Gelsolin, a Multifunctional Actin Regulatory Protein

polyphosphoinositide 4,5-bisphosphate phosphatidylinositol 5-kinase The actin cytoskeleton is an essential scaffold for integrating membrane and intracellular functions. It is very dynamic and is remodeled in response to a variety of signals. Growth factor stimulation promotes actin assembly at the plasma membrane to generate movement, whereas apoptotic signals cause cytoskeletal destruction to elicit characteristic membrane blebbing and morphological changes. Gelsolin is a Ca2+- and polyphosphoinositide 4,5-bisphosphate (PIP2)1-regulated actin filament severing and capping protein that is implicated in actin remodeling in growing and in apoptotic cells (reviewed in Refs. 1Liu Y.T. Rozelle A.L. Yin H.L. Maruta H. Kohama K. G Proteins, Cytoskeleton and Cancer. R. G. Landes Company, Austin, TX1998: 19-35Google Scholar and2Kwiatkowski D.J. Curr. Opin. Cell Biol. 1999; 11: 103-108Crossref PubMed Scopus (326) Google Scholar). This review summarizes data supporting the role of gelsolin in cytoskeletal remodeling and phosphoinositide signaling and discusses the structural basis for the Ca2+ and PIP2regulation of severing and capping by gelsolin. Gelsolin is the most potent actin filament severing protein identified to date. Severing is the weakening of enough non-covalent bonds between actin molecules within a filament to break the filament in two. Gelsolin severs stoichiometrically and with close to 100% efficiency (3Selden L.A. Kinosian H.J. Newman J. Lincoln B. Hurwitz C. Gershman L.C. Estes J.E. Biophys. J. 1998; 75: 3101-3109Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). Severing is initiated after gelsolin binds to the side of an actin filament. Gelsolin binds filaments rapidly but severs slowly (3Selden L.A. Kinosian H.J. Newman J. Lincoln B. Hurwitz C. Gershman L.C. Estes J.E. Biophys. J. 1998; 75: 3101-3109Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar); the delay may reflect the time required for structural rearrangement within gelsolin (see "Structural Basis for Ca2+ Regulation") and in the filament (4McGough A. Chiu W. Way M. Biophys. J. 1998; 74: 764-772Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar) prior to severing. Gelsolin changes actin conformation and kinks the actin filament (4McGough A. Chiu W. Way M. Biophys. J. 1998; 74: 764-772Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar), suggesting a mechanical basis for severing. After severing, gelsolin remains attached to the barbed end of the filament as a cap. As a result, short actin filaments that cannot reanneal with each other or elongate at their barbed ends are generated. In this way, the actin network is disassembled. The importance of Ca2+-mediated actin severing has been clearly documented during platelet activation (5Hartwig J.H. J. Cell Biol. 1992; 118: 1421-1442Crossref PubMed Scopus (336) Google Scholar), and gelsolin is the only known Ca2+-dependent severing protein identified to date. Gelsolin severing can also have a constructive effect because it increases the number of filaments. Uncapping of gelsolin from these filaments generates many polymerization-competent ends from which actin can grow to rebuild the cytoskeleton to new specifications. Therefore, gelsolin can promote actin polymerization by severing followed by uncapping (mechanism B, as discussed in the Prologue (74Yin H.L. Stull J.T. J. Biol. Chem. 1999; 274: 32529-32530Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar) of this series). Cells from gelsolin null mice exhibit a variety of motility and actin defects. Gelsolin null fibroblasts have pronounced actin stress fibers (6Witke W. Sharpe A.H. Hartwig J.H. Azuma T. Stossel T.P. Kwiatkowski D.J. Cell. 1995; 81: 41-51Abstract Full Text PDF PubMed Scopus (379) Google Scholar), and this