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Science at a Glance 637

The catenin family at study and discussion. The word catenin (from Catenins also act in the nucleus (Daniel, catena, latin for chain) (Ozawa et al., 1989), 2007; McCrea et al., 2009; Stepniak et al., 2009) a glance reflects the fact that some catenins contribute to (see the end of this section for references the indirect association of with the regarding -catenin). A prominent example is Pierre D. McCrea1,2,* and Dongmin b underlying , as indicated for the stabilization of a signaling pool of -catenin Gu1,2 b b-catenin (and probably g-catenin/) at in response to upstream Wnt signals (e.g. Wnt 1 Department of Biochemistry and Molecular Biology, adherens junctions (Abe and Takeichi, 2008; ligands). This occurs via inhibition of a multi- University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA Pappas and Rimm, 2006). Cytoskeletal component complex that would otherwise lead 2Program in Genes and Development, University of interactions assist, for example, with the to proteasomal destruction of b-catenin Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA execution of -dependent morphogenic (Kimelman and Xu, 2006). Upon entry to the *Author for correspondence movements by facilitating the application of nucleus, b-catenin alters gene activity in a ([email protected]) contractile forces at cell-cell contact zones context-dependent manner (Arce et al., 2006;

Journal of Cell Science 123, 637-642 (Gumbiner, 2005). In addition to adherens Willert and Jones, 2006). This takes place in © 2010. Published by The Company of Biologists Ltd junctions, catenins also function at desmosomes, association with transcription factors such as doi:10.1242/jcs.039842 where both (catenins) and those from the T-cell factor (TCF) and lymphoid g-catenin/plakoglobin are involved with linkages enhancer-binding factor (LEF) family, Members of the catenin family were first isolated to intermediate filaments (Garrod and Chidgey, which directly bind DNA, as well as several complexed with the cytoplasmic domains of 2008; Green and Simpson, 2007; Hatzfeld, 2007; transcription and chromatin co-regulators. cadherins at cell-cell junctions, and this Schmidt and Koch, 2007). Some additional roles Varied downstream outcomes are influenced, relationship is considered one of the defining of catenins, including the modulation of cadherin extending, for example, from stem-cell aspects of catenins. Their functions at such endocytosis and small GTPases, are summarized maintenance to differentiation, and from contacts are multifaceted and remain under active later. proliferation to apoptosis (Cadigan and Peifer,

The Catenin Family at a Glance jcs.biologists.org Pierre D. McCrea and Dongmin Gu

What are catenins? Phylogenetic tree of catenins Signaling roles of catenins Catenins at cell-cell junctions Catenins exhibit wide-ranging functions in multiple cellular compartments. Defining features are that catenins associate with the cytoplasmic domains of Wnt cadherins, and that they contain BAR-1 (C. elegans) HMP-2 (C. elegans) a central Armadillo domain (with β the exception of α-catenin). In β-catenin ARVCF p0071 Pkp-3 -catenin (human) β-catenin (mouse) accordance with their inclusion Xenopus ectoderm Xenopus ectoderm Xenopus ectoderm MCF-7 HCT8/E8 0.3 β-catenin (Xenopus) in various protein complexes, Reproduced from Hofmann et al., Reproduced from Bonné et al., 2008, with permission. 1999, with permission. 0.8 Filopodia Lamellipodia

catenins modulate the functional Armadillo (Drosophila) LRP state of cell-cell junctions and Catenins in the nucleus the cytoskeleton (and thereby Plakoglobin (human) Plakophilins Plakoglobin (mouse) Dishevelled cell motility and morphology). δ In addition, they modulate the SYS-1 (C. elegans) Plakoglobin (Xenopus) -catenin ARVCF p0071 activity of genes relevant to development and disease, as 1.7 p120 p190 RhoGAP exemplified by the participation of catenins in canonical Wnt Pkp-1a Vav2 signaling. β-catenin p120 δ-catenin Pkp-1b Pkp-3 1.4 Sea urchin embryo HeLa C2C12 Human keratinocytes HCT8/E8 GSK3β Wnt pathway

