Roles of cell-cell adhesion-dependent tyrosine phosphorylation of Gab-1

Gab-1 is a multiple docking protein that is tyrosine phosphorylated by rece ptor tyrosine kinases such as c-Met, hepatocyte growth factor/scatter facto r receptor, and epidermal growth factor receptor. We have now demonstrated that cell-cell adhesion also induces marked tyrosine phosphorylation of Gab -1 and that disruption of cell-cell adhesion results in its dephosphorylati on, An anti-E-cadherin antibody decreased cell-cell adhesion-dependent tyro sine phosphorylation of Gab-1, whereas the expression of E-cadherin specifi cally induced tyrosine phosphorylation of Gab-1, A relatively selective inh ibitor of Src family kinases reduced cell-cell adhesion-dependent tyrosine phosphorylation of Gab-1, whereas expression of a dominant-negative mutant of Csk increased it. Disruption of cell-cell adhesion, which reduced tyrosi ne phosphorylation of Gab-1, also reduced the activation of mitogen-activat ed protein kinase and Akt in response to cell cell adhesion. These results indicate that E-cadherin-mediated cell-cell adhesion induces tyrosine phosp horylation by a Src family kinase of Gab-1, thereby regulating the activati on of Ras/MAP kinase and phosphatidylinositol 3-kinase/Akt cascades.