We provide evidence that a class of integrins combines with the adaptor Shc and thereby with Grb2. Coimmunoprecipitation and mutagenesis experiments indicate that the recruitment of Shc is specified by the extracellular or transmembrane domain of integrin alpha subunit and suggest that this process is mediated by caveolin. Mutagenesis and dominant-negative inhibition studies reveal that Shc is necessary and sufficient for activation of the MAP kinase pathway in response to integrin ligation. Mitogens and Shc-activating integrins cooperate to promote transcription from the Fos serum response element and transit through G1. In contrast, adhesion mediated by integrins not linked to Shc results in cell cycle arrest and apoptosis even in presence of mitogens. These findings indicate that the association of specific integrins with Shc regulates cell survival and cell cycle progression.

Caveolin-1 functions as a membrane adaptor to link the integrin alpha subunit to the tyrosine kinase Fyn. Upon integrin ligation, Fyn is activated and binds, via its SH3 domain, to Shc. Shc is subsequently phosphorylated at tyrosine 317 and recruits Grb2. This sequence of events is necessary to couple integrins to the Ras-ERK pathway and promote cell cycle progression. These findings reveal an unexpected function of caveolin-1 and Fyn in integrin signaling and anchorage-dependent cell growth.

The signaling pathways linking integrins to nuclear events are incompletely understood. We have examined intracellular signaling by the α6β4 integrin, a laminin receptor expressed in basal keratinocytes and other cells. Ligation of α6β4 in primary human keratinocytes caused tyrosine phosphorylation of Shc, 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 α3β1 and α2β1 did not cause these events. While the stimulation of Erk by α6β4 was suppressed by dominant‐negative Shc, Ras and RhoA, the activation of Jnk was inhibited by dominant‐negative Ras and Rac1 and by the phosphoinositide 3‐kinase inhibitor Wortmannin. Adhesion mediated by α6β4induced transcription from the Fos serum response element and promoted cell cycle progression in response to mitogens. In contrast, α3β1‐ and α2β1‐dependent adhesion did not induce these events. These findings suggest that the coupling of α6β4 integrin to the control of cell cycle progression mediated by Shc regulates the proliferation of basal keratinocytes and possibly other cells which are in contact with the basement membrane in vivo.