See accompanying article Small GTPases Reproduced from Logan et al., Reproduced from Rodova et al., Reproduced from Schmidt et al., Reproduced from Bonné et al., WRM-1 (C. elegans) for full citations. 1999, with permission. 2004, with permission. 1997, with permission. 1999, with permission. Pkp-3 (Xenopus)

Journal of Cell Science APC Pkp-3 (mouse) Pkp-3 (human) Axin Cdc42 Rac1 RhoA Domain structure of human catenins Pkp-2 (mouse) 0.1 NH2 Armadillo domain COOH Pkp-2 (human) WFDTDL β-catenin 1 1-12 781 Pkp-1 (mouse) β-catenin p120 Pkp-1 (human) Cytokinesis Plakoglobin 1 1-12 745 β -catenin subfamily p0071 (Xenopus) p0071 (mouse) p120 1 1-9 968 p0071 (human) DSWV δ-catenin 1 1-9 1225 δ-catenin (Xenopus) δ-catenin (mouse) Dp120 DSWV δ-catenin (human) (Drosophila) ARVCF ( Xenopus) Stress fibers 1-9 962 ARVCF (mouse) ARVCF 1 p120 (Xenopus) ARVCF (human) DSWV p120 (mouse) p120 subfamily p0071 1 1-9 1221 JAC-1 (C. elegans) p120 (human)

Plakophilin-1 1 1-9 726 p120 β -2 1 1-9 837 -catenin β-catenin Kaiso κ Plakophilin-3 1 1-9 797 Centrosome NF B TCF Pkp subfamily p0071 - ? p120 Mutant phenotypes δ-catenin ARVCF p0071 Plakophilins

Nucleus Catenin Organism Knockout (KO) or knockdown (KD) Tissue Phenotype Reference* p120 β-catenin N/A The Wnt Homepage; Grigoryan et al., 2008 p120 Whole animal Embryonic lethality Davis and Reynolds, 2006 Blocked acinar differentiation; reduced E-cadherin levels and , polarity and abnormal + Salivary gland + epithelial morphology; embryonic lethality at E14 KO Mouse Reduced components; epidermal hyperplasia and chronic inflammation in aged mice; Skin Perez-Moreno et al., 2005; Perez-Moreno p120 PLEKHA7 Nezha NFκB activation; skin neoplasias; mitotic defects et al., 2008 p120 Dorsal forebrain Reduced spine and synapse densities; decreased cadherin levels and perturbations in Rho activities Elia et al., 2006 - δ-catenin ARVCF p0071 p120 Whole animal Disrupted gastrulation and axial elongation; reduced C-cadherin levels Fang et al., 2004 Adherens Endosome Xenopus KD (morpholino) Impaired evagination of optic vesicles and defective eye formation; perturbed cranial neural crest Anterior neural ectoderm Ciesiolka et al., 2004 migration and malformations in craniofacial cartilage p120 Mouse KO Whole animal Impaired cognitive functions; abnormal synaptic plasticity; reduced N-cadherin and PSD-95 levels Israely et al., 2004 δ -catenin Defects in gastrulation and axial elongation; cadherin reductions and Rho perturbations; Cadherin Xenopus KD (morpholino) Whole animal; anterior neural ectoderm Gu et al., 2009 malformations in craniofacial cartilage β-catenin p120 Howard Sirotkin and Raju Kucherlapati, Mouse KO Whole animal No obvious developmental defects α personal communication -catenin ARVCF Whole animal Disrupted gastrulation and axial elongation; reduced C-cadherin levels Fang et al., 2004 EPLIN Xenopus KD (morpholino) Mieke Delvaeye and Kris Vleminckx, Anterior neural ectoderm Perturbed cranial neural crest cell migration and malformations in craniofacial cartilage Plakoglobin personal communication F-actin JAC-1 C. elegans KD (RNAi) Whole animal No obvious developmental defects when depleted alone Pettitt et al., 2003 No obvious developmental defects except delayed dorsal closure Myster et al., 2003; Fox et al., 2005 p0071 Whole animal Dp120 Drosophila KO; KD (RNAi) Desmosome Defects in dorsal closure and head involution Magie et al., 2002 Plakoglobin Lysosome Peripheral nervous system Reduced numbers and density of spine-like neuronal potrusions Li et al., 2005 Desmoglein Plakophilins p0071 Not determined Desmocollin Intermediate Pkp-1 Not determined filaments Pkp-2 Mouse KO Whole animal Alterations in heart morphogenesis and lethality at midgestation; dissociation of desmoplakin Grossmann et al., 2004 from junction plaques and formation of cytoplasmic granular aggregates

