E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases

Qian, Xiaolan; Karpova, Tatiana S.; Sheppard, Allan; McNally, James G.; Lowy, Douglas R.

doi:10.1038/sj.emboj.7600136

Cited by 363 publications

(371 citation statements)

References 45 publications

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“…Several recent studies have shown that cadherins can interact with RTKs at the cell surface and modulate signaling pathways downstream of adherens junctions. For example, E-cadherin has been shown to interact with EGFR and modulate activation of the mitogen-activated protein kinase-ERK pathway, and N-cadherin associates with FGFR-1 to regulate FGFR-1 signaling (Pece and Gutkind, 2000;Suyama et al, 2002;Qian et al, 2004). Our finding is the first to report the activation of an RTK by P-cadherin.…”

Section: Discussionmentioning

confidence: 54%

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P-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin

et al. 2011

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Gonadotropin-releasing hormone (GnRH) is a potent prometastatic factor in ovarian cancer, but the intracellular signaling events are not well understood. The classical Ga q -phospholipase C signal transduction pathway known to operate in the pituitary is not involved in GnRH actions at non-pituitary targets. Here we showed that GnRH treatment of ovarian cancer cells led to a rapid and remarkable tyrosine phosphorylation of p120 catenin (p120 ctn ), which was mediated by P-cadherin. The use of P-cadherin small interfering RNA or neutralizing antibodies to inhibit P-cadherin expression and function resulted in diminished p120 ctn activation, confirming that the effect was P-cadherin specific. On exploring how P-cadherin, which lacks intrinsic kinase activity, might regulate the activation of p120 ctn , we found that P-cadherin could induce the ligandindependent activation of insulin-like growth factor-1 receptor (IGF-1R). Inhibition of IGF-1R expression or its activity significantly inhibited GnRH-induced p120 ctn activation, and the subsequent cell migration and invasion. In addition, we showed that IGF-1R regulation by P-cadherin was associated with complex formation between IGF-1R and P-cadherin, and this regulation was also observed to be in vivo correlated with metastasis. Furthermore, using a mouse model of ovarian cancer metastasis, GnRH receptor knockdown was shown to diminish peritoneal dissemination of tumors and ascites formation. These findings suggest for the first time that GnRH can initiate an outside-in p120 ctn signal transduction through the cross-talk between P-cadherin and IGF-1R, thus providing a novel molecular mechanism by which GnRH may control the high level of aggressiveness and invasion and metastasis potential that are characteristic of ovarian cancer.

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Section: Discussionmentioning

confidence: 54%

“…Unlike E-and N-cadherin in most cases (Pece and Gutkind, 2000;Suyama et al, 2002;Qian et al, 2004), IGF-1R regulation by P-cadherin is ligand-independent. IGF-1R transactivation has been reported to take place in various systems by both liganddependent and ligand-independent mechanisms.…”

Section: Discussionmentioning

confidence: 99%

P-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin

et al. 2011

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“…For example, E-cadherin is associated with epidermal growth factor receptor, thus activating the mitogenactivated protein kinase pathway, and N-cadherin has also been found to interact with fibroblast growth factor receptor (Pece and Gutkind, 2000;Suyama et al, 2002;Qian et al, 2004). In this context, we have found that P-cadherin was able to transactivate the insulin-like growth factor-1 receptor in regulation of p120 ctn signaling (our unpublished observations).…”

Section: Discussionmentioning

confidence: 71%

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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“…This suggests that E-cadherin may play a role in the early events leading to cellular transformation, a hypothesis supported by data showing that introduction of E-cadherin expression is sufficient for transformation of immortalized OSE [19]. Expression of E-cadherin may also interfere with the response of normal OSE to microenvironmental cues [61]. Acquisition of additional epithelial features including altered cell shape, formation of junctional complexes and expression of secretory products such as mucins and CA125 [19] provide further evidence of the mesenchymal-epithelial transition in early ovarian carcinogenesis.…”

Section: B Cadherin Expression In Eocmentioning

confidence: 89%

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Hudson

Zeineldin

Stack

2008

Clin Exp Metastasis

162

171

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The mesodermally derived normal ovarian surface epithelium (OSE) displays both epithelial and mesenchymal characteristics and exhibits remarkable phenotypic plasticity during post-ovulatory repair. The majority of epithelial ovarian carcinomas (EOC) are derived from the OSE and represent the most lethal of all gynecological malignancies, as most patients (~70%) present at diagnosis with disseminated intra-abdominal metastasis. The predominant pattern of EOC metastasis involves pelvic dissemination rather than lymphatic or hematologic spread, distinguishing EOC from other solid tumors. Acquisition of the metastatic phenotype involves a complex series of interrelated cellular events leading to dissociation (shedding) and dispersal of malignant cells. A key event in this process is disruption of cell-cell contacts via modulation of intercellular junctional components. In contrast to most carcinomas that downregulate E-cadherin expression during tumor progression, an unique feature of primary well-differentiated ovarian cancers is a gain of epithelial features, characterized by an increase in expression of E-cadherin. Subsequent reacquisition of mesenchymal features is observed in more advanced tumors with concomitant loss of E-cadherin expression and/ or function during progression to metastasis. The functional consequences of this remarkable phenotypic plasticity are not fully understood, but may play a role in modulation of cell survival in suspension (ascites), chemoresistance, and intraperitoneal anchoring of metastatic lesions. Keywords ovarian cancer; epithelium; cadherin; keratin; vimentin; epithelial-mesenchymal transition; plasticity Ovarian Cancer-OverviewTumors arising from the ovarian epithelium account for ~90% of ovarian malignancies and epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecologic malignancy, resulting in approximately 15,280 deaths in the United States alone in 2006 [1]. These distressing statistics are largely due to the low detection rate of disease confined to the ovary (stage 1) when 5-year survival is >90%. Approximately 75% of women are initially diagnosed with disseminated intra-abdominal disease (stage III-IV) and have a 5-year survival of <20%.Ovarian tumors are pathologically heterogeneous with four major histotypes: serous, endometroid, clear cell and mucinous. These classifications are histogenetically based on The early steps of EOC metastasis involve shedding of the cells from the primary tumor to form free floating cells or multi-cellular aggregates (MCAs) in ascites [ Fig. 1]. Cell-cell and cell-matrix adhesion molecules mediate interaction of metastasizing tumor cells with mesothelial cells lining the inner surface of the peritoneal cavity and the sub-mesothelial extracellular matrix (ECM). Localized proteolytic degradation of sub-mesothelial ECM components facilitates migration of tumor cells and anchoring of secondary lesions on adjacent pelvic organs, and at later stages, metastasis to distant organs [9,10]. However, the majority of wo...

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E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases

Cited by 363 publications

References 45 publications

P-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin

P-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin

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

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

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