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Published online 15 May 2006. doi:10.1083/jcb.200509067
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 173, Number 4, 571-585
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Article

Optimization of WAVE2 complex–induced actin polymerization by membrane-bound IRSp53, PIP3, and Rac



Shiro Suetsugu1,2, Shusaku Kurisu1,2, Tsukasa Oikawa1,2, Daisuke Yamazaki1,2, Atsushi Oda3, and Tadaomi Takenawa1,2

1 Department of Biochemistry, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
2 Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan
3 Laboratory of Environmental Biology, Department of Preventive Medicine, Hokkaido University School of Medicine, Kitaku, Sapporo 060-8638, Japan

Correspondence to Tadaomi Takenawa: takenawa{at}ims.u-tokyo.ac.jp

WAVE2 activates the actin-related protein (Arp) 2/3 complex for Rac-induced actin polymerization during lamellipodium formation and exists as a large WAVE2 protein complex with Sra1/PIR121, Nap1, Abi1, and HSPC300. IRSp53 binds to both Rac and Cdc42 and is proposed to link Rac to WAVE2. We found that the knockdown of IRSp53 by RNA interference decreased lamellipodium formation without a decrease in the amount of WAVE2 complex. Localization of WAVE2 at the cell periphery was retained in IRSp53 knockdown cells. Moreover, activated Cdc42 but not Rac weakened the association between WAVE2 and IRSp53. When we measured Arp2/3 activation in vitro, the WAVE2 complex isolated from the membrane fraction of cells was fully active in an IRSp53-dependent manner but WAVE2 isolated from the cytosol was not. Purified WAVE2 and purified WAVE2 complex were activated by IRSp53 in a Rac-dependent manner with PIP3-containing liposomes. Therefore, IRSp53 optimizes the activity of the WAVE2 complex in the presence of activated Rac and PIP3.

Abbreviations used in this paper: Arp, actin-related protein; CA, constitutively active; DN, dominant negative; IMD, IRSp53/missing in metastasis homology domain; IRTKS, insulin receptor tyrosine kinase substrate; MEF, mouse embryonic fibroblast; PC, phosphatidylcholine; PI, phosphatidylinositol; SH3, Src homology 3; N-WASP, neural WASP; RCB, Rac binding; WASP, Wiskott-Aldrich syndrome protein; WHD, WAVE homology domain.


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