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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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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
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Cascade pathway of filopodia formation downstream of SCAR.
A. Biyasheva, T. Svitkina, P. Kunda, B. Baum, and G. Borisy (2004)
J. Cell Sci. 117, 837-848
   Abstract »    Full Text »    PDF »
Regulated Exocytosis in Neuroendocrine Cells: A Role for Subplasmalemmal Cdc42/N-WASP-induced Actin Filaments.
S. Gasman, S. Chasserot-Golaz, M. Malacombe, M. Way, and M.-F. Bader (2004)
Mol. Biol. Cell 15, 520-531
   Abstract »    Full Text »    PDF »
Visualization of spatially and temporally regulated N-WASP activity during cytoskeletal reorganization in living cells.
M. E. Ward, J. Y. Wu, and Y. Rao (2004)
PNAS 101, 970-974
   Abstract »    Full Text »    PDF »
Tuba, a Novel Protein Containing Bin/Amphiphysin/Rvs and Dbl Homology Domains, Links Dynamin to Regulation of the Actin Cytoskeleton.
M. A. Salazar, A. V. Kwiatkowski, L. Pellegrini, G. Cestra, M. H. Butler, K. L. Rossman, D. M. Serna, J. Sondek, F. B. Gertler, and P. De Camilli (2003)
J. Biol. Chem. 278, 49031-49043
   Abstract »    Full Text »    PDF »
Translocation of N-WASP by Nuclear Localization and Export Signals into the Nucleus Modulates Expression of HSP90.
S. Suetsugu and T. Takenawa (2003)
J. Biol. Chem. 278, 42515-42523
   Abstract »    Full Text »    PDF »
Reprogramming Control of an Allosteric Signaling Switch Through Modular Recombination.
J. E. Dueber, B. J. Yeh, K. Chak, and W. A. Lim (2003)
Science 301, 1904-1908
   Abstract »    Full Text »    PDF »
Regulation of Actin Dynamics by WASP Family Proteins.
H. Miki and T. Takenawa (2003)
J. Biochem. 134, 309-313
   Abstract »    Full Text »    PDF »
Arf6 and Phosphoinositol-4-Phosphate-5-Kinase Activities Permit Bypass of the Rac1 Requirement for {beta}1 Integrin-mediated Bacterial Uptake.
K.-W. Wong and R. R. Isberg (2003)
J. Exp. Med. 198, 603-614
   Abstract »    Full Text »    PDF »
WIP participates in actin reorganization and ruffle formation induced by PDGF.
I. M. Anton, S. P. Saville, M. J. Byrne, C. Curcio, N. Ramesh, J. H. Hartwig, and R. S. Geha (2003)
J. Cell Sci. 116, 2443-2451
   Abstract »    Full Text »    PDF »
Membrane Ruffling Requires Coordination between Type I{alpha} Phosphatidylinositol Phosphate Kinase and Rac Signaling.
R. L. Doughman, A. J. Firestone, M. L. Wojtasiak, M. W. Bunce, and R. A. Anderson (2003)
J. Biol. Chem. 278, 23036-23045
   Abstract »    Full Text »    PDF »
Gene therapy for Wiskott-Aldrich syndrome: rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice.
C. Klein, D. Nguyen, C.-H. Liu, A. Mizoguchi, A. K. Bhan, H. Miki, T. Takenawa, F. S. Rosen, F. W. Alt, R. C. Mulligan, et al. (2003)
Blood 101, 2159-2166
   Abstract »    Full Text »    PDF »

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