The catenin family ata glancePierre D. McCrea1,2,* and DongminGu1,2

1Department of Biochemistry and Molecular Biology,University of Texas M.D. Anderson Cancer Center,Houston, TX 77030, USA2Program in Genes and Development, University ofTexas Graduate School of Biomedical Sciences,Houston, TX 77030, USA*Author for correspondence(pdmccrea@mdanderson.org)

Journal of Cell Science 123, 637-642 © 2010. Published by The Company of Biologists Ltddoi:10.1242/jcs.039842

Members of the catenin family were first isolatedcomplexed with the cytoplasmic domains ofcadherins at cell-cell junctions, and thisrelationship is considered one of the definingaspects of catenins. Their functions at suchcontacts are multifaceted and remain under active

study and discussion. The word catenin (fromcatena, latin for chain) (Ozawa et al., 1989),reflects the fact that some catenins contribute tothe indirect association of cadherins with theunderlying actin cytoskeleton, as indicated forb-catenin (and probably g-catenin/plakoglobin) atadherens junctions (Abe and Takeichi, 2008;Pappas and Rimm, 2006). Cytoskeletalinteractions assist, for example, with theexecution of cadherin-dependent morphogenicmovements by facilitating the application ofcontractile forces at cell-cell contact zones(Gumbiner, 2005). In addition to adherensjunctions, catenins also function at desmosomes,where both plakophilins (catenins) andg-catenin/plakoglobin are involved with linkagesto intermediate filaments (Garrod and Chidgey,2008; Green and Simpson, 2007; Hatzfeld, 2007;Schmidt and Koch, 2007). Some additional rolesof catenins, including the modulation of cadherinendocytosis and small GTPases, are summarizedlater.

Catenins also act in the nucleus (Daniel,2007; McCrea et al., 2009; Stepniak et al., 2009)(see the end of this section for referencesregarding b-catenin). A prominent example isthe stabilization of a signaling pool of b-cateninin response to upstream Wnt signals (e.g. Wntligands). This occurs via inhibition of a multi-component complex that would otherwise leadto proteasomal destruction of b-catenin(Kimelman and Xu, 2006). Upon entry to thenucleus, b-catenin alters gene activity in acontext-dependent manner (Arce et al., 2006;Willert and Jones, 2006). This takes place inassociation with transcription factors such asthose from the T-cell factor (TCF) and lymphoidenhancer-binding factor (LEF) protein family,which directly bind DNA, as well as severaltranscription and chromatin co-regulators.Varied downstream outcomes are influenced,extending, for example, from stem-cellmaintenance to differentiation, and fromproliferation to apoptosis (Cadigan and Peifer,

637Cell Science at a Glance

(See poster insert)

The Catenin Family at a GlancePierre D. McCrea and Dongmin Gujcs.biologists.org

© Journal of Cell Science 2010 (123, pp. 637-642)

Abbreviations: ARVCF, Armadillo repeat gene deleted in velocardiofacial syndrome; APC, adenomatous polyposis coli; BAR-1, β-catenin/Armadillo-related protein 1; Cdc42, cell division cycle 42; C. elegans, Caenorhabditis elegans; Dp120, Drosophila p120-catenin; EPLIN, epithelial protein lost in neoplasm; F-actin, filamentous actin; GSK3β, glycogen synthase kinase 3β; HMP-2, humpback 2; JAC-1, juxtamembrane domain-associated catenin; LRP, LDL receptor-related protein; NFκB, nuclear factor-κB; PLEKHA7, pleckstrin homology domain-containing, family A member 7; Pkp, Plakophilin; PSD-95, postsynaptic density protein 95; Rac1, Ras-related C3 botulinum toxin substrate 1; RhoGAP, Rho GTPase-activating protein; RNAi, RNA interference; TCF, T-cell factor; Wnt, Wingless; WRM-1, worm Armadillo.

Stress fibers

p0071ARVCFδ-catenin

β-catenin

?

