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J. Biol. Chem., Vol. 283, Issue 29, 20454-20472, July 18, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/29/20454    most recent M710185200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lim, K. B. Articles by Ahmed, S. Search for Related Content PubMed PubMed Citation Articles by Lim, K. B. Articles by Ahmed, S. Social Bookmarking                      What's this?

The Cdc42 Effector IRSp53 Generates Filopodia by Coupling Membrane Protrusion with Actin Dynamics^*

Kim Buay Lim, Wenyu Bu, Wah Ing Goh, Esther Koh, Siew Hwa Ong, Tony Pawson, Thankiah Sudhaharan, and Sohail Ahmed¹

From the Institute of Medical Biology, 8A Biomedical Grove, Singapore 138665, and the Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario M5G 1X5, Canada

The Cdc42 effector IRSp53 is a strong inducer of filopodia formation and consists of an Src homology domain 3 (SH3), a potential WW-binding motif, a partial-Cdc42/Rac interacting binding region motif, and an Inverse-Bin-Amphiphysins-Rvs (I-BAR) domain.We show that IRSp53 interacts directly with neuronal Wiskott-Aldrich syndrome protein (N-WASP) via its SH3 domain and furthermore that N-WASP is required for filopodia formation as IRSp53 failed to induce filopodia formation in N-WASP knock-out (KO) fibroblasts. IRSp53-induced filopodia formation can be reconstituted in N-WASP KO fibroblasts by full-length N-WASP, by N-WASPWA (a mutant unable to activate the Arp2/3 complex), and by N-WASPH208D (a mutant unable to bind Cdc42). IRSp53 failed to induce filopodia in mammalian enabled (Mena)/VASP KO cells, and N-WASP failed to induce filopodia when IRSp53 was knocked down with RNA interference. The IRSp53 I-BAR domain alone induces dynamic membrane protrusions that lack actin and are smaller than normal filopodia ("partial-filopodia") in both wild-type N-WASP and N-WASP KO cells. We propose that IRSp53 generates filopodia by coupling membrane protrusion through its I-BAR domain with actin dynamics through SH3 domain binding partners, including N-WASP and Mena.

Received for publication, December 14, 2007 , and in revised form, March 25, 2008.

^* 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-S4 and Movies 1-7.

¹ To whom correspondence should be addressed: Institute of Medical Biology, 8A, Biomedical Grove, Immunos, Singapore 138665. Tel.: 65-6407-0165; Fax: 65-6464-2048; E-mail: sohail.ahmed{at}imb.a-star.edu.sg.

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