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Integration of Multiple Signals Through Cooperative Regulation of the N-WASP-Arp2/3 Complex
Kenneth E. Prehoda,12Jessica
A. Scott,12R. Dyche Mullins,1Wendell A. Lim12*
The protein N-WASP [a homolog to the Wiskott-Aldrich
syndrome protein (WASP)] regulates actin polymerization by
stimulatingthe 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
regulationrequires N-WASP's constitutively active output domain
(VCA) andtwo regulatory domains: a Cdc42-binding domain and a
previouslyundescribed PIP2-binding domain. In the absence
of stimuli, theregulatory modules together hold the VCA-Arp2/3 complex
in aninactive "closed" conformation. In this state, both the
Cdc42-and PIP2-binding sites are masked. Binding of either
input destabilizesthe closed state and enhances binding of the other
input. Thiscooperative activation mechanism shows how combinations of
simplebinding domains can be used to integrate and amplify coincidentsignals.
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}itsa.ucsf.edu
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James Fawcett and Tony Pawson (27 October 2000) Science290 (5492), 725.
[DOI: 10.1126/science.290.5492.725] |Summary »|Full Text »
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