Nucleus

Cytokinesis

Plakophilins

p120Kaiso

TCF

p0071

p0071

p0071

ARVCFδ-catenin

β-catenin

β-catenin

Plakoglobin

PLEKHA7

F-actin

Intermediatefilaments

Desmosome

Adherensjunction

DesmogleinDesmocollin

NFκB

AxinAPC

Vav2

Nezha

p190 RhoGAP

Cdc42 Rac1

p120

p120

p120

p120

p120

Endosome

Microtubules

Centrosome

Lysosome

Signaling roles of catenins

LRP

Dishevelled

Wnt

p120

Cadherin

Plakoglobin

Desmoplakin

Plakophilins

GSK3βSm

all G

TP

ases

Wnt

pat

hway

p120β-catenin

RhoA

α-catenin

Kinesin

+

-

+

-

EPLIN

p120

p0071ARVCFδ-catenin

Plakophilins

Filopodia Lamellipodia

Cytoplasm

p120

Domain structure of human cateninsCOOHNH2

7811β-catenin

β-ca

teni

nsu

bfa

mily

p12

0 su

bfa

mily

Pkp

sub

fam

ily

7451

1 968p120

Plakoglobin

1 1225δ-catenin

1 962ARVCF

12211p0071

7261Plakophilin-1

1 837Plakophilin-2

7971Plakophilin-3

DSWV

DSWV

DSWV

Armadillo domainWFDTDL

1-12

1-12

1-9

1-9

1-9

1-9

1-9

1-9

1-9

Phylogenetic tree of catenins

Mutant phenotypes

*See accompanying article for full citations.

Catenins exhibit wide-ranging functions in multiple cellular compartments. Defining features are that catenins associate with the cytoplasmic domains of cadherins, and that they contain a central Armadillo domain (with the exception of α-catenin). In accordance with their inclusionin various protein complexes, catenins modulate the functional state of cell-cell junctions and the cytoskeleton (and thereby cell motility and morphology). In addition, they modulate the activity of genes relevant to development and disease, as exemplified by the participation of catenins in canonical Wnt signaling.

What are catenins?Catenins at cell-cell junctions

See accompanying articlefor full citations.

Reproduced from Hofmann et al.,2008, with permission.

Reproduced from Bonné et al.,1999, with permission.

Reproduced from Bonné et al., 1999, with permission.

Reproduced from Logan et al.,1999, with permission.

Reproduced from Rodova et al.,2004, with permission.

Reproduced from Schmidt et al.,1997, with permission.

Catenins in the nucleus

β-catenin

β-catenin

Xenopus ectoderm Xenopus ectodermXenopus ectodermARVCF p0071

MCF-7

p120HeLa C2C12

δ-cateninSea urchin embryo

p120

Pkp-3HCT8/E8

Pkp-1bHuman keratinocytes

Pkp-3HCT8/E8

Pkp-1a

Mouse KO

Whole animal

Blocked acinar differentiation; reduced E-cadherin levels and cell adhesion, polarity and abnormalepithelial morphology; embryonic lethality at E14

Embryonic lethality

Whole animal

Whole animal

Whole animal

Peripheral nervous system

Whole animal

Whole animal

Whole animal

Whole animal

Whole animal

Salivary gland

Skin

Dorsal forebrain

Anterior neural ectoderm

Anterior neural ectoderm

Whole animal; anterior neural ectoderm

KD (RNAi)

KO; KD (RNAi)

KO

KO

KO

KO

KD (morpholino)

KD (morpholino)

KD (morpholino)

Xenopus

Xenopus

Xenopus

C. elegans

Drosophila

Mouse

Mouse

Mouse

Mouse

Catenin

β-catenin N/A

δ-catenin

p120

ARVCF

JAC-1

Dp120

p0071Pkp-1

Pkp-2

Organism Tissue Phenotype Reference*Knockout (KO) or knockdown (KD)

Reduced adherens junction components; epidermal hyperplasia and chronic inflammation in aged mice;NFκB activation; skin neoplasias; mitotic defects

Reduced spine and synapse densities; decreased cadherin levels and perturbations in Rho activities

Disrupted gastrulation and axial elongation; reduced C-cadherin levels

Disrupted gastrulation and axial elongation; reduced C-cadherin levels

Perturbed cranial neural crest cell migration and malformations in craniofacial cartilage

No obvious developmental defects when depleted alone

No obvious developmental defects except delayed dorsal closure

Defects in dorsal closure and head involution

Reduced numbers and density of spine-like neuronal potrusions

Not determinedNot determined

Alterations in heart morphogenesis and lethality at midgestation; dissociation of desmoplakinfrom junction plaques and formation of cytoplasmic granular aggregates

Abnormal morphology of hair follicles; reduced medullar air columns in hair shafts; altereddensities of desmosome and adherens junctions

Impaired evagination of optic vesicles and defective eye formation; perturbed cranial neural crest cellmigration and malformations in craniofacial cartilage

Impaired cognitive functions; abnormal synaptic plasticity; reduced N-cadherin and PSD-95 levels

Defects in gastrulation and axial elongation; cadherin reductions and Rho perturbations;malformations in craniofacial cartilage

No obvious developmental defects

The Wnt Homepage; Grigoryan et al., 2008

Davis and Reynolds, 2006

Perez-Moreno et al., 2005; Perez-Morenoet al., 2008

Elia et al., 2006

Fang et al., 2004

Fang et al., 2004

Ciesiolka et al., 2004

Pettitt et al., 2003

Myster et al., 2003; Fox et al., 2005

Magie et al., 2002

Li et al., 2005

Grossmann et al., 2004

Sklyarova et al., 2008

Whole animalKD (morpholino)Xenopus Epidermal fragility; touch sensitivity and/or mobility defects William Munoz and Pierre McCrea, unpublished

Israely et al., 2004

Gu et al., 2009

Mieke Delvaeye and Kris Vleminckx, personal communication

Howard Sirotkin and Raju Kucherlapati,personal communication

Pkp-3

Xenopus)Pkp-3 (mouse)Pkp-3 (human)

Pkp-2 (mouse)Pkp-2 (human)

Pkp-1 (mouse)Pkp-1 (human)

JAC-1 (C. elegans)

p120 (Xenopusp120 (mouse)

p120 (human)

ARVCF ( XenopusARVCF (mouse)

ARVCF (human)

δ-catenin (Xenopusδ-catenin (mouse)δ-catenin (human)

p0071 (p0071 (mouse)p0071 (human)

Plakoglobin (human)

Plakoglobin (Xenopus)

)

)

Xenopus)

)

Pkp-3 (

Plakoglobin (mouse))

β-catenin (human)β-catenin (mouse)β-catenin (Xenopus)

WRM-1 (C. elegans)

SYS-1 (C. elegans)

BAR-1 (C. elegans) HMP-2 (C. elegans)

Armadillo (Drosophila)

1.4

0.1

0.80.3

1.7

Dp120(Drosophila)

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2009; Chien et al., 2009; Clevers, 2006;Grigoryan et al., 2008). Given the widebiological impact of catenins, basic andtranslational researchers from diverseviewpoints are working to generate insightsinto the mechanisms that govern and executetheir functions.

In this poster article, we present a conciseoverview of the function of catenin proteins,primarily for the non-specialist. We restrict ourattention to those catenins that contain anArmadillo domain [and therefore do not includethe structurally unrelated a-catenin (Benjaminand Nelson, 2008; Kobielak and Fuchs, 2004)].We direct the reader to other brief overviews(Harris and Peifer, 2005; Huelsken and Behrens,2002; Lien et al., 2008; Macdonald et al., 2007;Reynolds, 2007), or to more in-depth reviewsdiscussing b-catenin (Bienz, 2005; Cadigan andPeifer, 2009; Clevers, 2006; Nelson and Nusse,2004), or the p120 or plakophilin subfamilies ofcatenins (Anastasiadis, 2007; Daniel, 2007;Hartsock and Nelson, 2008; Hatzfeld, 2005;Hatzfeld, 2007; Kowalczyk and Reynolds,2004; Lien et al., 2006; McCrea et al., 2009;McCrea and Park, 2007; Perez-Moreno andFuchs, 2006; Reynolds and Roczniak-Ferguson,2004; van Hengel and van Roy, 2007; van Royand McCrea, 2005; Xiao et al., 2007; Yin andGreen, 2004).

