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J. Biol. Chem., Vol. 282, Issue 28, 20634-20646, July 13, 2007

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-Arrestin-dependent Regulation of the Cofilin Pathway Downstream of Protease-activated Receptor-2^*

Maria Zoudilova, Puneet Kumar, Lan Ge, Ping Wang, Gary M. Bokoch^¶, and Kathryn A. DeFea¹

From the Cell, Molecular, and Developmental Biology Program and Biomedical Sciences Division, University of California Riverside, California 92521 and ^¶Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

-Arrestins are pleiotropic molecules that mediate signal desensitization, G-protein-independent signaling, scaffolding of signaling molecules, and chemotaxis. Protease-activated receptor-2 (PAR-2), a G_q/11-coupled receptor, which has been proposed as a therapeutic target for inflammation and cancer, requires the scaffolding function of -arrestins for chemotaxis. We hypothesized that PAR-2 can trigger specific responses by differential activation of two pathways, one through classic G_q/Ca²⁺ signaling and one through -arrestins, and we proposed that the latter involves scaffolding of proteins involved in cell migration and actin assembly. Here we demonstrate the following. (a) PAR-2 promotes -arrestin-dependent dephosphorylation and activation of the actin filament-severing protein (cofilin) independently of G_q/Ca²⁺ signaling. (b) PAR-2-evoked cofilin dephosphorylation requires both the activity of a recently identified cofilin-specific phosphatase (chronophin) and inhibition of LIM kinase (LIMK) activity. (c) -Arrestins can interact with cofilin, LIMK, and chronophin and colocalize with them in membrane protrusions, suggesting that -arrestins may spatially regulate their activities. These findings identify cofilin as a novel target of -arrestin-dependent scaffolding and suggest that many PAR-2-induced processes may be independent of G_q/11 protein coupling.

Received for publication, February 16, 2007 , and in revised form, April 27, 2007.

^* This work was supported by National Institutes of Health Grants R01GM066151 (to K. A. D.) and R01GM44428 (to G. M. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ To whom correspondence should be addressed: Biomedical Sciences Division, University of California, B605 Statistics Rd., Riverside, CA 92521. Tel.: 951-827-2871; E-mail: kathryn.defea{at}ucr.edu.

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