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J. Cell Biol.,
Volume 142, Number 2, July 27, 1998 573-586
* Howard Hughes Medical Institute, 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.
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
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