Nuclear localization of the p120
            <sup>ctn</sup>
            Armadillo-like catenin is counteracted by a nuclear export signal and by E-cadherin expression

Hengel, Jolanda van; Vanhoenacker, Peter; Staes, Katrien; Roy, Frans Van

doi:10.1073/pnas.96.14.7980

Cited by 143 publications

(147 citation statements)

References 51 publications

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“…This raises the exciting possibility that Armadillo repeat proteins possess intrinsic nuclear import ability. Consistent with this idea, we and others have detected nuclear p120 ctn , particularly in cells of tumor lineage or in cells lacking functional cadherins (our unpublished data) (RoczniakFerguson and Reynolds, 2003;van Hengel et al, 1999). Interestingly, the nuclear localization of p120 ctn appears to be an isoform-specific phenomenon; all isoforms capable of inducing branching (e.g.…”

supporting

confidence: 85%

“…This suggests that alternative NESs may facilitate the nuclear export of p120 ctn splice variants lacking exon B. Consistent with this idea, some isoforms of p120 ctn lacking exon B are sensitive to leptomycin B (LMB), a specific inhibitor of CRM-1-mediated nuclear export (our unpublished data) (Roczniak-Ferguson and Reynolds, 2003;van Hengel et al, 1999). These results suggest that p120 ctn is capable of nucleocytoplasmic shuttling in a CRM-I-dependent manner.…”

supporting

confidence: 72%

“…Two putative p120 ctn nuclear localization signals (NLS) have been described (Aho et al, 2002;Roczniak-Ferguson and Reynolds, 2003) but neither has been directly or empirically tested for their ability to target a heterologous protein to the nucleus, the classical test for NLS functionality (Kalderon et al, 1984). To date, just one p120 ctn nuclear export signal (NES) has been characterized but this NES is present only in isoforms encoding exon B (van Hengel et al, 1999). This suggests that alternative NESs may facilitate the nuclear export of p120 ctn splice variants lacking exon B.…”

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confidence: 99%

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NLS-dependent nuclear localization of p120ctnis necessary to relieve Kaiso-mediated transcriptional repression

Kelly

Spring

Otchere

et al. 2004

Journal of Cell Science

104

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IntroductionThe Armadillo catenins, β-, γ-and p120 ctn , are multifunctional proteins whose malfunction contributes to tumor progression by various means (Behrens, 1999;Van Aken et al., 2001). They are members of a larger family of Armadillo proteins that are characterized by the presence of an Armadillo domain consisting of ten or more tandem copies of a 42 amino-acid Armadillo repeat (Peifer et al., 1994). The importance of the Armadillo catenins in tumorigenesis was first credited to their involvement in the multiprotein cadherin-catenin complex, which forms the major cell-cell adhesion system in epithelial cells. Dysfunction of this complex, through defects in any of its components, correlates with the metastatic phenotype iñ 50% of human carcinomas (Behrens, 1999;Yap, 1998). The key participant in this complex is the transmembrane glycoprotein and tumor suppressor E-cadherin that mediates cell-cell adhesion by the homophilic interactions of its extracellular domain. E-cadherin is then anchored to the underlying actin cytoskeleton by the classical catenin cofactors, β-and γ-catenin, that bind E-cadherin in a mutually exclusive manner (reviewed by Nollet et al., 1999). These classical catenins bind simultaneously to a highly conserved carboxy-terminal domain of E-cadherin and to the actinbinding protein α-catenin (reviewed by Behrens, 1999;Rimm et al., 1995). Like β-and γ-catenin, the nonclassical Armadillo catenin p120 ctn binds the cytoplasmic tail of E-cadherin via its Arm domain Reynolds et al., 1992). However, β-and γ-catenin compete for binding to the distal conserved catenin-binding domain, and function by anchoring E-cadherin to the actin cytoskeleton, whereas p120 ctn binds Ecadherin at a distinct juxtamembrane domain (JMD) and does not interact with α-catenin (Daniel and Reynolds, 1995;Thoreson et al., 2000). Importantly, the JMD is implicated in E-cadherin stability (Ireton et al., 2002;Pettitt et al., 2003), modulating cadherin adhesive strength (Aono et al., 1999;Ohkubo and Ozawa, 1999;Thoreson et al., 2000;Yap et al., 1998) and regulating cytoskeletal dynamics Grosheva et al., 2001;Noren et al., 2000), and as such p120 ctn is speculated to be a key mediator of these effects. This hypothesis is supported by recent observations that p120 ctn modulates the activities of RhoA, Rac and Cdc42, which are key mediators of cytoskeletal organization Grosheva et al., 2001;Noren et al., 2000).Originally identified as a Src kinase substrate (Reynolds et al., 1989), it was the structural similarity of p120 ctn to β-catenin that led to the discovery of p120 ctn as a novel catenin component of the cadherin complex (Daniel and Reynolds, 2675The Armadillo catenin p120 ctn regulates cadherin adhesive strength at the plasma membrane and interacts with the novel BTB/POZ transcriptional repressor Kaiso in the nucleus. The dual localization of p120 ctn at cell-cell junctions and in the nucleus suggests that its nucleocytoplasmic trafficking is tightly regulated. Here we report on the identification of a specific and h...