Mouse KO Whole animal Abnormal morphology of hair follicles; reduced medullar air columns in hair shafts; altered Sklyarova et al., 2008 densities of desmosome and adherens junctions Pkp-3 Xenopus KD (morpholino) Whole animal Epidermal fragility; touch sensitivity and/or mobility defects William Munoz and Pierre McCrea, unpublished

*See accompanying article for full citations.

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

(See poster insert) 638 Journal of Cell Science 123 (5)

2009; Chien et al., 2009; Clevers, 2006; the trans-activation of genes in response to Wnt invasion than do shorter isoforms, and Grigoryan et al., 2008). Given the wide signaling (Arce et al., 2006; Willert and Jones, consequently might be associated with the biological impact of catenins, basic and 2006). progression of certain cancers (Yanagisawa translational researchers from diverse On the basis of primary sequence homology, et al., 2008). of p120 at specific viewpoints are working to generate insights vertebrate catenins that contain Armadillo residues has also been found to modulate the into the mechanisms that govern and execute domains are divided into three subfamilies relationship of p120 with RhoA (Castano et al., their functions. referred to by each of three representative 2007). Even with these and other new findings, In this poster article, we present a concise members: b-catenin (b-catenin, g-catenin/ much remains to be learned regarding the roles overview of the function of catenin , plakoglobin); p120 [p120, ARVCF (Armadillo of differentially spliced, translated and primarily for the non-specialist. We restrict our repeat gene deleted in velocardiofacial phosphorylated isoforms of p120 or of other attention to those catenins that contain an syndrome), d-catenin, p0071]; and plakophilin subfamily members, in cancer and development Armadillo domain [and therefore do not include (plakophilin-1 to plakophilin-3). Invertebrates (Mo and Reynolds, 1996; Reynolds and the structurally unrelated a-catenin (Benjamin have fewer catenin proteins, namely b-catenin Roczniak-Ferguson, 2004; van Hengel and van and Nelson, 2008; Kobielak and Fuchs, 2004)]. (although variants exist in Caenorhabditis Roy, 2007). We direct the reader to other brief overviews elegans) (Hardin and King, 2008; Phillips and (Harris and Peifer, 2005; Huelsken and Behrens, Kimble, 2009), and a single representative of the The functions of catenins 2002; Lien et al., 2008; Macdonald et al., 2007; p120 subfamily that is most similar in sequence Wnt signaling and gene control Reynolds, 2007), or to more in-depth reviews homology to vertebrate d-catenin. As summarized above, b-catenin has broad, discussing b-catenin (Bienz, 2005; Cadigan and Divisions between the vertebrate catenin conserved functions, contributing to (among Peifer, 2009; Clevers, 2006; Nelson and Nusse, subfamilies are reflected at the functional level. other processes) cadherin-cytoskeletal 2004), or the p120 or plakophilin subfamilies of For example, plakophilins largely associate with associations (Abe and Takeichi, 2008; Pappas catenins (Anastasiadis, 2007; Daniel, 2007; desmosomal cadherins, whereas members of the and Rimm, 2006) and canonical Wnt signaling Hartsock and Nelson, 2008; Hatzfeld, 2005; b-catenin or p120 subfamilies bind to classic (Bienz, 2005; Chien et al., 2009; Clevers, 2006; Hatzfeld, 2007; Kowalczyk and Reynolds, cadherins that are present at adherens junctions. Grigoryan et al., 2008; Nelson and Nusse, 2004; Lien et al., 2006; McCrea et al., 2009; For plakophilin subfamily members, it is the 2004). More recently, evidence has surfaced in McCrea and Park, 2007; Perez-Moreno and N-terminal as opposed to the central Armadillo vertebrates that b-catenin is not the only catenin Fuchs, 2006; Reynolds and Roczniak-Ferguson, domain that binds desmosomal cadherins that transduces canonical Wnt signals to the 2004; van Hengel and van Roy, 2007; van Roy (desmocollins or desmogleins) (Hatzfeld, nucleus. For example, in common with and McCrea, 2005; Xiao et al., 2007; Yin and 2007). Further protein-protein interactions of b-catenin, isoform 1 of p120 is metabolically Green, 2004). catenins are modulated by C-terminal PDZ stabilized in response to Wnt-pathway motifs within most p120 subfamily members, or stimulation, acting at certain gene promoters in Basics of catenin structure and by more extended N- or C-terminal regions an additive manner with b-catenin to activate function (Choi et al., 2006; Gottardi and Gumbiner, 2004; transcription (Kim et al., 2004; Park et al., 2006; With the exception of the structurally unrelated Mo et al., 2009; Solanas et al., 2004). Park et al., 2005) (J. Y. Hong, J. I. Park, K. Cho,

Journal of Cell Science a-catenin (Benjamin and Nelson, 2008; Pokutta In several cases, the same catenin might bind D.G., H. Ji, S. E. Artandi and P.D.M., and Weis, 2000; Scott and Yap, 2006; Yang more than one cadherin type. For example, unpublished results). et al., 2001), all catenins contain a central g-catenin/plakoglobin, p120, plakophilins and Gene activation by vertebrate p120 seems Armadillo domain that contains between nine p0071 reside at both adherens and desmosomal to result from its ability to displace the and twelve repeats (each of roughly 40 amino junctions (Borrmann et al., 2006; Calkins et al., transcriptional repressor Kaiso from DNA acids) (Choi and Weis, 2005), which fold to 2003; Hatzfeld et al., 2003; Johnson and consensus sites in gene control regions (Daniel, produce a super-helix of helices that bears a Boekelheide, 2002; Kanno et al., 2008). 2007). Recently, alternative models of Kaiso positively charged groove and crucial binding Whereas b-catenin does not appear to bind function in the context of Wnt signaling have interfaces (Huber et al., 1997; Shapiro and Weis, desmosomal cadherins in vivo (Choi et al., arisen, which support its indirect (TCF- 2009). It is worth noting that several proteins 2009), it does associate and functionally interact mediated) association with DNA (Iioka et al., contain Armadillo domains but do not associate with other (non-cadherin) transmembrane 2009; Ruzov et al., 2009a; Ruzov et al., 2009b). with cadherins. By definition, these are not proteins, such as the epidermal growth factor Kaiso further binds to methylated sites in DNA catenins; one example is a-importin, which receptor and MUC1 (Hoschuetzky et al., 1994; that are important in transcriptional repression assists in bringing proteins bearing classic Yamamoto et al., 1997). Perhaps a clearer (Prokhortchouk et al., 2001; Yoon et al., 2003), nuclear localization signals into the nucleus functional distinction is that catenins of the p120 but no evidence exists that p120 acts to de- (Peifer et al., 1994). subfamily, and probably also the plakophilins repress these gene control regions. Although Catenin Armadillo regions engage in (Hatzfeld, 2007), modulate the activity of Rho- speculative, several catenins of the p120 numerous protein-protein interactions, and family GTPases (see below) (Anastasiadis, subfamily might ultimately prove to participate promote the association of b-catenin or p120 2007; Hatzfeld, 2007), a property that is lacking in transducing vertebrate Wnt or other signals subfamily members with cadherins (Bienz, in proteins of the b-catenin subfamily. during development or disease progression. 2005; Meng and Takeichi, 2009; Nelson and A further feature of members of the p120 and Nusse, 2004), nuclear gene regulatory factors plakophilin subfamilies is that they are subject Other nuclear roles? (Clevers, 2006) or cytoplasmic Rho-family to alternative transcript splicing and Beyond their presence at cell-cell contacts GTPases (Anastasiadis, 2007). The N- and translational initiation. With regards to p120, the (zonula adherens and/or desmosomal C-terminal domains of catenins exhibit further expression of isoform 1 (generated from junctions), most catenins localize to the nucleus interesting properties: for instance, the the most N-terminal translational start site) leads in restricted cellular or developmental contexts. C-terminal domain of b-catenin facilitates to more robust RhoA inhibition and cell Whereas nuclear binding partners for b-catenin Journal of Cell Science 123 (5) 639

(e.g. TCF/LEF) and p120 (e.g. Kaiso and Glis2) and the inhibition of cadherin endocytosis cytoskeletal regulation. This is reflected in have been described (Arce et al., 2006; Clevers, (leading to degradation or recycling) (Bryant and structures that are actin or based, and 2006; Daniel, 2007; Hosking et al., 2007; Stow, 2004; Erez et al., 2005; Kowalczyk in myriad coupled processes, such as cell Willert and Jones, 2006), little is known about and Reynolds, 2004; Nelson, 2008; Reynolds and adhesion, polarity, motility and gene regulation. the nuclear associations of other p120 or Carnahan, 2004; Troyanovsky, 2005; Yap et al., Maintaining small GTPases in active (GTP- plakophilin subfamily members (Hatzfeld, 2007). In summary, the contribution of b-catenin bound) versus inactive (GDP-bound) states is 2007; McCrea et al., 2009; Schmidt and Jager, and p120 subfamilies has been shown or is influenced by many factors that act in a positive 2005). ARVCF-catenin appears to bind the likely to influence cadherin-dependent adhesion, (e.g. GEFs) or negative (e.g. GDIs or GAPs) novel (scaffolding?) protein Kazrin (K. Cho, motility and , and consequently, manner. T. Vaught, J. M. Jennings, M. Kloc, D.G., C. larger processes such as development and When not bound to cadherin, p120 subfamily Papasakelariou, H. Ji, A. P. Kowalczyk and morphogenesis, tissue homeostasis and disease members associate with GEFs and GAPs to P.D.M., unpublished results), which shuttles in progression (e.g. cancer). facilitate small-GTPase activation or inhibition and out of the nucleus when not at junctional The plakophilins, which bind desmosomal (Wildenberg et al., 2006). This occurs, for regions or associated with microtubules (Groot cadherins (e.g. the desmocollins and/or example, during cytokinesis in the case of p0071 et al., 2004; Nachat et al., 2009; Sevilla et al., desmogleins), might share some functional (Wolf et al., 2006). Additionally, p120 2008). d-catenin associates with Kaiso (Rodova attributes with p120 subfamily members. For subfamily members can bind directly to small et al., 2004), possibly sharing gene targets with example, plakophilins appear to assist in GTPases, as has been shown for RhoA p120. Plakophilin-2 and an isoform of clustering or stabilizing desmosomal cadherins, (Anastasiadis et al., 2000). Small-GTPase plakophilin-1 exhibit nuclear localization (Chen and might also modulate small GTPases actions are often complex, which is due in part to et al., 2002; Schmidt et al., 1997), which is (Hatzfeld, 2007). Similarities with the b-catenin crosstalk between members, and they are phosphorylation dependent in the case of subfamily include plakophilin-mediated context dependent (e.g. effects vary according to plakophilin-2 (Muller et al., 2003), and allows interaction of desmosomal cadherins with the cell type) (Braga and Yap, 2005). Even so, RhoA association with RNA polymerase III and cytoskeleton, although the most obvious activation is frequently associated with Rho- perhaps other factors (Mertens et al., 2001). The associations at desmosomes occur with kinase activation, and thereby the promotion of nuclear localization of catenins thus raises intermediate filaments as opposed to actin stress-fiber formation and contractility in sessile the question of how expansive their functions (Garrod and Chidgey, 2008; cells. Conversely, activation of Rac1 or Cdc42 will ultimately prove to be within this Green and Simpson, 2007; Hatzfeld, 2007; often results in heightened lamellipodia and compartment. Schmidt and Koch, 2007). filopodia functions, respectively. Activation of Although much remains to be learned with Rac1 and Cdc42 might thus be reflected in Cell-cell junctions respect to specific functional outcomes, catenins cytoskeletal dynamism, and in a significant For classic cadherins that are present at adherens are subject to modification by kinases and/or proportion of contexts is associated with junctions, such as E-cadherin and N-cadherin, phosphatases that are enriched at cell-cell increased cell motility and invasion. Although there exist two distinct and conserved catenin- contacts (Andl and Rustgi, 2005; Daniel and isoform and context dependent (Yanagisawa binding sites (Yap et al., 2007). One resides Reynolds, 1997; Erez et al., 2005; Lilien et al., 2008), the p120 and plakophilin

Journal of Cell Science towards the cadherin C-terminus, and binds and Balsamo, 2005; Wheelock and Johnson, subfamilies have generally been found to either b-catenin or g-catenin/plakoglobin. The 2003). In some instances, phosphorylation activate Rac1 (and in some cases also Cdc42) other is membrane proximal, and binds a p120 promotes catenin release, enabling catenin and to inhibit RhoA (Anastasiadis, 2007; subfamily member (p120, ARVCF, d-catenin or cytoplasmic or nuclear relocalization and Hatzfeld, 2007). p0071). Similarly, desmosomal cadherins activity, and occurs simultaneously with altered An appealing hypothesis has compared p120 possess two distinct catenin-binding sites, one cadherin function. For example, distinct from family members with rheostats of cell adhesion associated with g-catenin/plakoglobin, and the canonical Wnt-pathway activation, receptor versus motility (Anastasiadis and Reynolds, other with any of the three plakophilin proteins tyrosine kinase stimulation has in some contexts 2001; Grosheva et al., 2001; Reynolds and (plakophilin-1, plakophilin-2 or plakophilin-3) been indicated to produce a signaling pool of Carnahan, 2004; Reynolds and Roczniak- (Hatzfeld, 2007). b-catenin upon its release from cadherin and Ferguson, 2004). That is, when bound to Most catenins were first isolated as part of a a-catenin (Brembeck et al., 2004; Wheelock cadherin, p120 protects E-cadherin from complex with various members of the cadherin and Johnson, 2003). Such phosphorylation- endocytosis and degradation, thereby promoting superfamily. Thus, their roles at adherens or induced movement of catenins to the cytoplasm cell-cell adhesion. Conversely, when desmosomal junctions, and in cell polarity and or nucleus suggests one mechanism for dissociated from cadherin, p120 exhibits more motility, were of immediate interest. These roles functional coordination between cadherin pronounced GTPase effects (e.g. RhoA are still under active study, and although junctions and other cell compartments. inhibition and Rac1 activation), which in some differing models exist (Abe and Takeichi, 2008; contexts is associated with motile cell states. Pappas and Rimm, 2006; Weis and Nelson, Modulation of small-GTPase activity and One can thus envisage physiological scenarios 2006), b-catenin and plakoglobin probably the cytoskeleton wherein an epithelial-mesenchymal transition facilitate indirect interactions between classic As noted, vertebrate p120 subfamily members (EMT) is facilitated upon release of p120 from cadherins and the actin cytoskeleton at adherens have certain intriguing properties that b-catenin cadherin, resulting in both reduced cadherin junctions in vivo. When associated with lacks. One other such property is their protein levels (reduced adhesive function) and cadherins, p120 subfamily members have been modulation of Rho-family GTPases, such as increased cytoskeletal activity and/or cell implicated in lateral (cis) clustering of cadherins RhoA, Rac1 and Cdc42 (Anastasiadis, 2007; motility. In pathological contexts, this might (Yap et al., 1998), the tethering of signaling or Keil et al., 2007). In their activated GTP-bound also be a significant factor. For example, regulatory entities, such as kinases and forms, small GTPases act in multiple cellular promoter methylation resulting in reduced phosphatases (Lilien and Balsamo, 2005), capacities, with a prominent activity being E-cadherin expression might not only have a 640 Journal of Cell Science 123 (5)

direct impact upon cell adhesion and thereby Grigoryan et al., 2008; Schneikert and Behrens, GTPases and are proposed to have nuclear cell polarity in cancer, but also upon cytoskeletal 2007; Stepniak et al., 2009) (www.stanford.edu/ roles (Hatzfeld, 2007), it will be interesting activity as a consequence of increased levels of ~rnusse/wntwindow.html; The Wnt Homepage). to examine further their contributions to cytoplasmic p120 (or of ARVCF, d-catenin or Numerous findings have also clarified the development and disease. p0071). pathological contributions of b-catenin to Finally, evidence exists that p120 cancer. For example, stabilized mutant forms Conclusions interacts with tubulin (Franz and Ridley, 2004; of b-catenin increase transcription from Wnt and Catenins have diverse roles in biology, and Ichii and Takeichi, 2007; Roczniak-Ferguson b-catenin (TCF/LEF) target genes, as well as function in the plasma membrane, cytoplasmic and Reynolds, 2003; Yanagisawa et al., disrupt other signaling pathways that are and nuclear compartments. The p120 and 2004), and has an impact upon responsive to the nuclear signaling pool of plakophilin subfamilies are distinguished from stability and dynamics, and thereby on cell b-catenin. the b-catenin subfamily in that they exhibit motility and directional migration. p120 further The removal of p120 also alters vertebrate alternative splice isoforms or translational binds the plus-end microtubule motor kinesin, development, because it is embryonic lethal in the initiation, and modulate Rho-family GTPases. apparently relating to the delivery of junctional whole animal (Fang et al., 2004) [unpublished Catenins require considerable further study to components to the plasma membrane (Chen results in Davis and Reynolds (Davis and better understand their nuclear, adhesive and et al., 2003; Yanagisawa et al., 2004) and, of Reynolds, 2006)]. Although the underlying bases cytoskeletal (among other) roles, and their further interest, to proteins providing for the phenotypes remain under study, evidence upstream modulation by signaling pathways and association with the minus-ends of junctional exists for effects upon cadherin stabilization, biochemical events (e.g. phosphorylation). microtubules that are required for organization GTPase modulation and nuclear signaling. Although much has been revealed concerning of the zonula adherens (Ichii and Takeichi, Furthermore, the targeting of mouse skin b-catenin in the context of Wnt signaling, 2007; Meng et al., 2008). The effects of the revealed a relationship between p120 and nuclear additional important findings will doubtless be action of catenins on the microtubule factor-kB (NFkB) signaling, and led to cell forthcoming, such as a deeper insight into its cytoskeleton appear to occur via mechanisms hyper-proliferation and neoplasias (Li et al., actions in stem cells. Given the multifaceted roles that are not directly attributable to their roles in 2005; Lynch and Hardin, 2009; McCrea and and diversity of vertebrate catenins and their conjunction with small GTPases. Indeed, even Park, 2007; Perez-Moreno et al., 2006; Perez- partially overlapping functions, it appears that b-catenin, in common with p120 subfamily Moreno et al., 2008; Stepniak et al., 2009). catenins together form an intricate functional members (Franz and Ridley, 2004; Ichii and Because invertebrates lack plakophilins and network that might ultimately be best addressed Takeichi, 2007; Myster et al., 2003; Wolf et al., contain only a single representative of the p120 using systems biology approaches. 2006), has been observed at the centrosome and subfamily (named ‘p120’, but in fact more This work was funded through an NIH RO1 is proposed to contribute to microtubule homologous to d-catenin), it might be expected (GM52112), a Texas ARP Grant, and the March of functions (Huang et al., 2007). In the context of that its loss would produce dramatic effects. Dimes (1-FY-07-461-01). Assistance with DNA the cadherin-catenin complex at adherens However, this has not proven to be the case in sequencing and other core facilities was provided from a National Cancer Institute Core Grant (CA-16672) to junctions, p120 appears to assist in minus-end most, if not all, studies (Magie et al., 2002; MD Anderson Cancer Center. We apologize that, owing capture (Ichii and Takeichi, 2007) and, McCrea and Park, 2007; Myster et al., 2003; to space limitations, the large number of key original contributions generated from many laboratories have

