife no 4 Article ID e04000 2015

[55] V Marsh D J Winton G T Williams et al ldquoEpithelialPten is dispensable for intestinal homeostasis but suppressesadenoma development and progression after Apc mutationrdquoNature Genetics vol 40 no 12 pp 1436ndash1444 2008

[56] S Matsuda M Kobayashi and Y Kitagishi ldquoRoles forPI3KAKTPTEN pathway in cell signaling of nonalcoholicfatty liver diseaserdquo ISRN Endocrinology vol 2013 Article ID472432 7 pages 2013

[57] X Qi J Xu P Gu X Yang and X Gao ldquoPTEN in smoothmuscle cells is essential for colonic immune homeostasisrdquoInternational Journal of Biochemistry and Cell Biology vol 53pp 108ndash114 2014

[58] A Pal T M Barber M Van de Bunt et al ldquoPTENmutations asa cause of constitutive insulin sensitivity and obesityrdquoThe NewEngland Journal of Medicine vol 367 no 11 pp 1002ndash1011 2012

[59] B L Stiles C Kuralwalla-Martinez W Guo et al ldquoSelectivedeletion of Pten in pancreatic 120573 cells leads to increased isletmass and resistance to STZ-induced diabetesrdquo Molecular andCellular Biology vol 26 no 7 pp 2772ndash2781 2006

[60] LWang C T Luk E P Cai et al ldquoPTEN deletion in pancreatic120572-cells protects against high-fat diet-induced hyperglucagone-mia and insulin resistancerdquo Diabetes vol 64 no 1 pp 147ndash1572015

[61] C Kurlawalla-Martinez B Stiles Y Wang S U Devaskar BB Kahn and H Wu ldquoInsulin hypersensitivity and resistanceto streptozotocin-induced diabetes in mice lacking PTEN inadipose tissuerdquo Molecular and Cellular Biology vol 25 no 6pp 2498ndash2510 2005

[62] N Wijesekara D Konrad M Eweida et al ldquoMuscle-specificPten deletion protects against insulin resistance and diabetesrdquoMolecular and Cellular Biology vol 25 no 3 pp 1135ndash11452005

[63] K Hamada T Sasaki P A Koni et al ldquoThe PTENPI3Kpathway governs normal vascular development and tumorangiogenesisrdquo Genes and Development vol 19 no 17 pp 2054ndash2065 2005

[64] N D Roe X Xu M R Kandadi et al ldquoTargeted deletionof PTEN in cardiomyocytes renders cardiac contractile dys-function through interruption of Pink1-AMPK signaling andautophagyrdquo Biochimica et Biophysica Acta Molecular Basis ofDisease vol 1852 no 2 pp 290ndash298 2015

[65] A F Ford-Hutchinson Z Ali S E Lines B HallgrımssonS K Boyd and F R Jirik ldquoInactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnor-malities and skeletal overgrowthrdquo Journal of Bone and MineralResearch vol 22 no 8 pp 1245ndash1259 2007

[66] T A Burgers M F Hoffmann C J Collins et al ldquoMice lackingpten in osteoblasts have improved intramembranous and lateendochondral fracture healingrdquo PLoS ONE vol 8 no 5 ArticleID e63857 2013

[67] N R Leslie L Spinelli P Tibarewal et al ldquoIndirect mecha-nisms of carcinogenesis via downregulation of PTEN functionrdquoAdvances in Enzyme Regulation vol 50 no 1 pp 112ndash118 2010

[68] L He ldquoPosttranscriptional regulation of PTEN dosage bynoncoding RNAsrdquo Science Signaling vol 3 no 146 article pe392010

[69] F Vazquez S R Grossman Y Takahashi M V Rokas NNakamura andWR Sellers ldquoPhosphorylation of the PTEN tailacts as an inhibitory switch by preventing its recruitment into aprotein complexrdquo The Journal of Biological Chemistry vol 276no 52 pp 48627ndash48630 2001

[70] X Wang L C Trotman T Koppie et al ldquoNEDD4-1 is a proto-oncogenic ubiquitin ligase for PTENrdquo Cell vol 128 no 1 pp129ndash139 2007

[71] N R Leslie and M Foti ldquoNon-genomic loss of PTEN functionin cancer not in my genesrdquo Trends in Pharmacological Sciencesvol 32 no 3 pp 131ndash140 2011

[72] Y Xing C Li L Hu et al ldquoMechanisms of TGF120573 inhibition ofLUNG endodermal morphogenesis the role of T120573RII SmadsNkx21 and Ptenrdquo Developmental Biology vol 320 no 2 pp340ndash350 2008

[73] J P Luyendyk G A Schabbauer M Tencati T Holscher RPawlinski and N Mackman ldquoGenetic analysis of the role ofthe PI3K-Akt pathway in lipopolysaccharide-induced cytokineand tissue factor gene expression in monocytesmacrophagesrdquoJournal of Immunology vol 180 no 6 pp 4218ndash4226 2008

12 Journal of Signal Transduction

[74] F Sun K K Park S Belin et al ldquoSustained axon regenerationinduced by co-deletion of PTEN and SOCS3rdquo Nature vol 480no 7377 pp 372ndash375 2011

[75] C B Knobbe V Lapin A Suzuki and T W Mak ldquoThe roles ofPTEN in development physiology and tumorigenesis in mousemodels a tissue-by-tissue surveyrdquo Oncogene vol 27 no 41 pp5398ndash5415 2008

[76] S J Assinder Q Dong Z Kovacevic and D R RichardsonldquoThe TGF-beta PI3KAkt and PTEN pathways establishedand proposed biochemical integration in prostate cancerrdquoBiochemical Journal vol 417 no 2 pp 411ndash421 2009

[77] K A Waite and C Eng ldquoFrom developmental disorder toheritable cancer itrsquos all in the BMPTGF-120573 familyrdquo NatureReviews Genetics vol 4 no 10 pp 763ndash773 2003

[78] H B Newton ldquoMolecular neuro-oncology and developmentof targeted therapeutic strategies for brain tumors Part2 PI3KAktPTEN mTOR SHHPTCH and angiogenesisrdquoExpert Review of Anticancer Therapy vol 4 no 1 pp 105ndash1282004

[79] R H KimM Peters Y Jang et al ldquoDJ-1 a novel regulator of thetumor suppressor PTENrdquo Cancer Cell vol 7 no 3 pp 263ndash2732005

[80] J Lu H W Jeong N Kong et al ldquoStem cell factor SALL4represses the transcriptions of PTEN and SALL1 through anepigenetic repressor complexrdquo PLoS ONE vol 4 no 5 ArticleID e5577 2009

[81] M M A Rizvi M S Alam A Ali S J Mehdi S Batra andA KMandal ldquoAberrant promotermethylation and inactivationof PTEN gene in cervical carcinoma from Indian populationrdquoJournal of Cancer Research and Clinical Oncology vol 137 no 8pp 1255ndash1262 2011

[82] J Liu ldquoControl of protein synthesis and mRNA degradation bymicroRNAsrdquo Current Opinion in Cell Biology vol 20 no 2 pp214ndash221 2008

[83] S W Shan L Fang T Shatseva et al ldquoMature miR-17-5pand passenger miR-17-3p induce hepatocellular carcinoma bytargeting PTEN GalNT7 and vimentin in different signalpathwaysrdquo Journal of Cell Science vol 126 part 6 pp 1517ndash15302013

[84] Z Liang Y Li K Huang N Wagar and H Shim ldquoRegulationof miR-19 to breast cancer chemoresistance through targetingPTENrdquo Pharmaceutical Research vol 28 no 12 pp 3091ndash31002011

[85] X Lu Q Fan L Xu et al ldquoUrsolic acid attenuates diabeticmesangial cell injury through the up-regulation of autophagyvia miRNA-21PTENAktmTOR suppressionrdquo PLoS ONE vol10 no 2 Article ID e0117400 2015

[86] L Poliseno L Salmena J Zhang B Carver W J Havemanand P P Pandolfi ldquoA coding-independent function of geneand pseudogenemRNAs regulates tumour biologyrdquoNature vol465 no 7301 pp 1033ndash1038 2010

