Expression of inappropriate cadherins by epithelial tumor cells promotes endocytosis and degradation of E-cadherin via competition for p120ctn

Maeda, Masato; Johnson, Emhonta; Mandal, Shyamali; Lawson, Kathryn; Keim, Sarah A.; Svoboda, Robert A.; Caplan, Steven H; Wahl, James K.; Wheelock, Margaret J.; Johnson, Keith R.

doi:10.1038/sj.onc.1209396

Cited by 56 publications

(54 citation statements)

References 51 publications

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“…Our finding that P-cadherin as a critical mediator of the invasive phenotype further supports the view that the incorrect expression of another adhesion molecule, rather than a decrease in E-cadherin, is associated with an increased invasive potential (Nieman et al, 1999;Feltes et al, 2002;Suyama et al, 2002;Maeda et al, 2006). Unlike E-cadherin, P-cadherin can promote motility and invasion in carcinoma cells.…”

Section: Discussionsupporting

confidence: 84%

“…Instead, GnRHa stimulated activation of the P-cadherin promoter (Figure 2b; Po0.05), suggesting a transcriptional mechanism of regulation. P-cadherin contributes to the invasive phenotype It has been suggested that expression of an inappropriate cadherin may directly contribute to the invasive phenotype (Nieman et al, 1999;Feltes et al, 2002;Suyama et al, 2002;Maeda et al, 2006). To test whether P-cadherin may promote migration/invasion, we stably transfected Caov-3 and OVCAR-3 cells with P-cadherin and analyzed their effects on cell migration/invasion.…”

Section: Resultsmentioning

confidence: 99%

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Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

2010

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Gonadotropin-releasing hormone (GnRH) receptor expression is often elevated in ovarian cancer, but its potential role in ovarian cancer metastasis has just begun to be revealed. Cadherin switching is a crucial step during tumorigenesis, particularly in metastasis. Here, we showed that GnRH is an inducer of E-to P-cadherin switching, which is reminiscent of that seen during ovarian tumor progression. Overexpression of P-cadherin significantly enhanced, whereas knockdown of P-cadherin reduced migration and invasion regardless of E-cadherin expression, suggesting that inappropriate expression of P-cadherin contributes to the invasive phenotype. These effects of P-cadherin were mediated by activation of the Rho GTPases, Rac1, and Cdc42, through accumulation of p120 catenin (p120 ctn ) in the cytoplasm. The use of p120 ctn small interfering RNA or chimeric cadherin construct to inhibit p120 ctn expression and cytoplasmic localization, respectively, resulted in significant inhibition of cell migration and invasion, with a concomitant reduction in Rac1 and Cdc42 activation, confirming that the effect was p120 ctn specific. Similarly, the migratory/invasive phenotype could be reversed by expression of dominant-negative Rac1 and Cdc42. These results identify for the first time cadherin switching and p120 ctn signaling as important targets of GnRH function and as novel mediators of invasiveness and tumor progression in ovarian cancer.

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Section: Discussionsupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

2010

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“…Induction of N-cadherin during EMT has previously been reported in other systems. 16 In addition to E-cadherin, UM-SCC-38 cells express P-cadherin and incorporate this cadherin into adherens junctions in these cells. Unlike E-cadherin, a significant amount of P-cadherin remains in UM-SCC-38/slug cells however the protein is not expressed in a homogeneous manner as was observed in control cells or as N-cadherin is expressed in UM-SCC-38/slug cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Slug (SNAI2) expression in oral SCC cells results in altered cell-cell adhesion and increased motility

Katafiasz

Smith

Wahl³

2011

Cell Adhesion & Migration

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“…The above studies on p120-catenin provide a hint as to why forced expression of an inappropriate cadherin promotes degradation of endogenous cadherins. In A431 cells, forced expression of R-cadherin results in degradation of endogenous Ecadherin and P-cadherin, and the degradation of endogenous cadherins is due to competition for binding to p120-catenin (Maeda et al, 2006). Thus, it is possible for cadherin switching to occur following modulation of transcription of only one cadherin.…”

Section: Post-transcriptional Control Of Cadherin Levelsmentioning

confidence: 99%

Cadherin switching

Wheelock

Shintani

Maeda

et al. 2008

Journal of Cell Science

754

726

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occurs during normal developmental processes to allow cell types to segregate from one another. Tumor cells often recapitulate this activity and the result is an aggressive tumor cell that gains the ability to leave the site of the tumor and metastasize. At present, we understand some of the mechanisms that promote cadherin switching and some of the pathways downstream of this process that influence cell behavior. Specific cadherin family members influence growthfactor-receptor signaling and Rho GTPases to promote cell motility and invasion. In addition, p120-catenin probably plays multiple roles in cadherin switching, regulating Rho GTPases and stabilizing cadherins. Journal of Cell Science 728cadherin expression has been shown to promote motility and invasion (Hazan et al., 2000; Islam et al., 1996;Nieman et al., 1999). This loss of E-cadherin expression and gain of N-cadherin expression is reminiscent of the cadherin switching that is seen during normal embryonic development and probably underpins many of the phenotypic changes that occur in the participating cells (reviewed in Cavallaro et al., 2002; Christofori, 2003; Gerhart et al., 2004).The term cadherin switching usually refers to a switch from expression of E-cadherin to expression of N-cadherin, but also includes situations in which E-cadherin expression levels do not change significantly but the cells turn on (or increase) expression of N-cadherin. It also includes examples in which other cadherins replace or are co-expressed with E-cadherin, including R-cadherin, cadherin 11, T-cadherin and even P-cadherin, and the expression of the 'inappropriate cadherin' might alter the behavior of the tumor cells (Derycke and Bracke, 2004;Nakajima et al., 2004;Paredes et al., 2005;Patel, I. et al., 2003;Riou et al., 2006;Stefansson et al., 2004;Taniuchi et al., 2005;Tomita et al., 2000). It has even been reported that E-cadherin can influence tumorigenesis in tissues that do not normally express this cadherin. For example, ovarian surface epithelium normally expresses N-cadherin. However, during progression to the neoplastic state, the cells show decreased N-cadherin expression and increased E-cadherin and Pcadherin expression; the E-cadherin might play a role in the initiation of the aberrant differentiation that characterizes ovarian carcinogenesis (Patel, I. et al., 2003;Wong et al., 1999;Wu et al., 2007). Table 1 presents examples of cadherin switching that have been reported during normal developmental processes and during tumorigenesis.One role of cadherin switching is to allow a select population of cells to separate from their neighbors -for example, during processes such as gastrulation, epiblast cell ingression through the primitive streak and neural crest emigration from the neural tube (Edelman et al., 1983; Hatta and Takeichi, 1986;Takeichi, 1988;Takeichi et al., 2000). It is well known that cells expressing different cadherins segregate from one another in in vitro aggregation assays (Nose et al., 1988;Steinberg and Takeichi, 1994) and it is easy...

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Expression of inappropriate cadherins by epithelial tumor cells promotes endocytosis and degradation of E-cadherin via competition for p120ctn

Cited by 56 publications

References 51 publications

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

Slug (SNAI2) expression in oral SCC cells results in altered cell-cell adhesion and increased motility

Cadherin switching

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