THE EPIDERMAL GROWTH-FACTOR RECEPTOR MODULATES THE INTERACTION OF E-CADHERIN WITH THE ACTIN CYTOSKELETON

Alterations in the expression or function of molecules that affect cel lular adhesion and proliferation are thought to be critical events for tumor progression, Loss of expression of the cell adhesion molecule E cadherin and increased expression of the epidermal growth factor rece ptor are two prominent molecular events that are associated with tumor igenesis, The regulation of E-cadherin-dependent cell adhesion by epid ermal growth factor (EGF) was therefore examined in the human breast c ancer cell line, MDA-MB-468. In this study, changes were observed in t he subcellular distribution of components that mediate the cytoplasmic connection between E-cadherin and the actin-based cytoskeleton in res ponse to activation of the EGF receptor, Serum withdrawal activated E- cadherin dependent cell-cell aggregation in MDA-MB-468 cells, and this treatment stimulated the interaction of actin, alpha-actinin, and vin culin with E cadherin complexes, despite the absence of alpha-catenin in these cells, By contrast, the co-precipitation of actin with E cadh erin was not detected in several alpha-catenin positive epithelial cel l lines, Treatment with EGF inhibited cellular aggregation but did not affect either the levels of E-cadherin or catenin expression nor the association of catenins (beta-catenin, plakoglobin/gamma-catenin, or p 120(cas)) with E cadherin. However, EGF treatment of the MDA-MB-468 ce ll line dissociated actin, alpha-actinin, and vinculin from the E cadh erin catenin complex, and this coincided with a robust phosphorylation of beta-catenin, plakoglobin/gamma-catenin, and p120(cas) on tyrosine residues, Furthermore, inactivation of the EGF receptor in serum-trea ted MDA-MB-468 cells with either a function-blocking antibody or EGF r eceptor kinase inhibitors mimicked the effects of serum starvation by stimulating both cellular aggregation and assembly of E-cadherin compl exes with vinculin and actin, These results demonstrate that the EGF r eceptor directly regulates cell-cell adhesion through modulation of th e interaction of E cadherin with the actin cytoskeleton and thus subst antiates the coordinate role of both of these molecules in tumor progr ession and metastasis.