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

Abstract

Adhesion of human primary skin fibroblasts and ECV304 endothelial cells to immobilized matrix proteins, β1 or αv 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 kinasenegative 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 (5⍥10 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.

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

“…In PC3 cells, integrin-mediated activation of c-Met was not dependent on Src activity. Prior studies indicate that ligand-independent activation of receptor kinases is required for signaling downstream of integrins (Moro et al, 1998;Bill et al, 2004). However, we found that inhibition of c-Met had no effect on integrin-induced Src activation per se.…”

“…Both integrins and receptor tyrosine kinases are involved in cell migration and metastasis. Furthermore, integrins have been shown to activate several receptor tyrosine kinases in a ligandindependent manner, including EGFR, c-Met, PDGFR, and Ron (Sundberg and Rubin, 1996;Wang et al, 1996Wang et al, , 2001Moro et al, 1998Moro et al, , 2002Danilkovitch-Miagkova et al, 2000;Bill et al, 2004). Both integrins and receptor tyrosine kinases can interact with CD82 (Hemler, 1998;Odintsova et al, 2000).…”

Anoikis: an emerging hallmark in health and diseases

“…Epidermal growth factor receptor (EGFR) [63], hepatocyte growth factor receptor (HGFR) [64] vascular endothelial growth factor receptor (VEGFR) [65] and platelet-derived growth factor receptor (PDGFR) [66] are the main growth factor receptors recruited in integrin platforms. In epithelial cells, either ligand-dependent or integrin-mediated ligand-independent EGFR activation stimulates ERK and PI3K signalling, thereby suppressing the activity of apoptotic factors.…”

“…The ligand-independent phosphorylation of EGF receptor in response to integrin ligation is strictly dependent by its association with the adaptor protein p130Cas and the c-Src tyrosine kinase [63,68]. Src kinase is activated in response to integrin ligation due to its redox sensitivity.…”

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

“…Integrin activation of MAPK requires FAK autophosphorylation and c-Src activation [6], and has been proposed to involve SH2-mediated recruitment of the adapter protein Grb2 involved in growth factor activation of Ras to a site of c-Src phosphorylation (Y925) in FAK [7,8]. Alternatively, integrins may cooperate with growth factor receptors such as the PDGF, insulin and EGF receptors to activate their respective downstream signaling mechanisms [9][10][11]. However, while some laboratories find that Ras is required for ERK activation during adhesion [8,12,13], others find that inhibiting Ras is without effect on adhesion stimulated ERK activation [14,15].…”