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Vol. 17, Issue 11, 4827-4836, November 2006

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Integrin Signaling through Arg Activates p190RhoGAP by Promoting Its Binding to p120RasGAP and Recruitment to the Membrane

William D. Bradley^*,, Samuel E. Hernández^,, Jeffrey Settleman, and Anthony J. Koleske^*,,||

*Department of Molecular Biophysics and Biochemistry, Interdepartmental Neuroscience Program, and ^||Department of Neurobiology, Yale University, New Haven, CT 06520; and Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129

Submitted February 14, 2006; Revised August 4, 2006; Accepted August 31, 2006
Monitoring Editor: Anne Ridley

The Rho family GTPases RhoA (Rho), Rac1, and Cdc42 are essential effectors of integrin-mediated cell attachment and spreading. Rho activity, which promotes formation of focal adhesions and actin stress fibers, is inhibited upon initial cell attachment to allow sampling of the new adhesive environment. The Abl-related gene (Arg) tyrosine kinase mediates adhesion-dependent inhibition of Rho through phosphorylation and activation of the Rho inhibitor p190RhoGAP-A (p190). p190 phosphorylation promotes its binding to p120RasGAP (p120). Here, we elucidate the mechanism by which p120 binding regulates p190 activation after adhesion. We show that p190 requires its p120-binding domain to undergo Arg-dependent activation in vivo. However, p120 binding does not activate p190RhoGAP activity in vitro. Instead, activation of p190 requires recruitment to the cell periphery. Integrin-mediated adhesion promotes relocalization of p190 and p120 to the cell periphery in wild-type fibroblasts, but not in arg^–/– fibroblasts. A dominant-negative p120 fragment blocks p190:p120 complex formation, prevents activation of p190 by adhesion, and disrupts the adhesion-dependent recruitment of p190 to the cell periphery. Our results demonstrate that integrin signaling through Arg activates p190 by promoting its association with p120, resulting in recruitment of p190 to the cell periphery where it inhibits Rho.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/10.1091/mbc.E06-02-0132) on September 13, 2006.

These authors contributed equally to this work.

Address correspondence to: Anthony J. Koleske (anthony.koleske{at}yale.edu)

Abbreviations used: 2-3-2 fragment, SH2-SH3-SH2-domain–containing p120RasGAP fragment; Arg, Abl-related gene; FN, fibronectin; HEK, human embryonic kidney; p120, 120-kDa Ras GTPase-activating protein; p190, 190-kDa Rho GTPase-activating protein; PLL, poly-L-lysine; RBR, RasGAP-binding region of p190RhoGAP.

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