phenotype is consistent with an inability to sever and remodel actin filaments. They do not ruffle in response to growth factor (7Azuma T. Witke W. Stossel T.P. Hartwig J.H. Kwiatkowski D.J. EMBO J. 1998; 17: 1362-1370Crossref PubMed Scopus (235) Google Scholar), and they exhibit defective chemotaxis and wound healing. The rate of clotting is reduced (6Witke W. Sharpe A.H. Hartwig J.H. Azuma T. Stossel T.P. Kwiatkowski D.J. Cell. 1995; 81: 41-51Abstract Full Text PDF PubMed Scopus (379) Google Scholar), as would be consistent with the requirement of actin severing for platelet activation (5Hartwig J.H. J. Cell Biol. 1992; 118: 1421-1442Crossref PubMed Scopus (336) Google Scholar). Neurite retraction is defective (8Lu M. Witke W. Kwiatkowski D.J. Kosik K.S. J. Cell Biol. 1997; 138: 1279-1287Crossref PubMed Scopus (118) Google Scholar), and neurons are more susceptible to glutamate-induced excito-toxicity (9Endres M. Fink K. Zhu J. Stagliano N.E. Bondala V. Geddes J.W. Azuma T. Mattson M.P. Kwiatkowski D.J. Moscowitz M.A. J. Clin. Invest. 1999; 10: 161-178Google Scholar). Neutrophil extravasation is compromised (6Witke W. Sharpe A.H. Hartwig J.H. Azuma T. Stossel T.P. Kwiatkowski D.J. Cell. 1995; 81: 41-51Abstract Full Text PDF PubMed Scopus (379) Google Scholar). These findings establish the importance of gelsolin in maintaining motility and actin dynamics. Despite multiple cellular pathology, the null animals (in a mixed strain background) are without gross phenotypic defects. This may reflect the existence of potent compensatory mechanisms. However, the compensation is incomplete and varies with the genetic background of the knockout animals. Gelsolin null animals in a pure strain mouse background are non-viable at perinatal and early postnatal stages (2Kwiatkowski D.J. Curr. Opin. Cell Biol. 1999; 11: 103-108Crossref PubMed Scopus (326) Google Scholar), indicating that gelsolin is necessary for survival. Membrane ruffling is a functional readout for a coordinated series of membrane and cytoskeletal events, and it is activated by the small GTPase, Rac. Gelsolin null fibroblasts have increased Rac expression (7Azuma T. Witke W. Stossel T.P. Hartwig J.H. Kwiatkowski D.J. EMBO J. 1998; 17: 1362-1370Crossref PubMed Scopus (235) Google Scholar), and Rac·GTP dissociates gelsolin-actin complexes (equivalent to uncapping) in cell extracts but not purified gelsolin-actin complexes (10Arcaro A. J. Biol. Chem. 1998; 273: 805-813Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). These results suggest that gelsolin is a downstream effector of Rac, but there are additional steps between Rac and gelsolin activation/inactivation. A number of studies suggest that linkage through the type I phosphatidylinositol 5-kinases (PIP5KIs), the major enzymes that synthesize PIP2 (reviewed in Refs. 11Fruman D.A. Meyers R.E. Cantley L.C. Annu. Rev. Biochem. 1998; 67: 481-507Crossref PubMed Scopus (1319) Google Scholar and 12Anderson R.A. Boronenkov I.V. Doughman S.D. Kunz J. Loijens J.C. J. Biol. Chem. 1999; 274: 9907-9910Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar), is an attractive possibility. PIP5KIs coimmunoprecipitate with Rac (13Tolias K.F. Cantley L.C. Carpenter C.L. J. Biol. Chem. 1995; 270: 17656-17659Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar) and also Rho (14Chong L.D. Traynor-Kaplan A. Bokoch G.M. Schwartz M.A. Cell. 1994; 79: 507-513Abstract Full Text PDF PubMed Scopus (594) Google Scholar), a small GTPase that promotes stress fiber formation. PIP5KIs may thus be incorporated into signaling complexes that are targeted to the plasma membrane through Rac·GTP or Rho·GTP. This increases the local concentration of PIP2 in membrane microdomains to selectively activate downstream cascades (reviewed in Refs. 12Anderson R.A. Boronenkov I.V. Doughman S.D. Kunz