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J. Biol. Chem., Vol. 281, Issue 49, 37527-37535, December 8, 2006

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Ack1 Mediates Cdc42-dependent Cell Migration and Signaling to p130^Cas*

From the Department of Pharmacology and Molecular and Cellular Pharmacology Program, University of Wisconsin Medical School, Madison, Wisconsin 53706

We previously showed that activation of the small GTPase Cdc42 promotes breast cell migration on a collagen matrix. Here we further define the signaling pathways that drive this response and show that Cdc42-mediated migration relies on the adaptor molecule p130^Cas. Activated Cdc42 enhanced p130^Cas phosphorylation and its binding to Crk. Cdc42-driven migration and p130^Cas phosphorylation were dependent on the Cdc42 effector Ack1 (activated Cdc42-associated kinase). Ack1 formed a signaling complex that also included Cdc42, p130^Cas, and Crk, formation of which was regulated by collagen stimulation. The interaction between Ack1 and p130^Cas occurred through their respective SH3 domains, while the substrate domain of p130^Cas was the major site of Ack1-dependent phosphorylation. Signaling through this complex is functionally relevant, because treatment with either p130^Cas or Ack1 siRNA blocked Cdc42-induced migration. These results suggest that Cdc42 exerts its effects on cell migration in part through its effector Ack1, which regulates p130^Cas signaling.

Received for publication, May 8, 2006 , and in revised form, October 11, 2006.

^* This work was supported in part by National Institutes of Health Grant R29 CA76537 (to P. J. K.) and the Department of Defense Breast Cancer Research Program Predoctoral Fellowship DAMD17-02-1-0626 (to K. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, University of Wisconsin, 3630 MSC, 1300 University Ave, Madison, WI 53706. Tel.: 608-265-2398; Fax: 608-262-1257; E-mail: pjkeely{at}wisc.edu.

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