[87] Y Tay L Kats L Salmena et al ldquoCoding-independent regula-tion of the tumor suppressor PTEN by competing endogenousmRNAsrdquo Cell vol 147 no 2 pp 344ndash357 2011

[88] L Odriozola G Singh T Hoang and A M Chan ldquoRegula-tion of PTEN activity by its carboxyl-terminal autoinhibitorydomainrdquo The Journal of Biological Chemistry vol 282 no 32pp 23306ndash23315 2007

[89] Z Li X Dong Z Wang et al ldquoRegulation of PTEN by Rhosmall GTPasesrdquo Nature Cell Biology vol 7 no 4 pp 399ndash4042005

[90] E-K Yim G Peng H Dai et al ldquoRak functions as a tumorsuppressor by regulating PTEN protein stability and functionrdquoCancer Cell vol 15 no 4 pp 304ndash314 2009

[91] AMAl-Khouri YMa SH Togo SWilliams andTMustelinldquoCooperative phosphorylation of the tumor suppressor phos-phatase and tensin homologue (PTEN) by casein kinasesand glycogen synthase kinase 3120573rdquo The Journal of BiologicalChemistry vol 280 no 42 pp 35195ndash35202 2005

[92] H Maccario N M Perera L Davidson C P Downes and NR Leslie ldquoPTEN is destabilized by phosphorylation onThr366rdquoBiochemical Journal vol 405 no 3 pp 439ndash444 2007

[93] K A Waite and C Eng ldquoBMP2 exposure results in decreasedPTEN protein degradation and increased PTEN levelsrdquoHumanMolecular Genetics vol 12 no 6 pp 679ndash684 2003

[94] T J Jerde Z Wu D Theodorescu and W Bushman ldquoRegu-lation of phosphatase homologue of tensin protein expressionby bone morphogenetic proteins in prostate epithelial cellsrdquoProstate vol 71 no 8 pp 791ndash800 2011

[95] G Singh and A M Chan ldquoPost-translational modificationsof PTEN and their potential therapeutic implicationsrdquo CurrentCancer Drug Targets vol 11 no 5 pp 536ndash547 2011

[96] T Ikenoue K Inoki B Zhao and K-L Guan ldquoPTEN acety-lation modulates its interaction with PDZ domainrdquo CancerResearch vol 68 no 17 pp 6908ndash6912 2008

[97] L C Trotman X Wang A Alimonti et al ldquoUbiquitinationregulates PTEN nuclear import and tumor suppressionrdquo Cellvol 128 no 1 pp 141ndash156 2007

[98] T Tolkacheva M Boddapati A Sanfiz K Tsuchida A CKimmelman and AM-L Chan ldquoRegulation of PTEN bindingto MAGI-2 by two putative phosphorylation sites at threonine382 and 383rdquo Cancer Research vol 61 no 13 pp 4985ndash49892001

[99] E Lima-Fernandes H Enslen E Camand et al ldquoDistinct func-tional outputs of PTEN signalling are controlled by dynamicassociation with 120573-arrestinsrdquoThe EMBO Journal vol 30 no 13pp 2557ndash2568 2011

[100] M T van Diepen M Parsons C P Downes N R Leslie RHindges and B J Eickholt ldquoMyosinV controls PTEN functionand neuronal cell sizerdquo Nature Cell Biology vol 11 no 10 pp1191ndash1196 2009

[101] R B Chagpar P H Links M C Pastor et al ldquoDirect positiveregulation of PTEN by the p85 subunit of phosphatidylinositol3-kinaserdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 107 no 12 pp 5471ndash5476 2010

[102] Y Takahashi F C Morales E L Kreimann and M-MGeorgescu ldquoPTEN tumor suppressor associates with NHERFproteins to attenuate PDGF receptor signalingrdquo The EMBOJournal vol 25 no 4 pp 910ndash920 2006

[103] M Valiente A Andres-Pons B Gomar et al ldquoBinding ofPTEN to specific PDZ domains contributes to PTEN proteinstability and phosphorylation by microtubule-associated ser-inethreonine kinasesrdquoThe Journal of Biological Chemistry vol280 no 32 pp 28936ndash28943 2005