J. Loijens J.C. J. Biol. Chem. 1999; 274: 9907-9910Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar and15Toker A. Curr. Opin. Cell Biol. 1998; 10: 254-261Crossref PubMed Scopus (245) Google Scholar). PIP2 has a pivotal role in the phosphoinositide cycle that drives signaling, cytoskeletal organization, and membrane trafficking (reviewed in Ref. 15Toker A. Curr. Opin. Cell Biol. 1998; 10: 254-261Crossref PubMed Scopus (245) Google Scholar). Numerous cytoskeletal proteins are affected by PIP2 in vitro. They include gelsolin family proteins (16Janmey P.A. Stossel T.P. Nature. 1987; 325: 362-364Crossref PubMed Scopus (496) Google Scholar), profilin (17Lassing I. Lindberg U. Nature. 1985; 314: 472-474Crossref PubMed Scopus (639) Google Scholar), capping protein (18Schafer D.A. Jennings P.B. Cooper J.A. J. Cell Biol. 1996; 135: 169-179Crossref PubMed Scopus (337) Google Scholar), ADF/cofilin (19Yonezawa N. Nishida E. Iida K. Yahara I. Sakai H. J. Biol. Chem. 1990; 265: 8382-8386Abstract Full Text PDF PubMed Google Scholar), α-actinin (20Fukami K. Furuhashi K. Inagaki M. Endo T. Hatano S. Takenawa T. Nature. 1992; 359: 150-152Crossref PubMed Scopus (304) Google Scholar), vinculin (21Gilmore A.P. Burridge K. Nature. 1996; 381: 531-535Crossref PubMed Scopus (457) Google Scholar), ezrin/radixin/moesin (22Hirao M. Sato N. Kondo T. Yonemura S. Monden M. Sasaki T. Takai Y. Tsukita S. J. Cell Biol. 1996; 135: 37-51Crossref PubMed Scopus (511) Google Scholar), and WASp family proteins (23Miki H. Miura K. Takenawa T. EMBO J. 1996; 15: 5326-5335Crossref PubMed Scopus (555) Google Scholar). The latter four proteins are activated by PIP2, whereas the first four are inactivated by PIP2. Ezrin/radixin/moesin, ADF/cofilin, and WASp are reviewed in this series (24Higgs H.N. Pollard T.D. J. Biol. Chem. 1999; 274: 32531-32534Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 25Tsukita S. Yonemura S. J. Biol. Chem. 1999; 274: 34507-34510Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, 26Carlier M.-F. Ressad F. Pantaloni D. J. Biol. Chem. 1999; 274: 33827-33830Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar). The challenge will be to identify cytoskeletal proteins that are physiologically regulated by PIP2 and determine how they are differentially regulated. PIP2 involvement in cytoskeletal regulation is supported by experiments that manipulate PIP2 content in intact cells and in cell-free models. Microinjection of a monoclonal antibody to PIP2 prevents stress fiber and focal adhesion formation (21Gilmore A.P. Burridge K. Nature. 1996; 381: 531-535Crossref PubMed Scopus (457) Google Scholar). PIP5KI overexpression induces the formation of short actin bundles (27Shibasaki Y. Ishihara H. Kizuki N. Asano T. Oka Y. Yazaki Y. J. Biol. Chem. 1997; 272: 7578-7581Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar) and increases the movement of dynamic actin spots containing a number of actin regulatory proteins (28Schafer 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). In contrast, overexpression of synaptojanin, the inositol polyphosphate 5-phosphatase that dephosphorylates PIP2, reduces actin stress fibers (29Sakisaka T. Itoh T. Miura K. Takenawa T. Mol. Cell. Biol. 1997; 17: 3841-3849Crossref PubMed Scopus (147) Google Scholar). Moreover, Hartwig et al. (30Hartwig J.H. Bokoch G.M. Carpenter C.L. Janmey P.A. Taylor L.A. Toker A. Stossel T.P. Cell. 1995; 82: 643-653Abstract Full Text PDF PubMed Scopus (613) Google Scholar) were able to reconstitute the entire pathway between thrombin stimulation, Rac activation, PIP2 synthesis, and barbed end nucleated actin assembly in permeabilized platelets. However, in neutrophils and other systems, the relation is less clear. Although Rac·GTP dissociates gelsolin-actin complexes (10Arcaro A. J. Biol. Chem. 1998; 273: 805-813Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar) and stimulates PIP2synthesis, it does not promote actin assembly in lysates (31Zigmond S.H. Joyce M. Borleis J. Bokoch G.M. Devreotes P.N. J. Cell Biol. 1997; 138: 363-374Crossref PubMed Scopus (145) Google Scholar). Instead, Cdc42, which stimulates filopodia formation in cells, promotes de novo actin assembly in vitro, in a PIP2-dependent manner that is mediated through WASp and the Arp2/3 complex (32Rohatgi 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 (1076) Google Scholar). The range of responses and the contradictory effects of small GTPases and PIP2 on nucleated actin assembly in vivo andin vitro and in different types of cells may be reconciled by postulating that there are multiple pathways for actin assembly. Plasma membrane lysis may disrupt the critical coupling between Rac and actin polymerization much more than that between Cdc42 and actin. Gelsolin overexpression increases membrane ruffling and chemotaxis (33Cunningham C.C. Stossel T.P. Kwiatkowski D.J. Science. 1991; 251: 1233-1236Crossref PubMed Scopus (259) Google Scholar, 34Sun H.-Q. Lin K.-M. Yin H.L. J. Cell Biol. 1997; 138: 811-820Crossref PubMed Scopus (84) Google Scholar), consistent with the role of gelsolin in dynamic actin remodeling. Surprisingly, CapG, a gelsolin relative that caps but does not sever actin, and the completely unrelated capping protein also increase cell motility when overexpressed (35Sun H.-Q. Kwiatkowska K. Wooten D.C. Yin H.L. J. Cell Biol. 1995; 129: 147-156Crossref PubMed Scopus (94) Google Scholar, 36Hug C. Jay P.Y. Reddy I. McNally J.G. Bridgman P.C. Elson E.L. Cooper J.A. Cell. 1995; 81: 591-600Abstract Full Text PDF PubMed Scopus (146) Google Scholar). A priori, pure capping proteins are expected to be less effective in promoting actin dynamics than severing/capping proteins, because they do not increase the number of actin filaments per se(compare mechanisms B (severing and uncapping) and C (uncapping only) in the Prologue to this minireview series (74Yin H.L. Stull J.T. J. Biol. Chem. 1999; 274: 32529-32530Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar)). These results indicate that capping/uncapping may be sufficient to increase actin dynamics. More detailed study will be required to distinguish between the contributions of severing and capping. Overexpression studies reveal that gelsolin may have other roles in addition to direct cytoskeletal regulation. Overexpressed gelsolin (34Sun H.-Q. Lin K.-M. Yin H.L. J. Cell Biol. 1997; 138: 811-820Crossref PubMed Scopus (84) Google Scholar) and CapG (35Sun H.-Q. Kwiatkowska K. Wooten D.C. Yin H.L. J. Cell Biol. 1995; 129: 147-156Crossref PubMed Scopus (94) Google Scholar) modulate phospholipase Cγ and phospholipase Cβ activity in a biphasic manner both in vivo and in vitro. These effects depend on PIP2 binding (34Sun H.-Q. Lin K.-M. Yin H.L. J. Cell Biol. 1997; 138: 811-820Crossref PubMed Scopus (84) Google Scholar), suggesting that gelsolin enhances or competes with other PIP2-binding proteins for their common substrate. This potent effect may be achieved by altering the packing of PIP2 molecules within the membrane bilayer (37Flanagan L.A. Cunningham C.C. Chen J. Prestwich G.D. Kosik K.S. Janmey P.A. Biophys. J. 1997; 73: 1440-1447Abstract Full Text PDF PubMed Scopus (75) Google Scholar). In conclusion, these results suggest that as PIP2 content and availability change during signaling, cross-talk between PIP2-regulated proteins provides a selective mechanism for positive as well as negative regulation of phosphoinositide signaling. This is particularly relevant as more PIP2-regulated proteins are identified. Gelsolin coimmunoprecipitates with several PIP2-interacting proteins, and it alters the activity of phosphatidylinositol 3-kinase and phospholipase D as well (reviewed in Refs. 1Liu Y.T. Rozelle A.L. Yin H.L. Maruta H. Kohama K. G Proteins, Cytoskeleton and Cancer. R. G. Landes Company, Austin, TX1998: 19-35Google Scholar and 2Kwiatkowski D.J. Curr. Opin. Cell Biol. 1999; 11: 103-108Crossref PubMed Scopus (326) Google Scholar). Gelsolin is phosphorylated by c-Src in vitro, and phosphorylation is enhanced by PIP2 (38De Corte V. Gettesmans J. Vandekerckhove J. FEBS Lett. 1997; 401: 191-196Crossref PubMed Scopus (74) Google Scholar). The physiological significance of these associations and phosphorylation has not been determined. Gelsolin is a substrate for caspase-3 (39Kothakota S. Azuma T. Reinhard C. Klippel A. Tang J. Chu K. McGarry T.J. Kirschner M.W. Koths K. Kwiatkowski D.J. Williams L.T. Science. 1997; 278: 294-298Crossref PubMed Scopus (1040) Google Scholar, 40Kamada S. Kusano H. Fujita H. Ohtsu M. Koya R.C. Kuzumaki N. Tsujimoto Y. Proc. Natl. U. S. A. 1998; PubMed Scopus Google Scholar), the effector in both the and apoptotic Gelsolin by caspase-3 Ca2+ to sever actin filaments (see also "Structural Basis for Ca2+ and it the membrane cytoskeleton to cause a of Overexpression of the severing induces whereas gelsolin null neutrophils have a of (39Kothakota S. Azuma T. Reinhard C. Klippel A. Tang J. Chu K. McGarry T.J. Kirschner M.W. Koths K. Kwiatkowski D.J. Williams L.T. Science. 1997; 278: 294-298Crossref PubMed Scopus (1040) Google Scholar). These findings the importance of gelsolin severing to the of the cell and to selectively activate gelsolin The role of gelsolin is supported by the that most cells have reduced have gelsolin expression Y. H.L. D. M. R. J. Cancer. 1999; 81: PubMed Scopus Google Scholar) (reviewed in Ref. 2Kwiatkowski D.J. Curr. Opin. Cell Biol. 1999; 11: 103-108Crossref PubMed Scopus (326) Google Scholar). gelsolin of a that is more to PIP2, H. Janmey P.A. Kwiatkowski D.J. Stossel T.P. Y. Y. L. A. Kuzumaki N. J. Biochem. 1995; PubMed Google Scholar). other data do not into this that gelsolin overexpression (39Kothakota S. Azuma T. Reinhard C. Klippel A. Tang J. Chu K. McGarry T.J. Kirschner M.W. Koths K. Kwiatkowski D.J. Williams L.T. Science. 1997; 278: 294-298Crossref PubMed Scopus (1040) Google Scholar). The relation between and a complex between the multiple effector of gelsolin. The structural basis for gelsolin regulation by to be Gelsolin has each of which a and Stossel T.P. S.H. J.E. Yin H.L. Nature. PubMed Scopus Google Scholar, L.D. J. R.C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) The and are by a which is by caspase-3 (39Kothakota S. Azuma T. Reinhard C. Klippel A. Tang J. Chu K. McGarry T.J. Kirschner M.W. Koths K. Kwiatkowski D.J. Williams L.T. Science. 1997; 278: 294-298Crossref PubMed Scopus (1040) Google Scholar, 40Kamada S. Kusano H. Fujita H. Ohtsu M. Koya R.C. Kuzumaki N. Tsujimoto Y. Proc. Natl. U. S. A. 1998; PubMed Scopus Google vivo and in vitro, and by many other vitro. The binds a actin only when Ca2+ is M. and H. L. for The binds actin molecules to sever and in the of severing by gelsolin the as a regulatory to severing by the In the severing by the through binding to the filament (3Selden L.A. Kinosian H.J. Newman J. Lincoln B. Hurwitz C. Gershman L.C. Estes J.E. Biophys. J. 1998; 75: 3101-3109Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). are of and a is on will results from the first and review results from the "Structural Basis for Ca2+ The J.T. Nature. PubMed Scopus Google Scholar) how a gelsolin binds actin. of the between Stossel T.P. S.H. J.E. Yin H.L. Nature. PubMed Scopus Google L.D. J. R.C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), it can be as a for how the other actin. The gelsolin in the of Ca2+ that gelsolin has a in the of Ca2+ L.D. J. R.C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). are by a which