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.
Microtubule (MT) stabilization is regulated by the small guanosine triphosphate (GTP)-binding protein Rho and its effector, mammalian homolog of Diaphanous (mDia), in migrating cells, but factors responsible for localized stabilization at the leading edge are unknown. We report that integrin-mediated activation of focal adhesion kinase (FAK) at the leading edge is required for MT stabilization by the Rho-mDia signaling pathway in mouse fibroblasts. MT stabilization also involved FAK-regulated localization of a lipid raft marker, ganglioside GM1, to the leading edge. The integrin-FAK signaling pathway may facilitate Rho-mDia signaling through GM1, or through a specialized membrane domain containing GM1, to stabilize MTs in the leading edge of migrating cells.
Focal adhesions (FAs) are clustered integrins and associated proteins that mediate cell adhesion and signaling. A green fluorescent protein-beta1 integrin chimera was used to label FAs in living cells. In stationary cells, FAs were highly motile, moving linearly for several plaque lengths toward the cell center. FA motility was independent of cell density and resulted from contraction of associated actin fibers. In migrating cells, FAs were stationary and only moved in the tail. FA motility in stationary cells suggests that cell movement may be regulated by a clutch-like mechanism by which the affinity of integrins to substrate may be altered in response to migratory cues.
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