[104] SQuintes SGoebbels G SaherMH Schwab andK-ANaveldquoNeuron-glia signaling and the protection of axon function bySchwann cellsrdquo Journal of the Peripheral Nervous System vol 15no 1 pp 10ndash16 2010

[105] B Fine C Hodakoski S Koujak et al ldquoActivation of the PI3Kpathway in cancer through inhibition of PTEN by exchangefactor P-REX2ardquo Science vol 325 no 5945 pp 1261ndash1265 2009

Journal of Signal Transduction 13

[106] L He A Ingram A P Rybak and D Tang ldquoShank-interactingprotein-like 1 promotes tumorigenesis via PTEN inhibition inhuman tumor cellsrdquo The Journal of Clinical Investigation vol120 no 6 pp 2094ndash2108 2010

[107] L He C Fan A Kapoor et al ldquo120572-Mannosidase 2C1 attenuatesPTEN function in prostate cancer cellsrdquo Nature Communica-tions vol 2 no 1 article 307 2011

[108] Z Radisavljevic ldquoAKT as locus of cancer positive feedbackloops and extreme robustnessrdquo Journal of Cellular Physiologyvol 228 no 3 pp 522ndash524 2013

[109] M Y Lee HW Lim S H Lee andH J Han ldquoSmad PI3KAktand wnt-dependent signaling pathways are involved in BMP-4-induced ESC self-renewalrdquo Stem Cells vol 27 no 8 pp 1858ndash1868 2009

[110] K Song S C Cornelius M Reiss and D Danielpour ldquoInsulin-like growth factor-I inhibits transcriptional responses of trans-forming growth factor-120573 by phosphatidylinositol 3-kinaseAkt-dependent suppression of the activation of Smad3 but notSmad2rdquoThe Journal of Biological Chemistry vol 278 no 40 pp38342ndash38351 2003

[111] D Fang D Hawke Y Zheng et al ldquoPhosphorylation of 120573-catenin by AKT promotes 120573-catenin transcriptional activityrdquoThe Journal of Biological Chemistry vol 282 no 15 pp 11221ndash11229 2007

[112] Q Lei J Jiao L Xin et al ldquoNKX31 stabilizes p53 inhibitsAKT activation and blocks prostate cancer initiation caused byPTEN lossrdquo Cancer Cell vol 9 no 5 pp 367ndash378 2006

[113] A Sengupta J D Molkentin J-H Paik R A DePinho and KE Yutzey ldquoFoxO transcription factors promote cardiomyocytesurvival upon induction of oxidative stressrdquo The Journal ofBiological Chemistry vol 286 no 9 pp 7468ndash7478 2011

[114] C H M Jamieson L E Ailles S J Dylla et al ldquoGranulocyte-macrophage progenitors as candidate leukemic stem cells inblast-crisis CMLrdquoTheNewEngland Journal ofMedicine vol 351no 7 pp 657ndash667 2004

[115] A Androutsellis-Theotokis R R Leker F Soldner et al ldquoNotchsignalling regulates stem cell numbers in vitro and in vivordquoNature vol 442 no 7104 pp 823ndash826 2006

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

Page 12: Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling TravisJ.Jerde Department of Pharmacology

12 Journal of Signal Transduction

[74] F Sun K K Park S Belin et al ldquoSustained axon regenerationinduced by co-deletion of PTEN and SOCS3rdquo Nature vol 480no 7377 pp 372ndash375 2011

[75] C B Knobbe V Lapin A Suzuki and T W Mak ldquoThe roles ofPTEN in development physiology and tumorigenesis in mousemodels a tissue-by-tissue surveyrdquo Oncogene vol 27 no 41 pp5398ndash5415 2008

[76] S J Assinder Q Dong Z Kovacevic and D R RichardsonldquoThe TGF-beta PI3KAkt and PTEN pathways establishedand proposed biochemical integration in prostate cancerrdquoBiochemical Journal vol 417 no 2 pp 411ndash421 2009

[77] K A Waite and C Eng ldquoFrom developmental disorder toheritable cancer itrsquos all in the BMPTGF-120573 familyrdquo NatureReviews Genetics vol 4 no 10 pp 763ndash773 2003

