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J. Biol. Chem., Vol. 281, Issue 46, 35487-35498, November 17, 2006

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Integrin 4 Regulates Migratory Behavior of Keratinocytes by Determining Laminin-332 Organization^*

Bernd U. Sehgal¹, Phillip J. DeBiase¹, Sumio Matzno, Teng-Leong Chew, Jessica N. Claiborne, Susan B. Hopkinson, Alan Russell, M. Peter Marinkovich^¶||, and Jonathan C. R. Jones²

From the Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, the Department of Molecular and Cell Biology, Cytokinetics, Inc., South San Francisco, California 94080, the ^¶Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, and the ^||Veterans Affairs Palo Alto Health Care System, Stanford, California 94304

Whether 64 integrin regulates migration remains controversial. 4 integrin-deficient (JEB) keratinocytes display aberrant migration in that they move in circles, a behavior that mirrors the circular arrays of laminin (LM)-332 in their matrix. In contrast, wild-type keratinocytes and JEB keratinocytes, induced to express 4 integrin, assemble laminin-332 in linear tracks over which they migrate. Moreover, laminin-332-dependent migration of JEB keratinocytes along linear tracks is restored when cells are plated on wild-type keratinocyte matrix, whereas wild-type keratinocytes show rotation over circular arrays of laminn-332 in JEB keratinocyte matrix. The activities of Rac1 and the actin cytoskeleton-severing protein cofilin are low in JEB keratinocytes compared with wild-type cells but are rescued following expression of wild-type 4 integrin in JEB cells. Additionally, in wild-type keratinocytes Rac1 is complexed with 64 integrin. Moreover, Rac1 or cofilin inactivation induces wild-type keratinocytes to move in circles over rings of laminin-332 in their matrix. Together these data indicate that laminin-332 matrix organization is determined by the 64 integrin/actin cytoskeleton via Rac1/cofilin signaling. Furthermore, our results imply that the organizational state of laminin-332 is a key determinant of the motility behavior of keratinocytes, an essential element of skin wound healing and the successful invasion of epidermal-derived tumor cells.

Received for publication, July 3, 2006 , and in revised form, August 30, 2006.

^* This work was supported by National Institutes of Health (NIH) Grant RO1 AR054184 (to J. C. R. J.) and by NIH Training Grant T32 AR007593 (to B. U. S.). 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-S3 and videos 1-6.

¹ Both authors contributed equally to this work.

² 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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