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J. Cell Biol. 150 (6): 1299-1310

Copyright © 2000 by the Rockefeller University Press.


Original Article

Mechanism of N-Wasp Activation by Cdc42 and Phosphatidylinositol 4,5-Bisphosphate

Rajat Rohatgia, Hsin-yi Henry Hoa, , and Marc W. Kirschnera

a Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115.(617) 432-0420(617) 432-2250

Abstract: Neuronal Wiskott-Aldrich Syndrome protein (N-WASP) transmits signals from Cdc42 to the nucleation of actin filaments by Arp2/3 complex. Although full-length N-WASP is a weak activator of Arp2/3 complex, its activity can be enhanced by upstream regulators such as Cdc42 and PI(4,5)P2. We dissected this activation reaction and found that the previously described physical interaction between the NH2-terminal domain and the COOH-terminal effector domain of N-WASP is a regulatory interaction because it can inhibit the actin nucleation activity of the effector domain by occluding the Arp2/3 binding site. This interaction between the NH2- and COOH termini must be intramolecular because in solution N-WASP is a monomer. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) influences the activity of N-WASP through a conserved basic sequence element located near the Cdc42 binding site rather than through the WASp homology domain 1. Like Cdc42, PI(4,5)P2 reduces the affinity between the NH2- and COOH termini of the molecule. The use of a mutant N-WASP molecule lacking this basic stretch allowed us to delineate a signaling pathway in Xenopus extracts leading from PI(4,5)P2 to actin nucleation through Cdc42, N-WASP, and Arp2/3 complex. In this pathway, PI(4,5)P2 serves two functions: first, as an activator of N-WASP; and second, as an indirect activator of Cdc42.

Key Words: phosphoinositides • Cdc42 GTP-binding protein • actin • signal transduction • Wiskott-Aldrich Syndrome protein



R. Rohatgi and H.H. Ho contributed equally to this study.

Abbreviations used in this paper: A, acidic region; BR, basic region; C, cofilin homology segment; CRIB, Cdc42/Rac interactive motif; G-actin, actin monomers; GBD, G-protein binding domain; G-protein, GTP binding protein; GBR, G-protein binding region; GST, glutathione S-transferase; HT, hexahistidine-tagged; HSS, high speed supernatant; MT, Myc-tagged; NMR, nuclear magnetic resonance; N-WASP, neuronal WASP; PC, phosphatidylcholine; PI, phosphatidylinositol; PI(4,5)P2, PI 4,5-bisphosphate; PRD, proline-rich domain; V, verprolin homology segment; VCA, COOH-terminal domain of WASP family proteins containing the V, C, and A segments; WASp, Wiskott-Aldrich Syndrome protein; WH1, WASp homology domain 1; WIP, WASp interacting protein.


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Genes & Dev. 19, 1-49
   Abstract »    Full Text »    PDF »
Nak1 interacts with Hob1 and Wsp1 to regulate cell growth and polarity in Schizosaccharomyces pombe.
T. Y. Huang, M. Renaud-Young, and D. Young (2005)
J. Cell Sci. 118, 199-210
   Abstract »    Full Text »    PDF »
Cortactin regulates cell migration through activation of N-WASP.
J. R. Kowalski, C. Egile, S. Gil, S. B. Snapper, R. Li, and S. M. Thomas (2005)
J. Cell Sci. 118, 79-87
   Abstract »    Full Text »    PDF »
The Small GTPase Cdc42 Regulates Actin Polymerization and Tension Development during Contractile Stimulation of Smooth Muscle.
D. D. Tang and S. J. Gunst (2004)
J. Biol. Chem. 279, 51722-51728
   Abstract »    Full Text »    PDF »
Mechanisms of WASp-mediated hematologic and immunologic disease.
S. Burns, G. O. Cory, W. Vainchenker, and A. J. Thrasher (2004)
Blood 104, 3454-3462
   Abstract »    Full Text »    PDF »
Early signaling events involved in the entry of Rickettsia conorii into mammalian cells.
J. J. Martinez and P. Cossart (2004)
J. Cell Sci. 117, 5097-5106
   Abstract »    Full Text »    PDF »
A neural-specific splicing event generates an active form of the Wiskott-Aldrich syndrome protein.
Y. Le Page, F. Demay, and G. Salbert (2004)
EMBO Rep. 5, 895-900
   Abstract »    Full Text »    PDF »
Interchangeable functions of Arabidopsis PIROGI and the human WAVE complex subunit SRA1 during leaf epidermal development.
D. Basu, S. E.-D. El-Assal, J. Le, E. L. Mallery, and D. B. Szymanski (2004)
Development 131, 4345-4355
   Abstract »    Full Text »    PDF »
The Activity of the Plexin-A1 Receptor Is Regulated by Rac.
L. J. Turner, S. Nicholls, and A. Hall (2004)
J. Biol. Chem. 279, 33199-33205
   Abstract »    Full Text »    PDF »
Cdc42, Rac1, and Rac2 Display Distinct Patterns of Activation during Phagocytosis.
A. D. Hoppe and J. A. Swanson (2004)
Mol. Biol. Cell 15, 3509-3519
   Abstract »    Full Text »    PDF »
Caenorhabditis elegans WASP and Ena/VASP Proteins Play Compensatory Roles in Morphogenesis and Neuronal Cell Migration.
J. Withee, B. Galligan, N. Hawkins, and G. Garriga (2004)
Genetics 167, 1165-1176
   Abstract »    Full Text »    PDF »
Erk/Src Phosphorylation of Cortactin Acts as a Switch On-Switch Off Mechanism That Controls Its Ability To Activate N-WASP.
N. Martinez-Quiles, H.-Y. H. Ho, M. W. Kirschner, N. Ramesh, and R. S. Geha (2004)
Mol. Cell. Biol. 24, 5269-5280
   Abstract »    Full Text »    PDF »
EHD2 and the Novel EH Domain Binding Protein EHBP1 Couple Endocytosis to the Actin Cytoskeleton.
A. Guilherme, N. A. Soriano, S. Bose, J. Holik, A. Bose, D. P. Pomerleau, P. Furcinitti, J. Leszyk, S. Corvera, and M. P. Czech (2004)
J. Biol. Chem. 279, 10593-10605
   Abstract »    Full Text »    PDF »

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