ACK1 mediates CDC42-dependent cell migration and signaling to p130cas

doi:10.1074/jbc.M604342200

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Papers In Press, published online ahead of print October 12, 2006
J. Biol. Chem, 10.1074/jbc.M604342200
Submitted on May 8, 2006
Revised on October 11, 2006
Accepted on October 12, 2006

ACK1 mediates CDC42-dependent cell migration and signaling to p130cas

Katarzyna Modzelewska, Laura P. Newman, Radhika Desai, and Patricia J. Keely

Dept. of Pharmacology, University of Wisconsin Madison, Madison, WI 53706

Corresponding Author: pjkeely{at}wisc.edu

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 p130Cas. Activated Cdc42 enhanced p130Cas phosphorylation and its binding to Crk. Cdc42-driven migration and p130Cas phosphorylation were dependent on the Cdc42 effector Ack1, Activated Cdc42-associated Kinase. Ack1 formed a signaling complex that also included Cdc42, p130Cas and Crk, formation of which was regulated by collagen stimulation. The interaction between Ack1 and p130Cas occurred through their respective SH3 domains, while the substrate domain of p130Cas was the major site of Ack1-dependent phosphorylation. Signaling through this complex is functionally relevant, since treatment with either p130Cas 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 p130Cas signaling.

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