Regulation of Actin Polymerization by Arp2/3 Complex and WASp/Scar Proteins

guanosine 5′-3-O-(thio)triphosphate WASp homology 2 WASp homology 1 phosphatidylinositol 4,5-bisphosphate WH2 and acidic acidic polyproline, WH2, and acidic GTPase-binding domain Actin polymerization is required for many types of cell motility, such as chemotaxis, nerve growth cone movement, cell spreading, and platelet activation (reviewed in Ref. 1Mitchison T.J. Cramer L.P. Cell. 1996; 84: 371-379Abstract Full Text Full Text PDF PubMed Scopus (1310) Google Scholar). In the lamellipodia that push forward the leading edge of motile cells, polymerizing filaments form a meshwork consisting of “Y branches” with the pointed end of one filament attached to the side of another filament (2Svitkina T.M. Verkhovsky A.B. McQuade K.M. Borisy G.G. J. Cell Biol. 1997; 139: 397-415Crossref PubMed Scopus (564) Google Scholar). This meshwork presumably may provide a rigid body against which polymerization can drive membrane protrusion (3Mogilner A. Oster G. Biophys. J. 1996; 71: 3030-3045Abstract Full Text PDF PubMed Scopus (714) Google Scholar). A major unanswered question is how cells integrate signals coming through a variety of pathways to control when and where actin polymerizes. The filaments grow from a huge pool of unpolymerized actin maintained by monomer-binding proteins at a concentration approximately 1000-fold higher than required for spontaneous polymerization of actin (reviewed in Ref. 4Pollard T.D. Cooper J.A. Annu. Rev. Biochem. 1986; 55: 987-1035Crossref PubMed Google Scholar). The monomer-binding protein profilin biases the direction of filament elongation, allowing growth at the fast growing barbed end but not the slow growing pointed end (reviewed in Ref. 4Pollard T.D. Cooper J.A. Annu. Rev. Biochem. 1986; 55: 987-1035Crossref PubMed Google Scholar). In cells capping proteins block the barbed end of most filaments, so some mechanism is required to start new filaments (5Schafer D.A. Jennings P.B. Cooper J.A. J. Cell Biol. 1996; 135: 169-179Crossref PubMed Scopus (337) Google Scholar). Cells might trigger actin polymerization in three ways: 1) de novo nucleation of filaments from monomeric actin; 2) severing existing filaments to create uncapped barbed ends; and 3) uncapping existing barbed ends. There is evidence for each of these mechanisms in various cellular processes, but new filaments are often created during cell motility (6Chan A.Y. Raft S. Bailly M. Wyckoff J.B. Segall J.E. Condeelis J.S. J. Cell Sci. 1998; 111: 199-211Crossref PubMed Google Scholar), placing emphasis on mechanisms 1 and 2. Although activation of de novo nucleation by cell stimulation has long been an attractive model (7Carson M. Weber A. Zigmond S.H. J. Cell Biol. 1986; 103: 2707-2714Crossref PubMed Scopus (61) Google Scholar), no barbed end nucleating factors were known until it was discovered that Arp2/3 complex promotes actin nucleation, creating filaments that grow at their barbed ends (8Mullins R.D. Heuser J.A. Pollard T.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6181-6186Crossref PubMed Scopus (1046) Google Scholar). Because nucleation is rate-limiting in actin polymerization and strongly suppressed by monomer-binding proteins, Arp2/3 complex may be a key mediator of actin polymerization in cells. Arp2/3 complex also cross-links actin filaments end-to-side, indistinguishable from the Y branches at the leading edge (8Mullins R.D. Heuser J.A. Pollard T.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6181-6186Crossref PubMed Scopus (1046) Google Scholar). Based on these biochemical activities, Mullins et al. (8Mullins R.D. Heuser J.A. Pollard T.