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Science 290 (5492): 801-806

Copyright © 2000 by the American Association for the Advancement of Science

Integration of Multiple Signals Through Cooperative Regulation of the N-WASP-Arp2/3 Complex

Kenneth E. Prehoda,12 Jessica A. Scott,12 R. Dyche Mullins,1 Wendell A. Lim12*

The protein N-WASP [a homolog to the Wiskott-Aldrich syndrome protein (WASP)] regulates actin polymerization by stimulating the actin-nucleating activity of the actin-related protein 2/3 (Arp2/3) complex. N-WASP is tightly regulated by multiple signals: Only costimulation by Cdc42 and phosphatidylinositol (4,5)-bisphosphate (PIP2) yields potent polymerization. We found that regulation requires N-WASP's constitutively active output domain (VCA) and two regulatory domains: a Cdc42-binding domain and a previously undescribed PIP2-binding domain. In the absence of stimuli, the regulatory modules together hold the VCA-Arp2/3 complex in an inactive "closed" conformation. In this state, both the Cdc42- and PIP2-binding sites are masked. Binding of either input destabilizes the closed state and enhances binding of the other input. This cooperative activation mechanism shows how combinations of simple binding domains can be used to integrate and amplify coincident signals.

1 Department of Cellular and Molecular Pharmacology, and
2 Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143-0450, USA.
*   To whom correspondence should be addressed. E-mail: wlim{at}

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Inhibition of Phosphatidylinositol-4-phosphate 5-Kinase Ialpha Impairs Localized Actin Remodeling and Suppresses Phagocytosis.
M. G. Coppolino, R. Dierckman, J. Loijens, R. F. Collins, M. Pouladi, J. Jongstra-Bilen, A. D. Schreiber, W. S. Trimble, R. Anderson, and S. Grinstein (2002)
J. Biol. Chem. 277, 43849-43857
   Abstract »    Full Text »    PDF »
Motility Determinants in WASP Family Proteins.
D. Yarar, J. A. D'Alessio, R. L. Jeng, and M. D. Welch (2002)
Mol. Biol. Cell 13, 4045-4059
   Abstract »    Full Text »    PDF »
Pairs of dipeptides synergistically activate the binding of substrate by ubiquitin ligase through dissociation of its autoinhibitory domain.
F. Du, F. Navarro-Garcia, Z. Xia, T. Tasaki, and A. Varshavsky (2002)
PNAS 99, 14110-14115
   Abstract »    Full Text »    PDF »
Phosphatidylinositol 4,5-Biphosphate (PIP2)-induced Vesicle Movement Depends on N-WASP and Involves Nck, WIP, and Grb2.
S. Benesch, S. Lommel, A. Steffen, T. E. B. Stradal, N. Scaplehorn, M. Way, J. Wehland, and K. Rottner (2002)
J. Biol. Chem. 277, 37771-37776
   Abstract »    Full Text »    PDF »

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