PTEN (Phosphatase and Tensin Homolog) a.k.a. MMAC1 , TEP1

Raymond Stadiem

PTEN - Overview

What is PTEN? Biochemistry/Cell Biology of PTEN protein

Biological function of the Pten gene

Why did Peifer and Duronio want us to know about PTEN?

Many proto-oncogenes are kinases (ex: Ras, Src) THEREFORE, it would make sense if there existed tumor suppressors, which regulate this activity by being …

PHOSPHATASESPHOSPHATASES

What is PTEN?

PTEN was discovered in 1997 as the first tumor suppressor phosphatase

Phosphatase and Tensin Homolog

PTEN is a phosphatase with two types of substrates(1)Lipid substrate (primary substrate)-involved in cell

signaling

key target: phosphatidylinositol 3,4,5-

trisphosphate(P3)

Yamada et al., 2001

PTEN and PI-3 Kinase act as antagonists in lipid signaling

Comer et al., 2002

PTEN activation of Akt/PKB Initiated by binding of growth factors (ex:TGF,

Insulin) to receptors Upon ligand binding to growth factor receptor,

PI-3 Kinase is activated PI-3 Kinase phosphorylates and activates

PtdIns(3,4,5)P3

PtdIns(3,4,5)P3 signals Akt/PKB PTEN dephosphorylates and inhibits

PtdIns(3,4,5)P3 (level of regulation)

PTEN is a lipid 3-phosphatase, which signals down the PI3 kinase/AKT proapoptotic pathway.

Backman et al.

Outcomes of the Akt/PKB pathway Role in proliferation complicated

PTEN does not merely block proliferation because studies showed that normal bacteria cells expressing PTEN can still undergo rapid proliferation (Liliental et al., 2000)

Role in apoptosis more clear Re-expression of PTEN in several carcinoma cell lines

induces apoptosis (Li et al, 1998) Especially important is Anoikis, a form of apoptosis

that occurs when cells lose contact with the e.c.m. -mediates the cell’s “anchorage dependence” (Davies et al., 1998)

PTEN is a phosphatase with two types of substrates (part 2)

(2) PTEN may be also a weak protein phosphatase for protein phosphate substrates - can remove phosphate groups from Ser, Thr, and Tyr residues (mechanisms still unclear)

•2 cytoplasmic phosphoprotein substrates: Focal Adhesion Kinase (FAK) and adapter protein Shc

•Pathway activated by Integrins and other transmembrane receptors and leads to control of mobility and adhesion of cells

Reported Sites of Action of PTEN

Yamada et al. 2001

Localization of signaling proteins during migration

Comer et al., 2002

• PI3K and PTEN show reciprocal localizations during chemotaxis

PTEN has an N-Terminal Phosphatase Domain and C-Terminal C2 Domain

Lee et al., 1999

What about the Pten gene?

Pten is a tumor suppressor gene that is essential for embryonic development

Pten gene located on Chrom 10 (10q23)

Several different Pten null mice lines were generated-produced varying results depending upon which genetic background of mouse was used (e.g.129SvEv vs. C57Bl6)

But in all cases mice do NOT survive to birth PTEN required for embryogenesis

Pten -/- cells show increased ability to develop teratomas

Di Cristofano et al., 1998

Pten is a key player in 3 human autosomal dominant diseases

Cowden Disease (CD),Lhermitte-Duclos Disease (LDD),Bannayan-Zonana Syndrom (BZS)

In all 3 disorders, germline mutations in PTEN have been observed

Still unclear why mutation in one gene leads to 3 related yet distinct disorders

Develop hamartomas of the skin, thyroid, breast, GI tract, CNS, and endometrium

Breast cancers develop in 25-50% of affected women and thyroid cancer in 3-10% of all affected individuals

Ali et al., 1999

Harmatomas, a common symptom

3 PTEN related diseases characterized by multiple harmatomasA focal malformation that grows by cellular proliferation more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease results from faulty development in an organ; composed of an abnormal mixture of tissue elements, or an abnormal proportion of a single element, normally present in that site, which develop and grow at virtually the same rate as normal components, and are not likely to result in compression of adjacent tissue (in contrast to a neoplasm).

www.uveitis.org/Enhanced/ MD_info/md_Cowden_sy.htm

PTEN: What might go wrong?

With PTEN Without PTEN

Echelon Biosciences

How is Pten involved in cancer? Most frequently mutated gene identified yet in

endometrial cancers (33-55% of tumors examined)-Mostly FS, MS, and NS mutations

Of 647 Malignant Glial Tumors examined, 24% showed mutations in PTEN- mostly MS and FS mutations

Ovarian tumors (of endometriod origin) showed mutations in 26% of tumors - mostly MS, FS, and NS mutations

Prostate Carcinoma-mutations in 18% of tumors-Homozygous Deletions, and FS mut.

Ali et al., 1999

Summary PTEN is both a lipid and protein phosphatase Shown to be involved in pathways that involve

apoptosis (or anoikis), mobility, and cell adhesion PTEN is necessary for embryogenesis and may also

control tumor development in mice PTEN involved in 3 major genetic diseases with

mutations in one gene that cause similar yet distinct phenotypes

PTEN mutated in many cancers but more needs to be learned about the pathways involved to better understand how cancers arise and to determine how to design new therapeutic treatments

“PTEN appears to serve as a hub or switchport linking complex signaling pathways. Its disruption…can be likened to disrupting a hub on the internet…(what we have learned about) possible regulations still need clarification.”

Yamada et al. 2001