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supporting

confidence: 85%

supporting

confidence: 72%

mentioning

confidence: 99%

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NLS-dependent nuclear localization of p120ctnis necessary to relieve Kaiso-mediated transcriptional repression

Kelly

Spring

Otchere

et al. 2004

Journal of Cell Science

104

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“…32 The Armadillo sequence-rich protein d-catenin, associates with the cytoplasmic domain of E-cadherin and together with b-catenin and acatenin accumulates at cell-cell junctions. An increased level of cytoplasmic d-catenin has been found in breast carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Frequent accumulation of nuclear E-cadherin and alterations in the Wnt signaling pathway in esophageal squamous cell carcinomas

et al. 2008

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Esophageal squamous cell carcinoma is frequently associated with poor prognosis, as a result of high levels of lymph node metastasis. So far, very few genetic abnormalities have been associated with this disease, and its molecular etiology remains largely unknown. To assess whether the Wnt pathway contributes to esophageal squamous cell carcinoma, we characterized the expression and subcellular localization of the key Wnt signaling components in all 30 cases of esophageal squamous cell carcinomas analyzed. We found abnormal expression and/or localization in glycogen synthase kinase-3 a/b (34%), Axin2 (48%), a-catenin (31%), MYC (73%) and cyclin D1 in 46% of cases. Only 13% of tumors showed nuclear accumulation of b-catenin. By contrast, 60% showed nuclear expression of E-cadherin using an antibody that recognizes the cytoplasmic domain of E-cadherin. When the same tumors were stained with antibody raised against the extracellular domain of E-cadherin, the expression was lost. A direct correlation was found between nuclear E-cadherin and the increased nuclear cyclin D1, one of the AP-1 target genes in these tumors. By transfection experiments, the cytoplasmic portion of E-cadherin was found to activate the AP-1 transcription factor pathway and induced cyclin D1 promoter activity, but b-catenin/Tcf transcription activity was unaffected. Nuclear expression of E-cadherin was also detected in tumors other than squamous cell carcinoma, including pancreatic and colon cancers, albeit at lower frequency. Nuclear accumulation of a portion of E-cadherin in esophageal squamous cell carcinoma and the other types of tumors indicates that, in addition to the previously implicated tumor suppressor activity of E-cadherin, modified forms of this glycoprotein might also play a role in growth promotion. Keywords: Wnt signaling; esophageal squamous cell carcinomas; pancreatic cancer; colon cancer; E-cadherin Esophageal cancer is one of the deadliest but least studied forms of cancer and the sixth ranking cause of death from cancer in North America. It shows a varied geographical distribution and very poor survival rates. 1 Esophageal cancer accounts for 5% of all gastrointestinal cancers, and the overall number of new cases each year is steadily increasing. 2 Esophageal cancer can be divided into squamous cell carcinomas and adenocarcinomas. So far, very few genetic abnormalities have directly been linked to esophageal carcinogenesis. In this study, we sought to examine the expression and localization of the key components of the Wnt signaling pathway that have previously been shown to play important roles in colorectal, breast, stomach and prostate cancer. Wnt signaling regulates cell growth, motility and differentiation. Upon binding to their receptor, specific Wnt ligands trigger phosphorylation of LRP5/6 (low density lipoprotein) by glycogen synthase kinase-3 (GSK3a/b) and casein kinase-1 (CK1g), which distances Axin (Axin1 and Axin2) from the b-catenin destruction-complex. [3][4][5][6] As a result, the b-catenin is stabilized a...

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“…Similarly to ␤-catenin, it can be detected in the nucleus (34), where it interacts with the transcriptional factor Kaiso (6). Studies performed with Xenopus laevis have demonstrated that association of p120-catenin relieves the repression caused by Kaiso on Wnt signaling (17,25).…”

mentioning

confidence: 99%

Specific Phosphorylation of p120-Catenin Regulatory Domain Differently Modulates Its Binding to RhoA

Castaño

Solanas

Casagolda

et al. 2007

Molecular and Cellular Biology

114

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p120-catenin is an adherens junction-associated protein that controls E-cadherin function and stability. p120-catenin also binds intracellular proteins, such as the small GTPase RhoA. In this paper, we identify the p120-catenin N-terminal regulatory domain as the docking site for RhoA. Moreover, we demonstrate that the binding of RhoA to p120-catenin is tightly controlled by the Src family-dependent phosphorylation of p120-catenin on tyrosine residues. The phosphorylation induced by Src and Fyn tyrosine kinases on p120-catenin induces opposite effects on RhoA binding. Fyn, by phosphorylating a residue located in the regulatory domain of p120-catenin (Tyr112), inhibits the interaction of this protein with RhoA. By contrast, the phosphorylation of Tyr217 and Tyr228 by Src promotes a better affinity of p120-catenin towards RhoA. In agreement with these biochemical data, results obtained in cell lines support the important role of these phosphorylation sites in the regulation of RhoA activity by p120-catenin. Taken together, these observations uncover a new regulatory mechanism acting on p120-catenin that contributes to the fine-tuned regulation of the RhoA pathways during specific signaling events.E-cadherin function is controlled posttranslationally by a family of proteins, named catenins, that bind to its cytosolic tail. Two members of this family, p120-catenin and ␤-catenin, interact at different sites of the E-cadherin molecule and are engaged in distinct functions. Whereas ␤-catenin is required for recruiting the actin cytoskeleton, p120-catenin is necessary for the stabilization of E-cadherin at the cell membrane (3). As a consequence, E-cadherin is rapidly internalized and degraded in the absence of p120-catenin (7, 13). Consequently, p120-catenin ablation in vivo causes E-cadherin deficiency, leading to severe defects in adhesion, cell polarity, and epithelial morphogenesis (7).Besides this role in regulating E-cadherin stability, p120-catenin interacts with other proteins involved in the modulation of cell-to-cell contacts. For instance, p120-catenin associates with Fer and Fyn tyrosine kinases (16,27,36). These kinases specifically phosphorylate ␤-catenin in Tyr142 (27), a modification that promotes release of ␤-catenin from the adherens junctional complex and transport to the nucleus (2, 27). Moreover, p120-catenin can interact with the Yes tyrosine kinase (27) and with a number of phosphotyrosine (PTyr) phosphatases, such as PTP (39), DEP1 (12), and SHP-1 (14, 21). These multiple associations suggest a role for p120-catenin as a scaffold protein for enzymes regulating events such as the stability of the adherens junctional complex (29).p120-catenin modulates the activity of other cellular factors. Similarly to ␤-catenin, it can be detected in the nucleus (34), where it interacts with the transcriptional factor Kaiso (6). Studies performed with Xenopus laevis have demonstrated that association of p120-catenin relieves the repression caused by Kaiso on Wnt signaling (17,25).Several results indicate that p...

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Nuclear localization of the p120 ^ctn Armadillo-like catenin is counteracted by a nuclear export signal and by E-cadherin expression

Cited by 143 publications

References 51 publications

NLS-dependent nuclear localization of p120ctnis necessary to relieve Kaiso-mediated transcriptional repression

NLS-dependent nuclear localization of p120ctnis necessary to relieve Kaiso-mediated transcriptional repression

Frequent accumulation of nuclear E-cadherin and alterations in the Wnt signaling pathway in esophageal squamous cell carcinomas

Specific Phosphorylation of p120-Catenin Regulatory Domain Differently Modulates Its Binding to RhoA

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Nuclear localization of the p120 ctn Armadillo-like catenin is counteracted by a nuclear export signal and by E-cadherin expression

Cited by 143 publications

References 51 publications

NLS-dependent nuclear localization of p120ctnis necessary to relieve Kaiso-mediated transcriptional repression

NLS-dependent nuclear localization of p120ctnis necessary to relieve Kaiso-mediated transcriptional repression

Frequent accumulation of nuclear E-cadherin and alterations in the Wnt signaling pathway in esophageal squamous cell carcinomas

Specific Phosphorylation of p120-Catenin Regulatory Domain Differently Modulates Its Binding to RhoA

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Nuclear localization of the p120 ^ctn Armadillo-like catenin is counteracted by a nuclear export signal and by E-cadherin expression