INTEGRIN-DEPENDENT ACTIVATION OF THE P70 RIBOSOMAL S6 KINASE SIGNALING PATHWAY

Interaction of the cell surface integrin receptors with extracellular matrix proteins results in the activation of intracellular signaling p athways, including activation of the p42/p44 mitogen-activated protein kinases. The protein tyrosine kinase focal adhesion kinase, or FAK, i s linked to integrin signaling and interacts with several molecules in volved in signal transduction, Here we report that exposure of fibrobl ast cells to extracellular matrix proteins activates the p70/p85 ribos omal S6 kinase (S6K) pathway in a ligand dependent manner. Treatment o f cells with inhibitors of phosphatidylinositol 3-kinase, or FRAP (FKB P 12/rapamycin-associated protein) blocks integrin-mediated activation of S6K. In contrast to the integrin-directed activation of the mitoge n-activated protein kinases, cytochalasin D treatment does not inhibit S6K activation, Treatment with the protein tyrosine kinase inhibitors herbimycin A and genistein completely blocks S6K activation, indicati ng a requirement for tyrosine kinase activity. Overexpression of the C OOH-terminal noncatalytic domain of FAK, FRNK (FAK-related non-kinase) in chick embryo cells results in a significant reduction in the integ rin-mediated activation of S6K and a concomitant reduction in FAK tyro sine phosphorylation, These results indicate at least a partial requir ement for FAK in the S6K activation pathway.