Epidermal growth factor receptor induced apoptosis: potentiation by inhibition of Ras signaling

Previous studies have shown that certain tumor cell lines which naturally e xpress high levels of the epidermal growth factor receptor (EGFR) undergo a poptosis when exposed to epidermal growth factor. Whether this phenomenon i s a direct result of receptor overexpression or some other genetic alterati on renders these cells sensitive to apoptosis is yet to be established. We show that experimentally increasing the level of EGFR expression predictabl y leads to apoptosis in a variety of cell types which requires an active ty rosine kinase but not EGFR autophosphorylation sites. Expression of a domin ant negative Pas mutant in EGFR overexpressing cells results in a significa nt potentiation of EGFR induced apoptosis suggesting that Ras activation is a key survival signal generated by the EGFR, We propose that potentiation of EGFR induced apoptosis by dominant negative Ras results, at least in par t, by a block of Akt activation. (C) 2001 Federation of European Biochemica l Societies. Published by Elsevier Science B.V. All rights reserved.