Journal of Cell Science conceivably, plus-end capture and stabilization Pacquelet et al., 2003; Pettitt et al., 2003), which had to be incorporated in the context of citing reviews. of microtubules (Bellett et al., 2009). Taken has led to the supposition that greater functional Deposited in PMC for release after 12 months. together, catenins appear to be well poised to prominence arose for p120-like proteins in assist in the coordination of cell-adhesive, vertebrates, perhaps owing to the greater References cytoskeletal, motility and gene-regulatory diversification of cell-cell junctions and the Abe, K. and Takeichi, M. (2008). EPLIN mediates linkage functions. structural demands that are placed upon them. of the cadherin catenin complex to F-actin and stabilizes the When assessing roles of other vertebrate p120 circumferential actin belt. Proc. Natl. Acad. Sci. USA 105, 13-19. Development and disease subfamily members such as ARVCF or Anastasiadis, P. Z. (2007). p120-ctn: A nexus for The key roles of b-catenin in development are d-catenin, results have varied according to the contextual signaling via Rho GTPases. Biochim. Biophys. Acta 1773, 34-46. well recognized, and include the modulation of system examined. For example, each catenin Anastasiadis, P. Z. and Reynolds, A. B. (2001). cadherin function (Zhurinsky et al., 2000) and the studied in the amphibian Xenopus laevis has Regulation of Rho GTPases by p120-catenin. Curr. Opin. transduction of canonical Wnt signals (see proved to be essential in early embryogenesis Cell Biol. 13, 604-610. Anastasiadis, P. Z., Moon, S. Y., Thoreson, M. A., reviews cited below). Many of the functions of (gastrulation, neural crest migration, etc.) Mariner, D. J., Crawford, H. C., Zheng, Y. and b-catenin are shared between vertebrates and (McCrea and Park, 2007; Stepniak et al., 2009). Reynolds, A. B. (2000). Inhibition of RhoA by p120 invertebrates (with some complexities arising in However, in the mouse, whole-animal removal catenin. Nat. Cell Biol. 2, 637-644. Andl, C. D. and Rustgi, A. K. (2005). No one-way street: C. elegans) (Hardin and King, 2008; Phillips and of ARVCF did not produce a phenotype cross-talk between e-cadherin and receptor tyrosine kinase Kimble, 2009), with whole-animal knockouts or (Howard Sirotkin and Raju Kucherlapati, (RTK) signaling: a mechanism to regulate RTK activity. Cancer Biol. Ther. 4, 28-31. knockdowns resulting in embryonic lethality. personal communication), and removal of Arce, L., Yokoyama, N. N. and Waterman, M. L. (2006). Given the large number of b-catenin conditional- d-catenin led to non-lethal alterations in Diversity of LEF/TCF action in development and disease. null and knockdown studies that have been dendritic spine architecture and to reduced Oncogene 25, 7492-7504. Bellett, G., Carter, J. M., Keynton, J., Goldspink, D., conducted, we will not summarize findings here. cognitive functions (Israely et al., 2004). The James, C., Moss, D. K. and Mogensen, M. M. (2009). Rather, the reader is directed to more complete loss of plakophilin family members in mice Microtubule plus-end and minus-end capture at adherens resources that outline the diverse roles of produces skin and heart phenotypes, probably junctions is involved in the assembly of apico-basal arrays in polarised epithelial cells. Cell Motil. Cytoskeleton 66, b-catenin in Wnt signaling, including its roles in reflecting effects upon desmosomes, which are 893-908. maintaining stem-cell compartments, differentia- enriched in tissues subject to high mechanical Benjamin, J. M. and Nelson, W. J. (2008). Bench to bedside and back again: molecular mechanisms of alpha- tion, apoptosis and proliferation (Cadigan and stress (Hatzfeld, 2007). Because plakophilins catenin function and roles in tumorigenesis. Semin. Cancer Peifer, 2009; Chien et al., 2009; Clevers, 2006; also modulate the activity of Rho-family Biol. 18, 53-64. Journal of Cell Science 123 (5) 641

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(2004). beta-Catenin and plakoglobin N- and available in the online version of this article Hardin, J. (2003). The Caenorhabditis elegans p120 C-tails determine ligand specificity. J. Biol. Chem. 279, at jcs.biologists.org. The JPEG images can catenin homologue, JAC-1, modulates cadherin-catenin 49849-49856. be downloaded for printing or used as function during epidermal morphogenesis. J. Cell Biol. 162, Stepniak, E., Radice, G. L. and Vasioukhin, V. (2009). slides. 15-22. Adhesive and signaling functions of cadherins and catenins