Differential activation of focal adhesion kinase, Rho and Rac by the ninthand tenth FIII domains of fibronectin

Fibronectins are widely expressed extracellular matrix ligands that are ess ential for many biological processes. Fibronectin-induced signaling pathway s are elicited in diverse cell types when specific integrin receptors bind to the ninth and tenth FIII domains, FIII9-10. Integrin-mediated signal tra nsduction involves activation of signaling pathways of the growth factor-de pendent Ras-related small GTP-binding proteins Rho and Rac, and phosphoryla tion of focal adhesion kinase, We have dissected the requirement of FIII9 a nd FIII10 for Rho and Rac activity and phosphorylation of focal adhesion ki nase in BHK fibroblasts and Swiss 3T3 cells. We demonstrate that FIII10 sup ports cell attachment but does not induce phosphorylation of focal adhesion kinase, In Swiss 3T3 cells, growth factor-independent phosphorylation of f ocal adhesion kinase and downstream adhesion events are dependent upon the presence of FIII9 in the intact FIII910 pair, whereas FIII10-mediated focal adhesion kinase phosphorylation requires a synergistic signal from growth factors. Furthermore, FIII10 is able to elicit cellular responses mediated by Rho, but not Rac, whereas FIII9-10 can elicit both Rho- and Rac-mediated responses. We propose that activation of specific integrin subunits by the FIII10 and FIII9-10 ligands elicits distinct signaling events. This may re present a general molecular mechanism for activation of receptor-specific s ignaling pathways by a multi-domain ligand.