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J. Biol. Chem., Vol. 282, Issue 44, 32520-32528, November 2, 2007

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The Slingshot Family of Phosphatases Mediates Rac1 Regulation of Cofilin Phosphorylation, Laminin-332 Organization, and Motility Behavior of Keratinocytes^*

Kristina Kligys, Jessica N. Claiborne, Phillip J. DeBiase, Susan B. Hopkinson, Yvonne Wu, Kensaku Mizuno, and Jonathan C. R. Jones¹

From the Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611 and Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan

The motility of keratinocytes is an essential component of wound closure and the development of epidermal tumors. In vitro, the specific motile behavior of keratinocytes is dictated by the assembly of laminin-332 tracks, a process that is dependent upon 64 integrin signaling to Rac1 and the actin-severing protein cofilin. Here we have analyzed how cofilin phosphorylation is regulated by phosphatases (slingshot (SSH) or chronophin (CIN)) downstream of signaling by 64 integrin/Rac1 in human keratinocytes. Keratinocytes express all members of the SSH family (SSH1, SSH2, and SSH3) and CIN. However, expression of phosphatase-dead versions of all three SSH proteins, but not dominant inactive CIN, results in phosphorylation/inactivation of cofilin, changes in actin cytoskeleton organization, loss of cell polarity, and assembly of aberrant arrays of laminin-332 in human keratinocytes. SSH activity is regulated by 14-3-3 protein binding, and intriguingly, 14-3-3/64 integrin protein interaction is required for keratinocyte migration. We wondered whether 14-3-3 proteins function as regulators of Rac1-mediated keratinocyte migration patterns. In support of this hypothesis, inhibition of Rac1 results in an increase in 14-3-3 protein association with SSH. Thus, we propose a novel mechanism in which 64 integrin signaling via Rac1, 14-3-3 proteins, and SSH family members regulates cofilin activation, cell polarity, and matrix assembly, leading to specific epidermal cell migration behavior.

Received for publication, August 22, 2007

^* This work was supported by National Institutes of Health Grant R01 AR054184 (to J. C. R. J.) and National Institutes of Health Training Grant T32 HL076139 (to K. K.). 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. S1 and S2 and supplemental Videos S1-S3.

¹ To whom correspondence should be addressed: Dept. of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Chicago, IL 60611. Tel.: 312-503-1412; Fax: 312-503-6475; E-mail: j-jones3{at}northwestern.edu.

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