Integrins induce activation of EGF receptor: role in MAP kinase induction and adhesion-dependent cell survival

Adhesion of human primary skin fibroblasts and ECV304 endothelial cells to immobilized matrix proteins, beta 1 or alpha v integrin antibodies stimulat es tyrosine phosphorylation of the epidermal growth factor (EGF) receptor. This tyrosine phosphorylation is transiently induced, reaching maximal leve ls 30 min after adhesion, and it occurs in the absence of receptor ligands. Similar results were observed with EGF receptor-transfected NIH-3T3 cells. Use of a kinase-negative EGF receptor mutant demonstrates that the integri n-stimulated tyrosine phosphorylation is due to activation of the receptor' s intrinsic kinase activity. Integrin-mediated EGF receptor activation lead s to Erk-1/MAP kinase induction, as shown by treatment with the specific in hibitor tyrphostin AG1478 and by expression of a dominant-negative EGF rece ptor mutant. EGF receptor and Erk-1/MAP kinase activation by integrins does not lead per se to cell proliferation, but is important for entry into S p hase in response to EGF or serum. EGF receptor activation is also required for extracellular matrix-mediated cell survival. Adhesion-dependent R IAP k inase activation and survival are regulated through EGF receptor activation in cells expressing this molecule above a threshold level (5 x 10(3) recep tors per cell). These results demonstrate that integrin-dependent EGF recep tor activation is a novel signaling mechanism involved in cell survival and proliferation in response to extracellular matrix.