THE COUPLING OF ALPHA(6)BETA(4) INTEGRIN TO RAS-MAP KINASE PATHWAYS MEDIATED BY SHC CONTROLS KERATINOCYTE PROLIFERATION

The signaling pathways linking integrins to nuclear events are incompl etely understood, We have examined intracellular signaling by the alph a(6) beta(4) integrin, a laminin receptor expressed in basal keratinoc ytes and other cells, Ligation of alpha(6) beta(4) in primary human ke ratinocytes caused tyrosine phosphorylation of She, recruitment of Grb 2, activation of Ras and stimulation of the MAP kinases Erk and Jnk. I n contrast, ligation of the laminin- and collagen-binding integrins al pha(3) beta(1) and alpha(2) beta(1) did not cause these events, While the stimulation of Erk by alpha(6) beta(4) was suppressed by dominant- negative Shc, Pas and RhoA, the activation of Jnk was inhibited by dom inant-negative Pas and Rad and by the phosphoinositide 3-kinase inhibi tor Wortmannin. Adhesion mediated by alpha(6) beta(4) induced transcri ption from the Fos serum response element and promoted a:ll cycle prog ression in response to mitogens, In contrast, alpha(3) beta(1)- and al pha(2) beta(1)-dependent adhesion did not induce these events, These f indings suggest that the coupling of alpha(6) beta(4) integrin to the control of cell cycle progression mediated by She regulates the prolif eration of basal keratinocytes and possibly other cells which are in c ontact with the basement membrane in vivo.