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 incompletely understood, We have examined intracellular signaling by the alpha(6) beta(4) integrin, a laminin receptor expressed in basal keratinocytes and other cells, Ligation of alpha(6) beta(4) in primary human keratinocytes caused tyrosine phosphorylation of She, recruitment of Grb2, activation of Ras and stimulation of the MAP kinases Erk and Jnk. In contrast, ligation of the laminin- and collagen-binding integrins alpha(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 dominant-negative Pas and Rad and by the phosphoinositide 3-kinase inhibitor Wortmannin. Adhesion mediated by alpha(6) beta(4) induced transcription from the Fos serum response element and promoted a:ll cycle progression in response to mitogens, In contrast, alpha(3) beta(1)- and alpha(2) beta(1)-dependent adhesion did not induce these events, These findings suggest that the coupling of alpha(6) beta(4) integrin to the control of cell cycle progression mediated by She regulates the proliferation of basal keratinocytes and possibly other cells which are in contact with the basement membrane in vivo.