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J. Biol. Chem., Vol. 280, Issue 11, 10624-10635, March 18, 2005

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Integrin Engagement Differentially Modulates Epithelial Cell Motility by RhoA/ROCK and PAK1^*

Hua Zhou and Randall H. Kramer

From the Department of Cell and Tissue Biology, University of California, San Francisco, California 94143

Integrin-ligand binding regulates tumor cell motility and invasion. Cell migration also involves the Rho GTPases that control the interplay between adhesion receptors and the cytoskeleton. We evaluated how specific extracellular matrix ligands modulate Rho GTPases and control motility of human squamous cell carcinoma cells. On laminin-5 substrates, the epithelial cells rapidly spread and migrated, but on type I collagen the cells spread slowly and showed reduced motility. We found that RhoA activity was suppressed in cells attached to laminin-5 through the 3 integrin receptor. In contrast, RhoA was strongly activated in cells bound to type I collagen and this was mediated by the 2 integrin. Inhibiting the RhoA pathway by expression of a dominant-negative RhoA mutant or by directly inhibiting ROCK, reduced focal adhesion formation and enhanced cell migration on type I collagen. Cdc42 and Rac and their downstream target PAK1 were activated following adhesion to laminin-5. PAK1 activation induced by laminin-5 was suppressed by expression of a dominant-negative Cdc42. Moreover, constitutively active PAK1 stimulated migration on collagen I substrates. Our results indicate that in squamous epithelial cells, collagen-21 integrin binding activates RhoA, slowing cell locomotion, whereas laminin-5-31 integrin interaction inhibits RhoA and activates PAK1, stimulating cell migration. The data demonstrate that specific ligand-integrin pairs regulate cell motility differentially by selectively modulating activities of Rho GTPases and their effectors.

Received for publication, October 20, 2004 , and in revised form, December 9, 2004.

^* This work was supported in part by National Institutes of Health Grants DE11436 and DE13904. 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.

Supported by predoctoral National Institutes of Health Graduate Training Grant 5T32DE007204 and the Graduate Program in Oral and Craniofacial Sciences.

To whom correspondence should be addressed: Dept. of Cell and Tissue Biology University of California, San Francisco, CA 94143. Tel.: 415-476-3275 or 476-3274; Fax: 415-476-4204; E-mail: rkramer{at}itsa.ucsf.edu.

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