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6181-6186Crossref PubMed Scopus (1046) Google Scholar) proposed the dendritic nucleation model, whereby Arp2/3 complex both creates new filaments and cross-links them into a branching meshwork. Cellular observations support this model. Arp2/3 complex is concentrated at the leading edge of motile cells (9Kelleher J.F. Atkinson S.J. Pollard T.D. J. Cell Biol. 1995; 131: 385-397Crossref PubMed Scopus (163) Google Scholar, 10Machesky L.M. Reeves E. Wientjes F. Mattheyse F.J. Grogan A. Totty N.F. Burlingame A.L. Hsuan J.J. Segal A.W. Biochem. J. 1997; 328: 105-112Crossref PubMed Scopus (178) Google Scholar, 11Schafer D.A. Welch M.D. Machesky L.M. Bridgman P.C. Meyer S.M. Cooper J.A. J. Cell Biol. 1998; 143: 1919-1930Crossref PubMed Scopus (152) Google Scholar, 12Bailly M. Macaluso F. Cammer M. Chan A. Segall J.E. Condeelis J.S. J. Cell Biol. 1999; 145: 331-345Crossref PubMed Scopus (175) Google Scholar, 13Svitkina T.M. Borisy G.G. J. Cell Biol. 1999; 145: 1009-1026Crossref PubMed Scopus (914) Google Scholar), specifically at the junctions of the Y branches (12Bailly M. Macaluso F. Cammer M. Chan A. Segall J.E. Condeelis J.S. J. Cell Biol. 1999; 145: 331-345Crossref PubMed Scopus (175) Google Scholar, 13Svitkina T.M. Borisy G.G. J. Cell Biol. 1999; 145: 1009-1026Crossref PubMed Scopus (914) Google Scholar). It exists in all eukaryotes examined, and ablation of Arp2/3 complex subunits inSaccharomyces cerevisiae and Schizosaccharomyces pombe is lethal or severely debilitating (14Schwob E. Martin R.P. Nature. 1992; 355: 179-182Crossref PubMed Scopus (98) Google Scholar, 15Lees-Miller J.P. Henry G. Helfman D.M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 80-83Crossref PubMed Scopus (75) Google Scholar, 16Balasubramanian M.K. Feoktistova A. McCollum D. Gould K.L. EMBO J. 1996; 15: 6426-6437Crossref PubMed Scopus (76) Google Scholar, 17McCollum D. Feoktistova A. Morphew M. Balasubramanian M. Gould K.L. EMBO J. 1996; 15: 6438-6446Crossref PubMed Scopus (114) Google Scholar, 18Moreau V. Madania A. Martin R.P. Winsor B. J. Cell Biol. 1996; 134: 117-132Crossref PubMed Scopus (111) Google Scholar, 19Moreau V. Galan J.M. Devilliers G. Haguenauer-Tsapis R. Winsor B. Mol. Biol. 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EMBO J. 1998; 17: 3797-3806Crossref PubMed Scopus (249) Google Scholar). This work suggested that cellular factors might activate Arp2/3 complex to nucleate actin. This year WASp/Scar proteins were identified as the first example of such factors (24Machesky L.M. Insall R.H. Curr. Biol. 1998; 8: 1347-1356Abstract Full Text Full Text PDF PubMed Scopus (756) Google Scholar, 25Machesky L.M. Mullins D.M. Higgs H.N. Kaiser D.A. Blanchoin L. May R.C. Hall M.E. Pollard T.D. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3739-3744Crossref PubMed Scopus (617) Google Scholar, 26Rohatgi R. Ma L. Miki H. Lopez M. Kirchhausen T. Takenawa T. Kirschner M.W. Cell. 1999; 97: 221-231Abstract Full Text Full Text PDF PubMed Scopus (1082) Google Scholar, 27Winter D. Lechler T. Li R. Curr. Biol. 1999; 9: 501-504Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 28Yarar D. To W. Abo A. Welch M.D. Curr. Biol. 1999; 9: 555-558Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). These proteins also interact with a variety of cell signaling molecules known to influence cytoskeletal dynamics, bringing us closer to forging a connection between surface receptor stimulation and actin polymerization. The rapid progress reviewed here depended upon groundwork from many laboratories. Analysis of Wiskott-Aldrich syndrome protein (WASp) and its neural homolog N-WASP revealed a binding site for Rho family GTPases and other domains that affect actin assembly in cells (29Ochs H.D. Semin. Hematol. 1998; 35: 332-345PubMed Google Scholar, 30Miki H. Miura K. Takenawa T. EMBO J. 1996; 15: 5326-5335Crossref PubMed Scopus (556) Google Scholar). Study of GTPγS1-stimulated actin polymerization in extracts of vertebrate cells (31Ma L. Cantley L.C. Janmey P.A. Kirschner M.W. J. Cell Biol. 1998; 140: 1125-1136Crossref PubMed Scopus (168) Google Scholar, 32Ma L. Rohatgi R. Kirschner M.W. Proc. Natl. Acad. Sci. U. S. 