Regulation of cell signaling induced by the cell adhesion molecule, E-cadherin

Cell adhesion is important in the regulation of many cellular behaviors including cell growth, differentiation, migration, cell survival and cell transformation. Adherens-type junctions are a specific type of cell-cell adhesion that are stabilized by the actin cytoskeleton. These adhesions are initiated by the homotypic binding of cadherin extracellular domains on neighboring cells and are linked to the actin cytoskeleton through a complex of proteins that includes the catenins. Recently, these sites of cell adhesion have been implicated in cell signaling. Here, we characterize novel signaling pathways activated by aggregation of E-cadherin. We show that during adherens-type junction formation, a rapid burst in epidermal growth factor receptor (EGFR) signaling occurs. This signaling represents a new alternative mechanism of EGFR activation. We propose a mechanism in which E-cadherin aggregation promotes oligomerization of both EGFR and a repressive phosphatase. Thus, oligomerization of the phosphatase results in its inactivation and allows activation of oligomerized EGFR. During colony formation, non-transformed epithelial cells form cell-cell contacts and decrease their cell-extracellular matrix adhesions called focal adhesions. Transformed cells are unable to form stable cell-cell adhesions and maintain their focal adhesions. We examined whether E-cadherin-mediated cell signaling influenced cell-extracellular matrix adhesion. Indeed, aggregation of E-cadherin in cells devoid of cell-cell contacts, stimulates the loss of focal adhesions. Inhibition of EGFR activity prevents E-cadherin induced focal adhesion disassembly. Preliminary examination of E-cadherin signaling in Ras transformed cells suggests that E-cadherin mediated signaling is non-functional. These results suggest a mechanism of coordinating soluble growth factor and cell-cell adhesion induced signaling to affect cell-extracellular matrix adhesion. Furthermore, these results implicate defects in cellular signaling in transformed cells that have altered cell adhesion