Signaling from E-cadherins to the MAPK Pathway by the Recruitment and Activation of Epidermal Growth Factor Receptors upon Cell-Cell Contact Formation

Abstract

E-cadherins are well characterized cell surface molecules expressed in epithelial cells, which play a major role in cell adhesion through the establishment of calcium-dependent homophilic interactions at sites of cell-cell contacts. They are also integral components of morphogenetic programs controlling the maintenance of the structural and functional integrity of epithelia. Accumulated evidence indicates that the E-cadherinmediated cell adhesion system is highly regulated from inside the cells by a number of intracellular signaling pathways. Recently available information suggests that E-cadherins may also play a role in the transduction of signals from the outside of the cell to the cytoplasm. However, the nature of the biochemical routes regulated by E-cadherins is still largely unknown. In this study, we set out to explore the possibility that E-cadherins may regulate the activity of MAPK, a key signaling pathway involved in cell fate decisions, upon the formation of cell-cell contacts among neighboring cells. By using an immortalized non-tumorigenic keratinocyte cell line, HaCat, as a model system, we provide evidence that the assembly of calcium-dependent adherens junctions leads to a rapid and remarkable increase in the state of activation of MAPK and that this event is mediated by E-cadherins. Furthermore, we found that E-cadherins stimulate the MAPK pathway through the ligandindependent activation of epidermal growth factor receptors and the consequent activation of a biochemical route leading to the stimulation of MAPKs. These findings suggest that E-cadherins can initiate outside-in signal transducing pathways through the engagement of tyrosine kinase receptors for epidermal growth factor, thus providing a novel molecular mechanism whereby these cell adhesion molecules may ultimately control the fate of normal and transformed epithelial cells.

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

“…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.…”

“…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.…”

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

“…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).…”

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

“…E-cadherin is also implicated in regulation of signal transduction through other mediators including Rho family GTPases [43], phosphatidylinositol 3-kinase (PI3K) [44,45], and epidermal growth factor (EGF) receptor [45,46], whereas N-cadherin modulates fibroblast growth factor (FGF) receptor signaling [47] as well as the PI3K/Akt pathway [48,49]. Due to the diverse nature of these dynamic multimolecular interactions, cadherins are properly positioned to functionally integrate cellcell adhesion with regulation of signal transduction pathways and their associated transcriptional programs to control multiple aspects of cell shape and behavior.…”