[78] H B Newton ldquoMolecular neuro-oncology and developmentof targeted therapeutic strategies for brain tumors Part2 PI3KAktPTEN mTOR SHHPTCH and angiogenesisrdquoExpert Review of Anticancer Therapy vol 4 no 1 pp 105ndash1282004

[79] R H KimM Peters Y Jang et al ldquoDJ-1 a novel regulator of thetumor suppressor PTENrdquo Cancer Cell vol 7 no 3 pp 263ndash2732005

[80] J Lu H W Jeong N Kong et al ldquoStem cell factor SALL4represses the transcriptions of PTEN and SALL1 through anepigenetic repressor complexrdquo PLoS ONE vol 4 no 5 ArticleID e5577 2009

[81] M M A Rizvi M S Alam A Ali S J Mehdi S Batra andA KMandal ldquoAberrant promotermethylation and inactivationof PTEN gene in cervical carcinoma from Indian populationrdquoJournal of Cancer Research and Clinical Oncology vol 137 no 8pp 1255ndash1262 2011

[82] J Liu ldquoControl of protein synthesis and mRNA degradation bymicroRNAsrdquo Current Opinion in Cell Biology vol 20 no 2 pp214ndash221 2008

[83] S W Shan L Fang T Shatseva et al ldquoMature miR-17-5pand passenger miR-17-3p induce hepatocellular carcinoma bytargeting PTEN GalNT7 and vimentin in different signalpathwaysrdquo Journal of Cell Science vol 126 part 6 pp 1517ndash15302013

[84] Z Liang Y Li K Huang N Wagar and H Shim ldquoRegulationof miR-19 to breast cancer chemoresistance through targetingPTENrdquo Pharmaceutical Research vol 28 no 12 pp 3091ndash31002011

[85] X Lu Q Fan L Xu et al ldquoUrsolic acid attenuates diabeticmesangial cell injury through the up-regulation of autophagyvia miRNA-21PTENAktmTOR suppressionrdquo PLoS ONE vol10 no 2 Article ID e0117400 2015

[86] L Poliseno L Salmena J Zhang B Carver W J Havemanand P P Pandolfi ldquoA coding-independent function of geneand pseudogenemRNAs regulates tumour biologyrdquoNature vol465 no 7301 pp 1033ndash1038 2010

[87] Y Tay L Kats L Salmena et al ldquoCoding-independent regula-tion of the tumor suppressor PTEN by competing endogenousmRNAsrdquo Cell vol 147 no 2 pp 344ndash357 2011

[88] L Odriozola G Singh T Hoang and A M Chan ldquoRegula-tion of PTEN activity by its carboxyl-terminal autoinhibitorydomainrdquo The Journal of Biological Chemistry vol 282 no 32pp 23306ndash23315 2007

[89] Z Li X Dong Z Wang et al ldquoRegulation of PTEN by Rhosmall GTPasesrdquo Nature Cell Biology vol 7 no 4 pp 399ndash4042005

[90] E-K Yim G Peng H Dai et al ldquoRak functions as a tumorsuppressor by regulating PTEN protein stability and functionrdquoCancer Cell vol 15 no 4 pp 304ndash314 2009

[91] AMAl-Khouri YMa SH Togo SWilliams andTMustelinldquoCooperative phosphorylation of the tumor suppressor phos-phatase and tensin homologue (PTEN) by casein kinasesand glycogen synthase kinase 3120573rdquo The Journal of BiologicalChemistry vol 280 no 42 pp 35195ndash35202 2005

[92] H Maccario N M Perera L Davidson C P Downes and NR Leslie ldquoPTEN is destabilized by phosphorylation onThr366rdquoBiochemical Journal vol 405 no 3 pp 439ndash444 2007

[93] K A Waite and C Eng ldquoBMP2 exposure results in decreasedPTEN protein degradation and increased PTEN levelsrdquoHumanMolecular Genetics vol 12 no 6 pp 679ndash684 2003

[94] T J Jerde Z Wu D Theodorescu and W Bushman ldquoRegu-lation of phosphatase homologue of tensin protein expressionby bone morphogenetic proteins in prostate epithelial cellsrdquoProstate vol 71 no 8 pp 791ndash800 2011

