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J. Biol. Chem., Vol. 280, Issue 28, 26533-26542, July 15, 2005

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LIM Kinase 1 Coordinates Microtubule Stability and Actin Polymerization in Human Endothelial Cells^*

Matvey Gorovoy, Jiaxin Niu, Ora Bernard, Jasmina Profirovic, Richard Minshall, Radu Neamu, and Tatyana Voyno-Yasenetskaya¶

From the Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612 and Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute, Victoria 3050, Australia

Microtubule (MT) destabilization promotes the formation of actin stress fibers and enhances the contractility of cells; however, the mechanism involved in the coordinated regulation of MTs and the actin cytoskeleton is poorly understood. LIM kinase 1 (LIMK1) regulates actin polymerization by phosphorylating the actin depolymerization factor, cofilin. Here we report that LIMK1 is also involved in the MT destabilization. In endothelial cells endogenous LIMK1 co-localizes with MTs and forms a complex with tubulin via the PDZ domain. MT destabilization induced by thrombin or nocodazole resulted in a decrease of LIMK1 colocalization with MTs. Overexpression of wild type LIMK1 resulted in MT destabilization, whereas the kinase-dead mutant of LIMK1 (KD) did not affect MT stability. Importantly, down-regulation of endogenous LIMK1 by small interference RNA resulted in abrogation of the thrombin-induced MTs destabilization and the inhibition of thrombin-induced actin polymerization. Expression of Rho kinase 2, which phosphorylates and activates LIMK1, dramatically decreases the interaction of LIMK1 with tubulin but increases its interaction with actin. Interestingly, expression of KD-LIMK1 or small interference RNA-LIMK1 prevents thrombin-induced microtubule destabilization and F-actin formation, suggesting that LIMK1 activity is required for thrombin-induced modulation of microtubule destabilization and actin polymerization. Our findings indicate that LIMK1 may coordinate microtubules and actin cytoskeleton.

Received for publication, March 16, 2005 , and in revised form, May 6, 2004.

^* These studies were supported by National Institutes of Health Grants GM56159, GM65160, and HL06078 and by a grant from American Heart Association (to T. V.-Y.) and by American Heart Association predoctoral fellowships (to M. G. and J. P.). 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.

^¶ An Established Investigator of the American Heart Association. To whom correspondence should be addressed: University of Illinois, Dept. of Pharmacology (MC 868), 835 S. Wolcott Ave, Chicago, IL 60612. Tel.: 312-996-9823; Fax: 312-996-1225; E-mail: tvy{at}uic.edu.

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