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Biol. 1997; 7: 519-529Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, T. Li R. J. Cell Biol. 1997; 138: PubMed Scopus Google Scholar, R. J. Cell Biol. 1997; PubMed Scopus Google Scholar). The Arp2/3 complex one of each of strongly protein subunits reviewed in in Ref. R.D. Pollard T.D. Curr. Biol. 1999; 9: PubMed Scopus Google Scholar). and are The other subunits are The complex is approximately 2 in the cytoplasm (9Kelleher J.F. Atkinson S.J. Pollard T.D. J. Cell Biol. 1995; 131: 385-397Crossref PubMed Scopus (163) Google Scholar). Analysis of of and first to the that form a that the pointed end of actin filaments and growth in the barbed direction (9Kelleher J.F. Atkinson S.J. Pollard T.D. J. Cell Biol. 1995; 131: 385-397Crossref PubMed Scopus (163) Google Scholar). that the complex the pointed end with and has nucleation (8Mullins R.D. Heuser J.A. Pollard T.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6181-6186Crossref PubMed Scopus (1046) Google Scholar). 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WASp/Scar proteins activate nucleation of actin filaments by Arp2/3 complex To the mechanism one first how actin by by actin is of the of actin and on the to filaments (reviewed in T.D. Cooper J.A. Annu. Rev. Biochem. 1986; 55: 987-1035Crossref PubMed Google Scholar). nucleation for the at the of spontaneous polymerization. the form but the of polymerization is the concentration of these is a of of rapid to and the of actin to form a The of filaments during the by nucleation but also by into in the end to end a of filament ends. in the the concentration of filament barbed ends can be from the polymerization Arp2/3 complex promotes polymerization, but the is (8Mullins R.D. Heuser J.A. Pollard T.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6181-6186Crossref PubMed Scopus (1046) Google Scholar). The are by a model where the complex actin which grow into filaments by of actin subunits at the barbed The model for the by the concentration of and by of of from the complex a The with of Arp2/3 of of WASp/Scar proteins to Arp2/3 complex but not the in polymerization also the of filament as by the in of the polymerization of actin filaments with Arp2/3 complex and WASp/Scar the This that the dendritic nucleation model is of Arp2/3 complex with the side of an existing filament its nucleation of a new This the in experiments with and work in that the with Arp2/3 complex and WASp is to the of filaments by spontaneous polymerization, with a of actin in filaments to activate Arp2/3 complex and L. and T. D. for The of is Arp2/3 complex both the of actin filaments and WASp/Scar so it filaments or with and actin The WH2 and A of are required to stimulate nucleation by Arp2/3 complex L.M. Mullins D.M. Higgs H.N. Kaiser D.A. Blanchoin L. May R.C. Hall M.E. Pollard T.D. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3739-3744Crossref PubMed Scopus (617) Google Scholar). The domain may one or in the but is not required in the or of The A of with the (24Machesky L.M. Insall R.H. Curr. Biol. 1998; 8: 1347-1356Abstract Full Text Full Text PDF PubMed Scopus (756) Google Scholar) but not activate nucleation L.M. Mullins D.M. Higgs H.N. Kaiser D.A. Blanchoin L. May R.C. Hall M.E. Pollard T.D. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3739-3744Crossref PubMed Scopus (617) Google Scholar). The A of N-WASP and WASp are also for Arp2/3 complex activation R. Ma L. Miki H. Lopez M. Kirchhausen T. Takenawa T. Kirschner M.W. Cell. 1999; 97: 221-231Abstract Full Text Full Text PDF PubMed Scopus (1082) Google Scholar). Higgs and T. D. the other the A an of yeast Bee1p to activate nucleation by yeast Arp2/3 complex D. Lechler T. Li R. Curr. Biol. 1999; 9: 501-504Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). Although the of these Bee1p may activate yeast Arp2/3 complex in a than other WASp/Scar of this is to the WASp/Scar and the of actin binding by WASp/Scar proteins in of evidence that Arp2/3 complex a major but not other most of the actin polymerization in cell extracts on Arp2/3 complex L. Rohatgi R. Kirschner M.W. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15362-15367Crossref PubMed Scopus (154) Google Scholar, R.D. Pollard T.D. Curr. Biol. 1999; 9: 405-415Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar), as actin in yeast D. Podtelejnikov A.V. Mann M. Li R. Curr. Biol. 1997; 7: 519-529Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar). most of the filaments at the leading edge of and are into branching with Arp2/3 complex at the branches T.M. Borisy G.G. J. Cell Biol. 1999; 145: 1009-1026Crossref PubMed Scopus (914) Google Scholar). The of Arp2/3 complex for both the pointed end and side of actin filaments the complex to form these (8Mullins R.D. Heuser J.A. Pollard T.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6181-6186Crossref PubMed Scopus (1046) Google Scholar, R.D. J.F. J. Pollard T.D. Mol. Biol. Cell. 1998; 9: PubMed Scopus (75) Google Scholar). WASp/Scar proteins are not required for branching by Arp2/3 complex but may or both the other experiments with yeast is for are and the may on the of the D.C. Choe E.Y. Li R. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 7288-7293Crossref PubMed Scopus (165) Google Scholar). A variety of cellular actin polymerization, through receptor protein and but an attractive (24Machesky L.M. Insall R.H. Curr. Biol. 1998; 8: 1347-1356Abstract Full Text Full Text PDF PubMed Scopus (756) Google Scholar) is that signals from of and signaling pathways on of WASp/Scar proteins, which these signals through Arp2/3 complex as a to actin filament of these signals in affect the of Arp2/3 complex or its in cells. The only demonstrated for WASp/Scar protein are Cdc42 and activate N-WASP and Arp2/3 complex to nucleate actin filaments in vitro R. Ma L. Miki H. Lopez M. Kirchhausen T. Takenawa T. Kirschner M.W. Cell. 1999; 97: 221-231Abstract Full Text Full Text PDF PubMed Scopus (1082) Google Scholar). of Cdc42 and in WASp/Scar not the and can all influence these signaling molecules A. Science. 1998; PubMed Scopus Google Scholar, L. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). and are other of WASp/Scar proteins Cdc42 and receptor might most not all of these These proteins in the as Cdc42 and WASp and N-WASP to activate Arp2/3 but might other such as WASp and N-WASP to of a effect of WASp by or is The of is the between and receptor in a for and the of proteins for WASp/Scar proteins, may actin filament nucleation by Arp2/3 the of ActA a for other protein of Arp2/3 complex subunits also to be with of in L.M. Reeves E. Wientjes F. Mattheyse F.J. Grogan A. Totty N.F. Burlingame A.L. Hsuan J.J. Segal A.W. Biochem. J. 1997; 328: 105-112Crossref PubMed Scopus (178) Google Scholar, M.D. S. A. Mitchison T.J. J. Cell Biol. 1997; 138: PubMed Scopus Google Scholar). It is not how WASp/Scar proteins and Arp2/3 complex interact with at the leading Because the nucleation often from a surface receptor and many of the molecules that activate WASp/Scar proteins are to or may activate Arp2/3 complex on the membrane R. Ma L. Miki H. Lopez M. Kirchhausen T. Takenawa T. Kirschner M.W. Cell. 1999; 97: 221-231Abstract Full Text Full Text PDF PubMed Scopus (1082) Google Scholar). Arp2/3 complex is concentrated in the actin filament than on (9Kelleher J.F. Atkinson S.J. Pollard T.D. J. Cell Biol. 1995; 131: 385-397Crossref PubMed Scopus (163) Google Scholar, 10Machesky L.M. Reeves E. Wientjes F. Mattheyse F.J. Grogan A. Totty N.F. Burlingame A.L. Hsuan J.J. Segal A.W. Biochem. J. 1997; 328: 105-112Crossref PubMed Scopus (178) Google Scholar, 12Bailly M. Macaluso F. 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