[95] G Singh and A M Chan ldquoPost-translational modificationsof PTEN and their potential therapeutic implicationsrdquo CurrentCancer Drug Targets vol 11 no 5 pp 536ndash547 2011

[96] T Ikenoue K Inoki B Zhao and K-L Guan ldquoPTEN acety-lation modulates its interaction with PDZ domainrdquo CancerResearch vol 68 no 17 pp 6908ndash6912 2008

[97] L C Trotman X Wang A Alimonti et al ldquoUbiquitinationregulates PTEN nuclear import and tumor suppressionrdquo Cellvol 128 no 1 pp 141ndash156 2007

[98] T Tolkacheva M Boddapati A Sanfiz K Tsuchida A CKimmelman and AM-L Chan ldquoRegulation of PTEN bindingto MAGI-2 by two putative phosphorylation sites at threonine382 and 383rdquo Cancer Research vol 61 no 13 pp 4985ndash49892001

[99] E Lima-Fernandes H Enslen E Camand et al ldquoDistinct func-tional outputs of PTEN signalling are controlled by dynamicassociation with 120573-arrestinsrdquoThe EMBO Journal vol 30 no 13pp 2557ndash2568 2011

[100] M T van Diepen M Parsons C P Downes N R Leslie RHindges and B J Eickholt ldquoMyosinV controls PTEN functionand neuronal cell sizerdquo Nature Cell Biology vol 11 no 10 pp1191ndash1196 2009

[101] R B Chagpar P H Links M C Pastor et al ldquoDirect positiveregulation of PTEN by the p85 subunit of phosphatidylinositol3-kinaserdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 107 no 12 pp 5471ndash5476 2010

[102] Y Takahashi F C Morales E L Kreimann and M-MGeorgescu ldquoPTEN tumor suppressor associates with NHERFproteins to attenuate PDGF receptor signalingrdquo The EMBOJournal vol 25 no 4 pp 910ndash920 2006

[103] M Valiente A Andres-Pons B Gomar et al ldquoBinding ofPTEN to specific PDZ domains contributes to PTEN proteinstability and phosphorylation by microtubule-associated ser-inethreonine kinasesrdquoThe Journal of Biological Chemistry vol280 no 32 pp 28936ndash28943 2005

[104] SQuintes SGoebbels G SaherMH Schwab andK-ANaveldquoNeuron-glia signaling and the protection of axon function bySchwann cellsrdquo Journal of the Peripheral Nervous System vol 15no 1 pp 10ndash16 2010

[105] B Fine C Hodakoski S Koujak et al ldquoActivation of the PI3Kpathway in cancer through inhibition of PTEN by exchangefactor P-REX2ardquo Science vol 325 no 5945 pp 1261ndash1265 2009

Journal of Signal Transduction 13

[106] L He A Ingram A P Rybak and D Tang ldquoShank-interactingprotein-like 1 promotes tumorigenesis via PTEN inhibition inhuman tumor cellsrdquo The Journal of Clinical Investigation vol120 no 6 pp 2094ndash2108 2010

[107] L He C Fan A Kapoor et al ldquo120572-Mannosidase 2C1 attenuatesPTEN function in prostate cancer cellsrdquo Nature Communica-tions vol 2 no 1 article 307 2011

[108] Z Radisavljevic ldquoAKT as locus of cancer positive feedbackloops and extreme robustnessrdquo Journal of Cellular Physiologyvol 228 no 3 pp 522ndash524 2013

[109] M Y Lee HW Lim S H Lee andH J Han ldquoSmad PI3KAktand wnt-dependent signaling pathways are involved in BMP-4-induced ESC self-renewalrdquo Stem Cells vol 27 no 8 pp 1858ndash1868 2009

[110] K Song S C Cornelius M Reiss and D Danielpour ldquoInsulin-like growth factor-I inhibits transcriptional responses of trans-forming growth factor-120573 by phosphatidylinositol 3-kinaseAkt-dependent suppression of the activation of Smad3 but notSmad2rdquoThe Journal of Biological Chemistry vol 278 no 40 pp38342ndash38351 2003