Basics of catenin structure andfunctionWith the exception of the structurally unrelateda-catenin (Benjamin and Nelson, 2008; Pokuttaand Weis, 2000; Scott and Yap, 2006; Yanget al., 2001), all catenins contain a centralArmadillo domain that contains between nineand twelve repeats (each of roughly 40 aminoacids) (Choi and Weis, 2005), which fold toproduce a super-helix of helices that bears apositively charged groove and crucial bindinginterfaces (Huber et al., 1997; Shapiro and Weis,2009). It is worth noting that several proteinscontain Armadillo domains but do not associatewith cadherins. By definition, these are notcatenins; one example is a-importin, whichassists in bringing proteins bearing classicnuclear localization signals into the nucleus(Peifer et al., 1994).

Catenin Armadillo regions engage innumerous protein-protein interactions, andpromote the association of b-catenin or p120subfamily members with cadherins (Bienz,2005; Meng and Takeichi, 2009; Nelson andNusse, 2004), nuclear gene regulatory factors(Clevers, 2006) or cytoplasmic Rho-familyGTPases (Anastasiadis, 2007). The N- andC-terminal domains of catenins exhibit furtherinteresting properties: for instance, theC-terminal domain of b-catenin facilitates

the trans-activation of genes in response to Wntsignaling (Arce et al., 2006; Willert and Jones,2006).

On the basis of primary sequence homology,vertebrate catenins that contain Armadillodomains are divided into three subfamiliesreferred to by each of three representativemembers: b-catenin (b-catenin, g-catenin/plakoglobin); p120 [p120, ARVCF (Armadillorepeat gene deleted in velocardiofacialsyndrome), d-catenin, p0071]; and plakophilin(plakophilin-1 to plakophilin-3). Invertebrateshave fewer catenin proteins, namely b-catenin(although variants exist in Caenorhabditiselegans) (Hardin and King, 2008; Phillips andKimble, 2009), and a single representative of thep120 subfamily that is most similar in sequencehomology to vertebrate d-catenin.

Divisions between the vertebrate cateninsubfamilies are reflected at the functional level.For example, plakophilins largely associate withdesmosomal cadherins, whereas members of theb-catenin or p120 subfamilies bind to classiccadherins that are present at adherens junctions.For plakophilin subfamily members, it is theN-terminal as opposed to the central Armadillodomain that binds desmosomal cadherins(desmocollins or desmogleins) (Hatzfeld,2007). Further protein-protein interactions ofcatenins are modulated by C-terminal PDZmotifs within most p120 subfamily members, orby more extended N- or C-terminal regions(Choi et al., 2006; Gottardi and Gumbiner, 2004;Mo et al., 2009; Solanas et al., 2004).

In several cases, the same catenin might bindmore than one cadherin type. For example,g-catenin/plakoglobin, p120, plakophilins andp0071 reside at both adherens and desmosomaljunctions (Borrmann et al., 2006; Calkins et al.,2003; Hatzfeld et al., 2003; Johnson andBoekelheide, 2002; Kanno et al., 2008).Whereas b-catenin does not appear to binddesmosomal cadherins in vivo (Choi et al.,2009), it does associate and functionally interactwith other (non-cadherin) transmembraneproteins, such as the epidermal growth factorreceptor and MUC1 (Hoschuetzky et al., 1994;Yamamoto et al., 1997). Perhaps a clearerfunctional distinction is that catenins of the p120subfamily, and probably also the plakophilins(Hatzfeld, 2007), modulate the activity of Rho-family GTPases (see below) (Anastasiadis,2007; Hatzfeld, 2007), a property that is lackingin proteins of the b-catenin subfamily.

A further feature of members of the p120 andplakophilin subfamilies is that they are subjectto alternative transcript splicing andtranslational initiation. With regards to p120, theexpression of isoform 1 (generated fromthe most N-terminal translational start site) leadsto more robust RhoA inhibition and cell

invasion than do shorter isoforms, andconsequently might be associated with theprogression of certain cancers (Yanagisawaet al., 2008). Phosphorylation of p120 at specificresidues has also been found to modulate therelationship of p120 with RhoA (Castano et al.,2007). Even with these and other new findings,much remains to be learned regarding the rolesof differentially spliced, translated andphosphorylated isoforms of p120 or of othersubfamily members, in cancer and development(Mo and Reynolds, 1996; Reynolds andRoczniak-Ferguson, 2004; van Hengel and vanRoy, 2007).

The functions of cateninsWnt signaling and gene control As summarized above, b-catenin has broad,conserved functions, contributing to (amongother processes) cadherin-cytoskeletalassociations (Abe and Takeichi, 2008; Pappasand Rimm, 2006) and canonical Wnt signaling(Bienz, 2005; Chien et al., 2009; Clevers, 2006;Grigoryan et al., 2008; Nelson and Nusse,2004). More recently, evidence has surfaced invertebrates that b-catenin is not the only cateninthat transduces canonical Wnt signals to thenucleus. For example, in common withb-catenin, isoform 1 of p120 is metabolicallystabilized in response to Wnt-pathwaystimulation, acting at certain gene promoters inan additive manner with b-catenin to activatetranscription (Kim et al., 2004; Park et al., 2006;Park et al., 2005) (J. Y. Hong, J. I. Park, K. Cho,D.G., H. Ji, S. E. Artandi and P.D.M.,unpublished results).

Gene activation by vertebrate p120 seemsto result from its ability to displace thetranscriptional repressor Kaiso from DNAconsensus sites in gene control regions (Daniel,2007). Recently, alternative models of Kaisofunction in the context of Wnt signaling havearisen, which support its indirect (TCF-mediated) association with DNA (Iioka et al.,2009; Ruzov et al., 2009a; Ruzov et al., 2009b).Kaiso further binds to methylated sites in DNAthat are important in transcriptional repression(Prokhortchouk et al., 2001; Yoon et al., 2003),but no evidence exists that p120 acts to de-repress these gene control regions. Althoughspeculative, several catenins of the p120subfamily might ultimately prove to participatein transducing vertebrate Wnt or other signalsduring development or disease progression.

Other nuclear roles? Beyond their presence at cell-cell contacts(zonula adherens and/or desmosomaljunctions), most catenins localize to the nucleusin restricted cellular or developmental contexts.Whereas nuclear binding partners for b-catenin

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(e.g. TCF/LEF) and p120 (e.g. Kaiso and Glis2)have been described (Arce et al., 2006; Clevers,2006; Daniel, 2007; Hosking et al., 2007;Willert and Jones, 2006), little is known aboutthe nuclear associations of other p120 orplakophilin subfamily members (Hatzfeld,2007; McCrea et al., 2009; Schmidt and Jager,2005). ARVCF-catenin appears to bind thenovel (scaffolding?) protein Kazrin (K. Cho,T. Vaught, J. M. Jennings, M. Kloc, D.G., C.Papasakelariou, H. Ji, A. P. Kowalczyk andP.D.M., unpublished results), which shuttles inand out of the nucleus when not at junctionalregions or associated with microtubules (Grootet al., 2004; Nachat et al., 2009; Sevilla et al.,2008). d-catenin associates with Kaiso (Rodovaet al., 2004), possibly sharing gene targets withp120. Plakophilin-2 and an isoform ofplakophilin-1 exhibit nuclear localization (Chenet al., 2002; Schmidt et al., 1997), which isphosphorylation dependent in the case ofplakophilin-2 (Muller et al., 2003), and allowsassociation with RNA polymerase III andperhaps other factors (Mertens et al., 2001). Thenuclear localization of catenins thus raisesthe question of how expansive their functionswill ultimately prove to be within thiscompartment.

Cell-cell junctionsFor classic cadherins that are present at adherensjunctions, such as E-cadherin and N-cadherin,there exist two distinct and conserved catenin-binding sites (Yap et al., 2007). One residestowards the cadherin C-terminus, and bindseither b-catenin or g-catenin/plakoglobin. Theother is membrane proximal, and binds a p120subfamily member (p120, ARVCF, d-catenin orp0071). Similarly, desmosomal cadherinspossess two distinct catenin-binding sites, oneassociated with g-catenin/plakoglobin, and theother with any of the three plakophilin proteins(plakophilin-1, plakophilin-2 or plakophilin-3)(Hatzfeld, 2007).

Most catenins were first isolated as part of acomplex with various members of the cadherinsuperfamily. Thus, their roles at adherens ordesmosomal junctions, and in cell polarity andmotility, were of immediate interest. These rolesare still under active study, and althoughdiffering models exist (Abe and Takeichi, 2008;Pappas and Rimm, 2006; Weis and Nelson,2006), b-catenin and plakoglobin probablyfacilitate indirect interactions between classiccadherins and the actin cytoskeleton at adherensjunctions in vivo. When associated withcadherins, p120 subfamily members have beenimplicated in lateral (cis) clustering of cadherins(Yap et al., 1998), the tethering of signaling orregulatory entities, such as kinases andphosphatases (Lilien and Balsamo, 2005),

and the inhibition of cadherin endocytosis(leading to degradation or recycling) (Bryant andStow, 2004; Erez et al., 2005; Kowalczykand Reynolds, 2004; Nelson, 2008; Reynolds andCarnahan, 2004; Troyanovsky, 2005; Yap et al.,2007). In summary, the contribution of b-cateninand p120 subfamilies has been shown or islikely to influence cadherin-dependent adhesion,motility and cell polarity, and consequently,larger processes such as development andmorphogenesis, tissue homeostasis and diseaseprogression (e.g. cancer).

The plakophilins, which bind desmosomalcadherins (e.g. the desmocollins and/ordesmogleins), might share some functionalattributes with p120 subfamily members. Forexample, plakophilins appear to assist inclustering or stabilizing desmosomal cadherins,and might also modulate small GTPases(Hatzfeld, 2007). Similarities with the b-cateninsubfamily include plakophilin-mediatedinteraction of desmosomal cadherins with thecytoskeleton, although the most obviousassociations at desmosomes occur withintermediate filaments as opposed to actinmicrofilaments (Garrod and Chidgey, 2008;Green and Simpson, 2007; Hatzfeld, 2007;Schmidt and Koch, 2007).

Although much remains to be learned withrespect to specific functional outcomes, cateninsare subject to modification by kinases and/orphosphatases that are enriched at cell-cellcontacts (Andl and Rustgi, 2005; Daniel andReynolds, 1997; Erez et al., 2005; Lilienand Balsamo, 2005; Wheelock and Johnson,2003). In some instances, phosphorylationpromotes catenin release, enabling catenincytoplasmic or nuclear relocalization andactivity, and occurs simultaneously with alteredcadherin function. For example, distinct fromcanonical Wnt-pathway activation, receptortyrosine kinase stimulation has in some contextsbeen indicated to produce a signaling pool ofb-catenin upon its release from cadherin anda-catenin (Brembeck et al., 2004; Wheelockand Johnson, 2003). Such phosphorylation-induced movement of catenins to the cytoplasmor nucleus suggests one mechanism forfunctional coordination between cadherinjunctions and other cell compartments.

Modulation of small-GTPase activity andthe cytoskeletonAs noted, vertebrate p120 subfamily membershave certain intriguing properties that b-cateninlacks. One other such property is theirmodulation of Rho-family GTPases, such asRhoA, Rac1 and Cdc42 (Anastasiadis, 2007;Keil et al., 2007). In their activated GTP-boundforms, small GTPases act in multiple cellularcapacities, with a prominent activity being

cytoskeletal regulation. This is reflected instructures that are actin or tubulin based, andin myriad coupled processes, such as celladhesion, polarity, motility and gene regulation.Maintaining small GTPases in active (GTP-bound) versus inactive (GDP-bound) states isinfluenced by many factors that act in a positive(e.g. GEFs) or negative (e.g. GDIs or GAPs)manner.

When not bound to cadherin, p120 subfamilymembers associate with GEFs and GAPs tofacilitate small-GTPase activation or inhibition(Wildenberg et al., 2006). This occurs, forexample, during cytokinesis in the case of p0071(Wolf et al., 2006). Additionally, p120subfamily members can bind directly to smallGTPases, as has been shown for RhoA(Anastasiadis et al., 2000). Small-GTPaseactions are often complex, which is due in part tocrosstalk between members, and they arecontext dependent (e.g. effects vary according tocell type) (Braga and Yap, 2005). Even so, RhoAactivation is frequently associated with Rho-kinase activation, and thereby the promotion ofstress-fiber formation and contractility in sessilecells. Conversely, activation of Rac1 or Cdc42often results in heightened lamellipodia andfilopodia functions, respectively. Activation ofRac1 and Cdc42 might thus be reflected incytoskeletal dynamism, and in a significantproportion of contexts is associated withincreased cell motility and invasion. Althoughisoform and context dependent (Yanagisawaet al., 2008), the p120 and plakophilinsubfamilies have generally been found toactivate Rac1 (and in some cases also Cdc42)and to inhibit RhoA (Anastasiadis, 2007;Hatzfeld, 2007).

An appealing hypothesis has compared p120family members with rheostats of cell adhesionversus motility (Anastasiadis and Reynolds,2001; Grosheva et al., 2001; Reynolds andCarnahan, 2004; Reynolds and Roczniak-Ferguson, 2004). That is, when bound tocadherin, p120 protects E-cadherin fromendocytosis and degradation, thereby promotingcell-cell adhesion. Conversely, whendissociated from cadherin, p120 exhibits morepronounced GTPase effects (e.g. RhoAinhibition and Rac1 activation), which in somecontexts is associated with motile cell states.One can thus envisage physiological scenarioswherein an epithelial-mesenchymal transition(EMT) is facilitated upon release of p120 fromcadherin, resulting in both reduced cadherinprotein levels (reduced adhesive function) andincreased cytoskeletal activity and/or cellmotility. In pathological contexts, this mightalso be a significant factor. For example,promoter methylation resulting in reducedE-cadherin expression might not only have a

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direct impact upon cell adhesion and therebycell polarity in cancer, but also upon cytoskeletalactivity as a consequence of increased levels ofcytoplasmic p120 (or of ARVCF, d-catenin orp0071).

Finally, evidence exists that p120interacts with tubulin (Franz and Ridley, 2004;Ichii and Takeichi, 2007; Roczniak-Fergusonand Reynolds, 2003; Yanagisawa et al.,2004), and has an impact upon microtubulestability and dynamics, and thereby on cellmotility and directional migration. p120 furtherbinds the plus-end microtubule motor kinesin,apparently relating to the delivery of junctionalcomponents to the plasma membrane (Chenet al., 2003; Yanagisawa et al., 2004) and, offurther interest, to proteins providingassociation with the minus-ends of junctionalmicrotubules that are required for organizationof the zonula adherens (Ichii and Takeichi,2007; Meng et al., 2008). The effects of theaction of catenins on the microtubulecytoskeleton appear to occur via mechanismsthat are not directly attributable to their roles inconjunction with small GTPases. Indeed, evenb-catenin, in common with p120 subfamilymembers (Franz and Ridley, 2004; Ichii andTakeichi, 2007; Myster et al., 2003; Wolf et al.,2006), has been observed at the centrosome andis proposed to contribute to microtubulefunctions (Huang et al., 2007). In the context ofthe cadherin-catenin complex at adherensjunctions, p120 appears to assist in minus-endcapture (Ichii and Takeichi, 2007) and,conceivably, plus-end capture and stabilizationof microtubules (Bellett et al., 2009). Takentogether, catenins appear to be well poised toassist in the coordination of cell-adhesive,cytoskeletal, motility and gene-regulatoryfunctions.

Development and diseaseThe key roles of b-catenin in development arewell recognized, and include the modulation ofcadherin function (Zhurinsky et al., 2000) and thetransduction of canonical Wnt signals (seereviews cited below). Many of the functions ofb-catenin are shared between vertebrates andinvertebrates (with some complexities arising inC. elegans) (Hardin and King, 2008; Phillips andKimble, 2009), with whole-animal knockouts orknockdowns resulting in embryonic lethality.Given the large number of b-catenin conditional-null and knockdown studies that have beenconducted, we will not summarize findings here.Rather, the reader is directed to more completeresources that outline the diverse roles ofb-catenin in Wnt signaling, including its roles inmaintaining stem-cell compartments, differentia-tion, apoptosis and proliferation (Cadigan andPeifer, 2009; Chien et al., 2009; Clevers, 2006;

Grigoryan et al., 2008; Schneikert and Behrens,2007; Stepniak et al., 2009) (www.stanford.edu/~rnusse/wntwindow.html; The Wnt Homepage).Numerous findings have also clarified thepathological contributions of b-catenin tocancer. For example, stabilized mutant formsof b-catenin increase transcription from Wnt andb-catenin (TCF/LEF) target genes, as well asdisrupt other signaling pathways that areresponsive to the nuclear signaling pool ofb-catenin.

