CROSS-TALK BETWEEN INSULIN-RECEPTOR AND INTEGRIN ALPHA(5)BETA(1) SIGNALING PATHWAYS

The ligation and clustering of cell surface crp heterodimeric integrin s enhances cell adhesion and initiates signaling pathways that regulat e such processes as cell spreading, migration, differentiation, prolif eration and apoptosis, Here we show that insulin treatment of Chinese hamster ovary cells expressing insulin receptors (CHO-T) markedly prom otes cell adhesion onto a fibronectin matrix, but not onto bovine seru m albumin or poly-lysine. Incubation of cells with a GRGDSP peptide th at specifically binds integrins (but not the nonspecific GRADSP peptid e) abolishes this insulin effect, as does the potent phosphoinositide 3-kinase (PI 3-kinase) inhibitor wortmannin. Moreover, a specific bloc king monoclonal anti-alpha(5)beta(1) integrin antibody, PB-1, blocks i nsulin-stimulated cell adhesion onto fibronectin. Conversely, activati ng alpha(5)beta(1) integrins on CHO-T cells by adherence onto fibronec tin markedly potentiates the action of insulin to enhance insulin rece ptor and insulin receptor substrate (IRS)-1 tyrosine phosphorylation, Activation of alpha(5)beta(1) integrin also markedly potentiates the r ecruitment of p85-associated PI 3-kinase activity to IRS-1 in response to submaximal levels of insulin in CHO-T cells. These data indicate t hat insulin potently activates integrin alpha(5)beta(1) mediated CHO-T cell adhesion, while integrin alpha(5)beta(1) signaling in turn enhan ces insulin receptor kinase activity and formation of complexes contai ning IRS-1 and PI 3-kinase, These findings raise the hypothesis that i nsulin receptor and alpha(5)beta(1) integrin signaling act synergistic ally to enhance cell adhesion.