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J. Biol. Chem., Vol. 279, Issue 52, 54131-54139, December 24, 2004

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The Integrin-linked Kinase Regulates Cell Morphology and Motility in a Rho-associated Kinase-dependent Manner^*

Wara A. K. M. Khyrul, David P. LaLonde, Michael C. Brown, Howard Levinson¶, and Christopher E. Turner||

From the Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, New York 13210 and the ^¶Department of Surgery, Brookdale University Hospital, Brooklyn, New York 11212

The integrin-linked kinase (ILK) is a multidomain focal adhesion protein implicated in signal transmission from integrin and growth factor receptors. We have determined that ILK regulates U2OS osteosarcoma cell spreading and motility in a manner requiring both kinase activity and localization. Overexpression of wild-type (WT) ILK resulted in suppression of cell spreading, polarization, and motility to fibronectin. Cell lines overexpressing kinase-dead (S343A) or paxillin binding site mutant ILK proteins display inhibited haptotaxis to fibronectin. Conversely, spreading and motility was potentiated in cells expressing the "dominant negative," non-targeting, kinase-deficient E359K ILK protein. Suppression of cell spreading and motility of WT ILK U2OS cells could be rescued by treatment with the Rho-associated kinase (ROCK) inhibitor Y-27632 or introduction of dominant negative ROCK or RhoA, suggesting these cells have increased RhoA signaling. Activation of focal adhesion kinase (FAK), a negative regulator of RhoA, was reduced in WT ILK cells, whereas overexpression of FAK rescued the observed defects in spreading and cell polarity. Thus, ILK-dependent effects on ROCK and/or RhoA signaling may be mediated through FAK.

Received for publication, September 1, 2004

^* This work was supported by National Institutes of Health Grant RO1 HL070244 (to C. E. T.). 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.

Both authors contributed equally to this research.

^|| To whom correspondence should be addressed: Dept. of Cell and Developmental Biology, SUNY Upstate Medical University, 750 E. Adams St., Syracuse, NY 13210. Tel.: 315-464-8598; Fax: 315-464-8535; E-mail: Turnerce{at}upstate.edu.

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