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EMBO J. Dec 1, 1998; 17(23): 6932–6941.
PMCID: PMC1171041

WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac.

Abstract

Rac is a Rho-family small GTPase that induces the formation of membrane ruffles. However, it is poorly understood how Rac-induced reorganization of the actin cytoskeleton, which is essential for ruffle formation, is regulated. Here we identify a novel Wiskott-Aldrich syndrome protein (WASP)-family protein, WASP family Verprolin-homologous protein (WAVE), as a regulator of actin reorganization downstream of Rac. Ectopically expressed WAVE induces the formation of actin filament clusters that overlap with the expressed WAVE itself. In this actin clustering, profilin, a monomeric actin-binding protein that has been suggested to be involved in actin polymerization, was shown to be essential. The expression of a dominant-active Rac mutant induces the translocation of endogenous WAVE from the cytosol to membrane ruffling areas. Furthermore, the co-expression of a deltaVPH WAVE mutant that cannot induce actin reorganization specifically suppresses the ruffle formation induced by Rac, but has no effect on Cdc42-induced actin-microspike formation, a phenomenon that is also known to be dependent on rapid actin reorganization. The deltaVPH WAVE also suppresses membrane-ruffling formation induced by platelet-derived growth factor in Swiss 3T3 cells. Taken together, we conclude that WAVE plays a critical role downstream of Rac in regulating the actin cytoskeleton required for membrane ruffling.

