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Vol. 17, Issue 1, 239-250, January 2006

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Proteolysis of Cortactin by Calpain Regulates Membrane Protrusion during Cell Migration

Benjamin J. Perrin ^*, Kurt J. Amann , and Anna Huttenlocher 

^* Cellular and Molecular Biology Program, University of Wisconsin–Madison, Madison, WI 53706; Department of Zoology and Laboratory of Molecular Biology, University of Wisconsin–Madison, Madison, WI 53706; and Department of Pediatrics and Pharmacology, University of Wisconsin–Madison, Madison, WI 53706

Submitted June 3, 2005; Revised October 25, 2005; Accepted October 31, 2005
Monitoring Editor: Martin A. Schwartz

Calpain 2 regulates membrane protrusion during cell migration. However, relevant substrates that mediate the effects of calpain on protrusion have not been identified. One potential candidate substrate is the actin binding protein cortactin. Cortactin is a Src substrate that drives actin polymerization by activating the Arp2/3 complex and also stabilizes the cortical actin network. We now provide evidence that proteolysis of cortactin by calpain 2 regulates membrane protrusion dynamics during cell migration. We show that cortactin is a calpain 2 substrate in fibroblasts and that the preferred cleavage site occurs in a region between the actin binding repeats and the -helical domain. We have generated a mutant cortactin that is resistant to calpain proteolysis but retains other biochemical properties of cortactin. Expression of the calpain-resistant cortactin, but not wild-type cortactin, impairs cell migration and increases transient membrane protrusion, suggesting that calpain proteolysis of cortactin limits membrane protrusions and regulates migration in fibroblasts. Furthermore, the enhanced protrusion observed with the calpain-resistant cortactin requires both the Arp2/3 binding site and the Src homology 3 domain of cortactin. Together, these findings suggest a novel role for calpain-mediated proteolysis of cortactin in regulating membrane protrusion dynamics during cell migration.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Anna Huttenlocher (huttenlocher{at}wisc.edu).

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