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 pathways, including activation of the p42/p44 mitogen-activated protein kinases. The protein tyrosine kinase focal adhesion kinase, or FAK, is linked to integrin signaling and interacts with several molecules involved in signal transduction. Here we report that exposure of fibroblast cells to extracellular matrix proteins activates the p70/p85 ribosomal S6 kinase (S6K) pathway in a ligand dependent manner. Treatment of cells with inhibitors of phosphatidylinositol 3-kinase, or FRAP (FKBP 12/rapamycin-associated protein) blocks integrin-mediated activation of S6K. In contrast to the integrin-directed activation of the mitogen-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, indicating a requirement for tyrosine kinase activity. Overexpression of the COOH-terminal noncatalytic domain of FAK, FRNK (FAK-related non-kinase) in chick embryo cells results in a significant reduction in the integrin-mediated activation of S6K and a concomitant reduction in FAK tyrosine phosphorylation. These results indicate at least a partial requirement for FAK in the S6K activation pathway.
Malik
R K
RK
Department of Pediatrics, Health Sciences Center, University of Virginia, Charlottesville, Virginia 22908, USA. jtp@virginia.edu
Parsons
J T
JT
D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D015638:Cytochalasin D / Q000494:pharmacology; D004789:Enzyme Activation; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016023:Integrins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction
D015815:Cell Adhesion Molecules; D016023:Integrins; D015638:Cytochalasin D; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases