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J. Biol. Chem., Vol. 282, Issue 47, 34568-34580, November 23, 2007

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Integrin-linked Kinase Regulates N-WASp-mediated Actin Polymerization and Tension Development in Tracheal Smooth Muscle^*

Wenwu Zhang, Yidi Wu, Chuanyue Wu, and Susan J. Gunst¹

From the Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202 and the Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

The contractile stimulation of smooth muscle tissues stimulates the recruitment of proteins to membrane adhesion complexes and the initiation of actin polymerization. We hypothesized that integrin-linked kinase (ILK), a -integrin-binding scaffolding protein and serine/threonine kinase, and its binding proteins, PINCH, and -parvin may be recruited to membrane adhesion sites during contractile stimulation of tracheal smooth muscle to mediate cytoskeletal processes required for tension development. Immunoprecipitation analysis indicted that ILK, PINCH, and -parvin form a stable cytosolic complex and that the ILK·PINCH·-parvin complex is recruited to integrin adhesion complexes in response to acetylcholine (ACh) stimulation where it associates with paxillin and vinculin. Green fluorescent protein (GFP)-ILK and GFP-PINCH were expressed in tracheal muscle tissues and both endogenous and recombinant ILK and PINCH were recruited to the membrane in response to ACh stimulation. The N-terminal LIM1 domain of PINCH binds to ILK and is required for the targeting of the ILK-PINCH complex to focal adhesion sites in fibroblasts during cell adhesion. We expressed the GFP-PINCH LIM1-2 fragment, consisting only of LIM1-2 domains, in tracheal smooth muscle tissues to competitively inhibit the interaction of ILK with PINCH. The PINCH LIM1-2 fragment inhibited the recruitment of endogenous ILK and PINCH to integrin adhesion sites and prevented their association of ILK with -integrins, paxillin, and vinculin. The PINCH LIM1-2 fragment also inhibited tension development, actin polymerization, and activation of the actin nucleation initiator, N-WASp. We conclude that the recruitment of the ILK·PINCH·-parvin complex to membrane adhesion complexes is required to initiate cytoskeletal processes required for tension development in smooth muscle.

Received for publication, June 15, 2007 , and in revised form, August 31, 2007.

^* This work was supported by National Institutes of Health NHLBI Grants HL-29289 and HL074099 (to S. J. G.), National Institutes of Health Grant GM65188 (to C. W.), a senior postdoctoral training fellowship from the American Lung Association (to W. Z.), and a postdoctoral fellowship from the American Heart Association (to Y. W.). 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 Movies S1 and S2.

¹ To whom correspondence should be addressed: 635 Barnhill Dr., MS313, Indianapolis, IN 46202. Tel.: 317-274-4108; Fax: 317-274-3318; E-mail: sgunst{at}iupui.edu.

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