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Selected References

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  • Arber S, Barbayannis FA, Hanser H, Schneider C, Stanyon CA, Bernard O, Caroni P. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature. 1998 Jun 25;393(6687):805–809. [PubMed]
  • Arcaro A. The small GTP-binding protein Rac promotes the dissociation of gelsolin from actin filaments in neutrophils. J Biol Chem. 1998 Jan 9;273(2):805–813. [PubMed]
  • Aspenström P, Lindberg U, Hall A. Two GTPases, Cdc42 and Rac, bind directly to a protein implicated in the immunodeficiency disorder Wiskott-Aldrich syndrome. Curr Biol. 1996 Jan 1;6(1):70–75. [PubMed]
  • Azuma T, Witke W, Stossel TP, Hartwig JH, Kwiatkowski DJ. Gelsolin is a downstream effector of rac for fibroblast motility. EMBO J. 1998 Mar 2;17(5):1362–1370. [PMC free article] [PubMed]
  • Derry JM, Ochs HD, Francke U. Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell. 1994 Aug 26;78(4):635–644. [PubMed]
  • Hartwig JH, Bokoch GM, Carpenter CL, Janmey PA, Taylor LA, Toker A, Stossel TP. Thrombin receptor ligation and activated Rac uncap actin filament barbed ends through phosphoinositide synthesis in permeabilized human platelets. Cell. 1995 Aug 25;82(4):643–653. [PubMed]
  • Kozma R, Ahmed S, Best A, Lim L. The Ras-related protein Cdc42Hs and bradykinin promote formation of peripheral actin microspikes and filopodia in Swiss 3T3 fibroblasts. Mol Cell Biol. 1995 Apr;15(4):1942–1952. [PMC free article] [PubMed]
  • Kozma R, Sarner S, Ahmed S, Lim L. Rho family GTPases and neuronal growth cone remodelling: relationship between increased complexity induced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoA and lysophosphatidic acid. Mol Cell Biol. 1997 Mar;17(3):1201–1211. [PMC free article] [PubMed]
  • Lauffenburger DA, Horwitz AF. Cell migration: a physically integrated molecular process. Cell. 1996 Feb 9;84(3):359–369. [PubMed]
  • Lechler T, Li R. In vitro reconstitution of cortical actin assembly sites in budding yeast. J Cell Biol. 1997 Jul 14;138(1):95–103. [PMC free article] [PubMed]
  • Leeuwen FN, Kain HE, Kammen RA, Michiels F, Kranenburg OW, Collard JG. The guanine nucleotide exchange factor Tiam1 affects neuronal morphology; opposing roles for the small GTPases Rac and Rho. J Cell Biol. 1997 Nov 3;139(3):797–807. [PMC free article] [PubMed]
  • Li R. Bee1, a yeast protein with homology to Wiscott-Aldrich syndrome protein, is critical for the assembly of cortical actin cytoskeleton. J Cell Biol. 1997 Feb 10;136(3):649–658. [PMC free article] [PubMed]
  • Machesky LM, Hall A. Role of actin polymerization and adhesion to extracellular matrix in Rac- and Rho-induced cytoskeletal reorganization. J Cell Biol. 1997 Aug 25;138(4):913–926. [PMC free article] [PubMed]
  • Miki H, Takenawa T. Direct binding of the verprolin-homology domain in N-WASP to actin is essential for cytoskeletal reorganization. Biochem Biophys Res Commun. 1998 Feb 4;243(1):73–78. [PubMed]
  • Miki H, Miura K, Matuoka K, Nakata T, Hirokawa N, Orita S, Kaibuchi K, Takai Y, Takenawa T. Association of Ash/Grb-2 with dynamin through the Src homology 3 domain. J Biol Chem. 1994 Feb 25;269(8):5489–5492. [PubMed]
  • Miki H, Miura K, Takenawa T. N-WASP, a novel actin-depolymerizing protein, regulates the cortical cytoskeletal rearrangement in a PIP2-dependent manner downstream of tyrosine kinases. EMBO J. 1996 Oct 1;15(19):5326–5335. [PMC free article] [PubMed]
  • Miki H, Sasaki T, Takai Y, Takenawa T. Induction of filopodium formation by a WASP-related actin-depolymerizing protein N-WASP. Nature. 1998 Jan 1;391(6662):93–96. [PubMed]
  • Mitchison TJ, Cramer LP. Actin-based cell motility and cell locomotion. Cell. 1996 Feb 9;84(3):371–379. [PubMed]
  • Nagase T, Seki N, Ishikawa K, Ohira M, Kawarabayasi Y, Ohara O, Tanaka A, Kotani H, Miyajima N, Nomura N. Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain. DNA Res. 1996 Oct 31;3(5):321–354. [PubMed]
  • Nishida E, Maekawa S, Sakai H. Cofilin, a protein in porcine brain that binds to actin filaments and inhibits their interactions with myosin and tropomyosin. Biochemistry. 1984 Oct 23;23(22):5307–5313. [PubMed]
  • Nobes CD, Hall A. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell. 1995 Apr 7;81(1):53–62. [PubMed]
  • Pantaloni D, Carlier MF. How profilin promotes actin filament assembly in the presence of thymosin beta 4. Cell. 1993 Dec 3;75(5):1007–1014. [PubMed]
  • Rameh LE, Tolias KF, Duckworth BC, Cantley LC. A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate. Nature. 1997 Nov 13;390(6656):192–196. [PubMed]
  • Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell. 1992 Aug 7;70(3):389–399. [PubMed]
  • Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell. 1992 Aug 7;70(3):401–410. [PubMed]
  • Rosenblatt J, Mitchison TJ. Actin, cofilin and cognition. Nature. 1998 Jun 25;393(6687):739–740. [PubMed]
  • Shibasaki F, McKeon F. Calcineurin functions in Ca(2+)-activated cell death in mammalian cells. J Cell Biol. 1995 Nov;131(3):735–743. [PMC free article] [PubMed]
  • Stossel TP. On the crawling of animal cells. Science. 1993 May 21;260(5111):1086–1094. [PubMed]
  • Suetsugu S, Miki H, Takenawa T. The essential role of profilin in the assembly of actin for microspike formation. EMBO J. 1998 Nov 16;17(22):6516–6526. [PMC free article] [PubMed]
  • Suzuki T, Miki H, Takenawa T, Sasakawa C. Neural Wiskott-Aldrich syndrome protein is implicated in the actin-based motility of Shigella flexneri. EMBO J. 1998 May 15;17(10):2767–2776. [PMC free article] [PubMed]
  • Symons M, Derry JM, Karlak B, Jiang S, Lemahieu V, Mccormick F, Francke U, Abo A. Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization. Cell. 1996 Mar 8;84(5):723–734. [PubMed]
  • Theriot JA, Rosenblatt J, Portnoy DA, Goldschmidt-Clermont PJ, Mitchison TJ. Involvement of profilin in the actin-based motility of L. monocytogenes in cells and in cell-free extracts. Cell. 1994 Feb 11;76(3):505–517. [PubMed]
  • Tolias KF, Cantley LC, Carpenter CL. Rho family GTPases bind to phosphoinositide kinases. J Biol Chem. 1995 Jul 28;270(30):17656–17659. [PubMed]
  • Watanabe N, Madaule P, Reid T, Ishizaki T, Watanabe G, Kakizuka A, Saito Y, Nakao K, Jockusch BM, Narumiya S. p140mDia, a mammalian homolog of Drosophila diaphanous, is a target protein for Rho small GTPase and is a ligand for profilin. EMBO J. 1997 Jun 2;16(11):3044–3056. [PMC free article] [PubMed]
  • Yang N, Higuchi O, Ohashi K, Nagata K, Wada A, Kangawa K, Nishida E, Mizuno K. Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature. 1998 Jun 25;393(6687):809–812. [PubMed]
  • Zhao ZS, Manser E, Chen XQ, Chong C, Leung T, Lim L. A conserved negative regulatory region in alphaPAK: inhibition of PAK kinases reveals their morphological roles downstream of Cdc42 and Rac1. Mol Cell Biol. 1998 Apr;18(4):2153–2163. [PMC free article] [PubMed]
  • Bear JE, Rawls JF, Saxe CL., 3rd SCAR, a WASP-related protein, isolated as a suppressor of receptor defects in late Dictyostelium development. J Cell Biol. 1998 Sep 7;142(5):1325–1335. [PMC free article] [PubMed]

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