The removal of p120 also alters vertebratedevelopment, because it is embryonic lethal in thewhole animal (Fang et al., 2004) [unpublishedresults in Davis and Reynolds (Davis andReynolds, 2006)]. Although the underlying basesfor the phenotypes remain under study, evidenceexists for effects upon cadherin stabilization,GTPase modulation and nuclear signaling.Furthermore, the targeting of mouse skinrevealed a relationship between p120 and nuclearfactor-kB (NFkB) signaling, and led to cellhyper-proliferation and neoplasias (Li et al.,2005; Lynch and Hardin, 2009; McCrea andPark, 2007; Perez-Moreno et al., 2006; Perez-Moreno et al., 2008; Stepniak et al., 2009).Because invertebrates lack plakophilins andcontain only a single representative of the p120subfamily (named ‘p120’, but in fact morehomologous to d-catenin), it might be expectedthat its loss would produce dramatic effects.However, this has not proven to be the case inmost, if not all, studies (Magie et al., 2002;McCrea and Park, 2007; Myster et al., 2003;Pacquelet et al., 2003; Pettitt et al., 2003), whichhas led to the supposition that greater functionalprominence arose for p120-like proteins invertebrates, perhaps owing to the greaterdiversification of cell-cell junctions and thestructural demands that are placed upon them.

When assessing roles of other vertebrate p120subfamily members such as ARVCF ord-catenin, results have varied according to thesystem examined. For example, each cateninstudied in the amphibian Xenopus laevis hasproved to be essential in early embryogenesis(gastrulation, neural crest migration, etc.)(McCrea and Park, 2007; Stepniak et al., 2009).However, in the mouse, whole-animal removalof ARVCF did not produce a phenotype(Howard Sirotkin and Raju Kucherlapati,personal communication), and removal ofd-catenin led to non-lethal alterations indendritic spine architecture and to reducedcognitive functions (Israely et al., 2004). Theloss of plakophilin family members in miceproduces skin and heart phenotypes, probablyreflecting effects upon desmosomes, which areenriched in tissues subject to high mechanicalstress (Hatzfeld, 2007). Because plakophilinsalso modulate the activity of Rho-family

GTPases and are proposed to have nuclearroles (Hatzfeld, 2007), it will be interestingto examine further their contributions todevelopment and disease.

ConclusionsCatenins have diverse roles in biology, andfunction in the plasma membrane, cytoplasmicand nuclear compartments. The p120 andplakophilin subfamilies are distinguished fromthe b-catenin subfamily in that they exhibitalternative splice isoforms or translationalinitiation, and modulate Rho-family GTPases.Catenins require considerable further study tobetter understand their nuclear, adhesive andcytoskeletal (among other) roles, and theirupstream modulation by signaling pathways andbiochemical events (e.g. phosphorylation).Although much has been revealed concerningb-catenin in the context of Wnt signaling,additional important findings will doubtless beforthcoming, such as a deeper insight into itsactions in stem cells. Given the multifaceted rolesand diversity of vertebrate catenins and theirpartially overlapping functions, it appears thatcatenins together form an intricate functionalnetwork that might ultimately be best addressedusing systems biology approaches.

This work was funded through an NIH RO1(GM52112), a Texas ARP Grant, and the March ofDimes (1-FY-07-461-01). Assistance with DNAsequencing and other core facilities was provided froma National Cancer Institute Core Grant (CA-16672) toMD Anderson Cancer Center. We apologize that, owingto space limitations, the large number of key originalcontributions generated from many laboratories havehad to be incorporated in the context of citing reviews.Deposited in PMC for release after 12 months.

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