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© The Rockefeller University Press, 0021-9525/1998//573 $5.00
The Journal of Cell Biology, Volume 142, Number 2, , 1998 573-586

Articles

Integrin-mediated Signals Regulated by Members of the Rho Family of GTPases



Edwin A. Clark*, Warren G. King§, Joan S. Brugge§, Marc Symons||, and Richard O. Hynes*,{ddagger}

* Howard Hughes Medical Institute, Center for Cancer Research, {ddagger} Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; § Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115; and || Onyx Pharmaceuticals, 3031 Research Drive, Richmond, California 94806

The organization of the actin cytoskeleton can be regulated by soluble factors that trigger signal transduction events involving the Rho family of GTPases. Since adhesive interactions are also capable of organizing the actin-based cytoskeleton, we examined the role of Cdc42-, Rac-, and Rho-dependent signaling pathways in regulating the cytoskeleton during integrin-mediated adhesion and cell spreading using dominant-inhibitory mutants of these GTPases. When Rat1 cells initially adhere to the extracellular matrix protein fibronectin, punctate focal complexes form at the cell periphery. Concomitant with focal complex formation, we observed some phosphorylation of the focal adhesion kinase (FAK) and Src, which occurred independently of Rho family GTPases. However, subsequent phosphorylation of FAK and paxillin occurs in a Rho-dependent manner. Moreover, we found Rho dependence of the assembly of large focal adhesions from which actin stress fibers radiate. Initial adhesion to fibronectin also stimulates membrane ruffling; we show that this ruffling is independent of Rho but is dependent on both Cdc42 and Rac. Furthermore, we observed that Cdc42 controls the integrin-dependent activation of extracellular signal–regulated kinase 2 and of Akt, a kinase whose activity has been demonstrated to be dependent on phosphatidylinositol (PI) 3-kinase. Since Rac-dependent membrane ruffling can be stimulated by PI 3-kinase, it appears that Cdc42, PI 3-kinase, and Rac lie on a distinct pathway that regulates adhesion-induced membrane ruffling. In contrast to the differential regulation of integrin-mediated signaling by Cdc42, Rac, and Rho, we observed that all three GTPases regulate cell spreading, an event that may indirectly control cellular architecture. Therefore, several separable signaling pathways regulated by different members of the Rho family of GTPases converge to control adhesion-dependent changes in the organization of the cytoskeleton, changes that regulate cell morphology and behavior.

Key Words: integrins • adhesion • cytoskeleton • Rho • Cdc42

Abbreviations used in this paper: ECM, extracellular matrix; Erk, extracellular signal-regulated kinase; F-actin, filamentous actin; FAK, focal adhesion kinase; HA, hemagglutinin; LPA, lysophosphatidic acid; MAP, mitogen-activated protein; PI, phosphatidylinositol; SH2, Src homology 2.

Address all correspondence to Richard O. Hynes, Massachusetts Institute of Technology, Center for Cancer Research, 77 Massachusetts Avenue, E17-227, Cambridge, MA 02139. Tel.: (617) 253-6422. Fax: (617) 253-8357. E-mail: rohynes{at}mit.edu


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