[111] D Fang D Hawke Y Zheng et al ldquoPhosphorylation of 120573-catenin by AKT promotes 120573-catenin transcriptional activityrdquoThe Journal of Biological Chemistry vol 282 no 15 pp 11221ndash11229 2007

[112] Q Lei J Jiao L Xin et al ldquoNKX31 stabilizes p53 inhibitsAKT activation and blocks prostate cancer initiation caused byPTEN lossrdquo Cancer Cell vol 9 no 5 pp 367ndash378 2006

[113] A Sengupta J D Molkentin J-H Paik R A DePinho and KE Yutzey ldquoFoxO transcription factors promote cardiomyocytesurvival upon induction of oxidative stressrdquo The Journal ofBiological Chemistry vol 286 no 9 pp 7468ndash7478 2011

[114] C H M Jamieson L E Ailles S J Dylla et al ldquoGranulocyte-macrophage progenitors as candidate leukemic stem cells inblast-crisis CMLrdquoTheNewEngland Journal ofMedicine vol 351no 7 pp 657ndash667 2004

[115] A Androutsellis-Theotokis R R Leker F Soldner et al ldquoNotchsignalling regulates stem cell numbers in vitro and in vivordquoNature vol 442 no 7104 pp 823ndash826 2006

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

Page 13: Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling TravisJ.Jerde Department of Pharmacology

Journal of Signal Transduction 13

[106] L He A Ingram A P Rybak and D Tang ldquoShank-interactingprotein-like 1 promotes tumorigenesis via PTEN inhibition inhuman tumor cellsrdquo The Journal of Clinical Investigation vol120 no 6 pp 2094ndash2108 2010

[107] L He C Fan A Kapoor et al ldquo120572-Mannosidase 2C1 attenuatesPTEN function in prostate cancer cellsrdquo Nature Communica-tions vol 2 no 1 article 307 2011

[108] Z Radisavljevic ldquoAKT as locus of cancer positive feedbackloops and extreme robustnessrdquo Journal of Cellular Physiologyvol 228 no 3 pp 522ndash524 2013

[109] M Y Lee HW Lim S H Lee andH J Han ldquoSmad PI3KAktand wnt-dependent signaling pathways are involved in BMP-4-induced ESC self-renewalrdquo Stem Cells vol 27 no 8 pp 1858ndash1868 2009

[110] K Song S C Cornelius M Reiss and D Danielpour ldquoInsulin-like growth factor-I inhibits transcriptional responses of trans-forming growth factor-120573 by phosphatidylinositol 3-kinaseAkt-dependent suppression of the activation of Smad3 but notSmad2rdquoThe Journal of Biological Chemistry vol 278 no 40 pp38342ndash38351 2003

[111] D Fang D Hawke Y Zheng et al ldquoPhosphorylation of 120573-catenin by AKT promotes 120573-catenin transcriptional activityrdquoThe Journal of Biological Chemistry vol 282 no 15 pp 11221ndash11229 2007

[112] Q Lei J Jiao L Xin et al ldquoNKX31 stabilizes p53 inhibitsAKT activation and blocks prostate cancer initiation caused byPTEN lossrdquo Cancer Cell vol 9 no 5 pp 367ndash378 2006

[113] A Sengupta J D Molkentin J-H Paik R A DePinho and KE Yutzey ldquoFoxO transcription factors promote cardiomyocytesurvival upon induction of oxidative stressrdquo The Journal ofBiological Chemistry vol 286 no 9 pp 7468ndash7478 2011

[114] C H M Jamieson L E Ailles S J Dylla et al ldquoGranulocyte-macrophage progenitors as candidate leukemic stem cells inblast-crisis CMLrdquoTheNewEngland Journal ofMedicine vol 351no 7 pp 657ndash667 2004

[115] A Androutsellis-Theotokis R R Leker F Soldner et al ldquoNotchsignalling regulates stem cell numbers in vitro and in vivordquoNature vol 442 no 7104 pp 823ndash826 2006

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

Page 14: Review Article Phosphatase and Tensin Homologue: Novel ...Review Article Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling TravisJ.Jerde Department of Pharmacology

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology