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J. Biol. Chem., Vol. 282, Issue 1, 426-435, January 5, 2007

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IQGAP1 Stimulates Actin Assembly through the N-Wasp-Arp2/3 Pathway^*

Christophe Le Clainche¹, Dominik Schlaepfer¹, Aldo Ferrari¹, Mirko Klingauf^¶, Katarina Grohmanova², Alexey Veligodskiy^¶, Dominique Didry, Diep Le, Coumaran Egile³, Marie-France Carlier⁴, and Ruth Kroschewski⁵

From the Institute of Biochemistry, ETH Zurich, 8093 Zurich, Switzerland, the Dynamics of Cytoskeleton and Motility Group, Laboratoire d'Enzymologie et Biochimie Structurale, CNRS, 91198 Gif-sur-Yvette, France, and the ^¶Molecular Life Science Ph.D. Program, Institute of Molecular Biology, University of Zurich, 8057 Zurich, Switzerland

IQGAP1 is a conserved modular protein overexpressed in cancer and involved in organizing actin and microtubules in motile processes such as adhesion, migration, and cytokinesis. A variety of proteins have been shown to interact with IQGAP1, including the small G proteins Rac1 and Cdc42, actin, calmodulin, -catenin, the microtubule plus end-binding proteins CLIP170 (cytoplasmic linker protein) and adenomatous polyposis coli. However, the molecular mechanism by which IQGAP1 controls actin dynamics in cell motility is not understood. Quantitative co-localization analysis and down-regulation of IQGAP1 revealed that IQGAP1 controls the co-localization of N-WASP with the Arp2/3 complex in lamellipodia. Co-immunoprecipitation supports an in vivo link between IQGAP1 and N-WASP. Pull-down experiments and kinetic assays of branched actin polymerization with N-WASP and Arp2/3 complex demonstrated that the C-terminal half of IQGAP1 activates N-WASP by interacting with its BR-CRIB domain in a Cdc42-like manner, whereas the N-terminal half of IQGAP1 antagonizes this activation by association with a C-terminal region of IQGAP1. We propose that signal-induced relief of the autoinhibited fold of IQGAP1 allows activation of N-WASP to stimulate Arp2/3-dependent actin assembly.

Received for publication, August 11, 2006 , and in revised form, October 17, 2006.

^* This work was supported by the Light Microscopy Center at ETH-Zurich, Switzerland, the Swiss National Science Foundation (to R. K.), the Innovation Promotion Agency (to R. K.), the Roche Research Foundation (to R. K.), the Schwyzer Foundation (to R. K.), Oncoswiss (to R. K.), the Human Frontiers in Science Program Organization (to M.-F. C.), the Ligue Nationale contre le Cancer (équipe labelisée Ligue, to M.-F. C.), and the Strategic Targeted Research European Program (Biomics grant to M.-F. C.). 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.

¹ These authors contributed equally to this work.

² Current address: Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR 97239.

³ Current address: Dept. of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.

⁴ To whom correspondence may be addressed. Tel.: 33-1-69-82-34-65; Fax: 33-1-69-82-34-78: E-mail: carlier{at}lebs.cnrs-gif.fr. ⁵ To whom correspondence may be addressed. Tel.: 41-44-632-63-46; Fax: 41-44-632-15-91; E-mail: ruth.kroschewski{at}bc.biol.ethz.ch.

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