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, beta1 or alphav integrin antibodies stimulates tyrosine phosphorylation of the epidermal growth factor (EGF) receptor. This tyrosine phosphorylation is transiently induced, reaching maximal levels 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 integrin-stimulated tyrosine phosphorylation is due to activation of the receptor's intrinsic kinase activity. Integrin-mediated EGF receptor activation leads to Erk-1/MAP kinase induction, as shown by treatment with the specific inhibitor tyrphostin AG1478 and by expression of a dominant-negative EGF receptor 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 phase in response to EGF or serum. EGF receptor activation is also required for extracellular matrix-mediated cell survival. Adhesion-dependent MAP kinase activation and survival are regulated through EGF receptor activation in cells expressing this molecule above a threshold level (5x10(3) receptors per cell). These results demonstrate that integrin-dependent EGF receptor activation is a novel signaling mechanism involved in cell survival and proliferation in response to extracellular matrix.
Moro
L
L
Dipartimento di Scienze Mediche, Biochimica, Universitá di Torino, Italy.
Venturino
M
M
Bozzo
C
C
Silengo
L
L
Altruda
F
F
Beguinot
L
L
Tarone
G
G
Defilippi
P
P
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis*; D002448:Cell Adhesion; D002455:Cell Division; D002470:Cell Survival; D003599:Cytoskeleton / Q000378:metabolism; D017931:DNA Primers; D004789:Enzyme Activation; D004790:Enzyme Induction; D066246:ErbB Receptors / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D000199:Actins; D017931:DNA Primers; D016023:Integrins; D014443:Tyrosine; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases