Differential Nuclear Translocation and Transactivation Potential of β-Catenin and Plakoglobin

Simcha, Inbal; Shtutman, Michael; Salomon, Daniela; Zhurinsky, Jacob; Sadot, Einat; Geiger, Benjamin; Ben-Ze’ev, Avri

doi:10.1083/jcb.141.6.1433

Cited by 258 publications

(308 citation statements)

References 87 publications

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“…Numerous studies have implicated cell ± cell adhesion as a key regulatory point in the transition from benign to highly invasive tumors. Focus has been directed toward the tumor suppressor role of adhesion molecules such as cadherins, C-CAM, acatenin, and plakoglobin in tumor progression (BenZe'ev, 1997;Davies et al, 1998;Ewing et al, 1995;Simcha et al, 1996). Conn et al (1990) demonstrated that the loss of expression of major components of the desmosome correlated with invasiveness of TCC.…”

Section: Discussionmentioning

confidence: 99%

“…Down-regulation of adhesion-related molecules in tumors have indicated that these proteins may function as TSs (Birchmeier, 1995;Bullions et al, 1997;Hoover et al, 1998;Hsieh et al, 1995;Simcha et al, 1996;Taverna et al, 1998). The loss of E-cadherinmediated cell adhesion was shown to be an important rate-limiting step in the progression of several somatic and hereditary carcinomas (Berx et al, 1998;Birchmeier et al, 1996;Guilford et al, 1998;Hirohashi, 1998;Perl et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the gene encoding pinin/DRS/memA and evidence for its potential tumor suppressor function

Shi

Ouyang²,

Sugrue

2000

Oncogene

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Several cell adhesion-related proteins have been shown to act as tumor-suppressors (TS) in the neoplastic progression of epithelial-derived tumors. Pinin/DRS/memA was ®rst identi®ed in our laboratory and it was shown to be a cell adhesion-related molecule. Our previous study demonstrated that restoration of pinin expression in transformed cells not only positively in¯uenced cellular adhesive properties but also reversed the transformed phenotype to more epithelial-like. Here, we show by FISH analysis that the gene locus for pinin is within 14q13. The alignment of the pinin gene with STS markers localized the gene to the previously identi®ed TS locus D14S75-D14S288. Northern analyses revealed diminished pinin mRNA in renal cell carcinomas (RCC) and certain cancer cell lines. Immunohistochemical examination of tumor samples demonstrated absent or greatly reduced pinin in transitional cell carcinoma (TCC) and RCC tumors. TCC-derived J82 cells as well as EcR-293 cells transfected with full-length pinin cDNA demonstrated inhibition of anchorage-independent growth of cells in soft agar. Furthermore, methylation analyses revealed that aberrant methylation of pinin CpG islands was correlated with decreased/absent pinin expression in a subset of tumor tissues. These data lend signi®cant support to the hypothesis that pinin/DRS/memA may act as a tumor suppressor in certain types of cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of the gene encoding pinin/DRS/memA and evidence for its potential tumor suppressor function

Shi

Ouyang²,

Sugrue

2000

Oncogene

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“…In addition to its associations with classic cadherins, plakoglobin interacts with desmosomal cadherins and is essential for the formation of desmosomes (Parker et al, 1998;Holthofer et al, 2007;Garrod and Chidgey, 2008), whereas b-catenin typically does not. Furthermore, although both b-catenin and plakoglobin can interact with the Tcf/Lef family of transcription factors, only the b-catenin-Tcf complexes have transcriptional activity, whereas the plakoglobin-Tcf complex is unable to bind DNA (Simcha et al, 1998;Zhurinsky et al, 2000a).…”

Section: Introductionmentioning

confidence: 99%

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

et al. 2010

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Plakoglobin (c-catenin) is a homolog of b-catenin with similar dual adhesive and signaling functions. The adhesive function of these proteins is mediated by their interactions with cadherins, whereas their signaling activity is regulated by association with various intracellular partners. In this respect, b-catenin has a well-defined oncogenic activity through its role in the Wnt signaling pathway, whereas plakoglobin acts as a tumor/metastasis suppressor through mechanisms that remain unclear. We previously expressed plakoglobin in SCC9 squamous carcinoma cells (SCC9-P) and observed a mesenchymalto-epidermoid transition. Comparison of the protein and RNA profiles of parental SCC9 cells and SCC9-P transfectants identified various differentially expressed proteins and transcripts, including the nonmetastatic protein 23 (Nm23). In this study, we show that Nm23-H1 mRNA and Nm23-H2 protein are increased after plakoglobin expression. Coimmunoprecipitation and confocal microscopy studies using SCC9-P and various epithelial cell lines with endogenous plakoglobin expression revealed that Nm23 interacts with plakoglobin, cadherins and a-catenin. Furthermore, Nm23-H2 is the primary isoform involved in these interactions, which occur prominently in the cytoskeleton-associated pool of cellular proteins. In addition, we show that plakoglobinNm23 interaction requires the N-terminal (a-catenin interacting) domain of plakoglobin. Our data suggest that by increasing the expression and stability of Nm23, plakoglobin has a role in regulating the metastasis suppressor activity of Nm23, which may further provide a potential mechanism for the tumor/metastasis suppressor function of plakoglobin itself.

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“…In addition to this structural role in cell adhesion, bcatenin and its Drosophila homolog, armadillo, are key components of the wg/wnt-signaling pathway (Peifer and Wieschaus, 1990;Peifer et al, 1993;Wodarz and Nusse, 1998) that regulates developmental processes, including speci®cation of the anterior-posterior segment polarity in Drosophila (Peifer et al, 1993), and axis determination in developing Xenopus embryos (Heasman et al, 1994). Signaling by b-catenin is carried out mainly by the nuclear pool of the protein, and recruitment of this protein to adherens junctions, by overexpressing cadherins inhibits its signaling activity (Fagotto et al, 1996;Sanson et al, 1996;Simcha et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, the level of plakoglobin is often reduced in cancer cells (Navarro et al, 1993;Aberle et al, 1995;Simcha et al, 1996) and the human plakoglobin gene displays loss of heterozygosity in certain tumors (Aberle et al, 1995). Moreover, plakoglobin was shown to suppress tumorigenicity when overexpressed in various transformed cell lines (Simcha et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Differential interaction of plakoglobin and β-catenin with the ubiquitin-proteasome system

et al. 2000

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b-Catenin and plakoglobin are closely related armadillo family proteins with shared and distinct properties; Both are associated with cadherins in actin-containing adherens junctions. Plakoglobin is also found in desmosomes where it anchors intermediate ®laments to the desmosomal plaques. b-Catenin, on the other hand, is a component of the Wnt signaling pathway, which is involved in embryonic morphogenesis and tumorigenesis. A key step in the regulation of this pathway involves modulation of b-catenin stability. A multiprotein complex, regulated by Wnt, directs the phosphorylation of bcatenin and its degradation by the ubiquitin-proteasome system. Plakoglobin can also associate with members of this complex, but inhibition of proteasomal degradation has little e ect on its levels while dramatically increasing the levels of b-catenin. b-TrCP, an F-box protein of the SCF E3 ubiquitin ligase complex, was recently shown to play a role in the turnover of b-catenin. To elucidate the basis for the apparent di erences in the turnover of bcatenin and plakoglobin we compared the handling of these two proteins by the ubiquitin-proteasome system. We show here that a deletion mutant of b-TrCP, lacking the F-box, can stabilize the endogenous b-catenin leading to its nuclear translocation and induction of b-catenin/ LEF-1-directed transcription, without a ecting the levels of plakoglobin. However, when plakoglobin was overexpressed, it readily associated with b-TrCP, e ciently competed with b-catenin for binding to b-TrCP and became polyubiquitinated. Fractionation studies revealed that about 85% of plakoglobin in 293 cells, is Triton X-100-insoluble compared to 50% of b-catenin. These results suggest that while both plakoglobin and b-catenin can comparably interact with b-TrCP and the ubiquitination system, the sequestration of plakoglobin by the membrane-cytoskeleton system renders it inaccessible to the proteolytic machinery and stabilizes it.

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Differential Nuclear Translocation and Transactivation Potential of β-Catenin and Plakoglobin

Cited by 258 publications

References 87 publications

Characterization of the gene encoding pinin/DRS/memA and evidence for its potential tumor suppressor function

Characterization of the gene encoding pinin/DRS/memA and evidence for its potential tumor suppressor function

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

Differential interaction of plakoglobin and β-catenin with the ubiquitin-proteasome system

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