and "Structural Basis for Ca2+ each the first and and and for the and are into a that is with actin binding This binds actin in the of It also that major changes in each and in the relation between the to actin A study of a gelsolin attached to an actin filament (4McGough A. Chiu W. Way M. Biophys. J. 1998; 74: 764-772Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar) at the of the change that is The that gelsolin binds to actin molecules in filament and The between the and and the and on the filament indicate that there be changes and can actin. The and of the or may have to to the between and in Refs. L.D. J. R.C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar and A. Curr. Opin. Biol. 1998; PubMed Scopus Google Scholar). A for how this of may is in The of how gelsolin is in the Ca2+ and how Ca2+ gelsolin on are clearly because they to and apoptotic signaling. Although gelsolin first identified as a protein that binds Ca2+ with H.L. K.S. Stossel T.P. J. Biol. Chem. Full Text PDF PubMed Google Scholar), studies that gelsolin with Ca2+ is more gelsolin have at with and B. S. A. 1995; PubMed Scopus Google Scholar). binding actin, and are J.T. Nature. PubMed Scopus Google J. B. M. R. FEBS Lett. 1995; PubMed Scopus Google Scholar), C. M. V. L. D. H. L. and S. for gelsolin can more Ca2+ a study that gelsolin binds only Ca2+ in the of actin, and they D. A. J. Biochem. 1999; PubMed Scopus Google Scholar). The challenge will be to determine which of the identified are physiologically relevant and how their alters gelsolin severing is at which is well within the physiological range during A small in also reduces the for severing H.J. Newman J. Lincoln B. L.A. Gershman L.C. Estes J.E. Biophys. J. 1998; 75: Full Text Full Text PDF PubMed Scopus Google Scholar, J.A. Janmey P.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar, K.-M. Chen Yin H.L. J. Biol. 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J. 1998; 75: Full Text Full Text PDF PubMed Scopus Google Scholar, J.T. 1997; PubMed Scopus Google Therefore, the is the major that the on the to the severing Gelsolin is the gelsolin family proteins (see Gelsolin in Ca2+ regulation of to the through It may have the mechanism to regulation of severing and capping and to with Ca2+ regulation during by the severing from the regulatory has a for many it is the for gelsolin. The can be because a of the with actin and Ca2+ has As discussed in the of and are into an L.D. J. R.C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) In the of the is and are completely their from and new with into the by and an coordinated by and actin. These results that that there are during Ca2+ Although there is for gelsolin-actin in cells (reviewed in Ref. 1Liu Y.T. Rozelle A.L. Yin H.L. Maruta H. Kohama K. G Proteins, Cytoskeleton and Cancer. R. G. 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Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) and does not inositol (17Lassing I. Lindberg U. Nature. 1985; 314: 472-474Crossref PubMed Scopus (639) Google Scholar). Therefore, gelsolin binding is and enhanced by the This requirement is the with many proteins, which and the inositol with G. A. B. M.P. K.S. Chen Cantley L.C. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). Gelsolin can between and within and binding is on the of the bilayer Chen J. Prestwich G.D. Janmey P.A. J. Biochem. 1999; PubMed Scopus Google Scholar). Therefore, gelsolin regulation by PIP2 does not depend on the PIP2 but is by a complex relation between bilayer and with the of gelsolin to change for PIP2 in response to Ca2+ and K.-M. Chen Yin H.L. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus (77) Google Scholar) and to changes in PIP2 packing within the membrane (37Flanagan L.A. Cunningham C.C. Chen J. Prestwich G.D. Kosik K.S. Janmey P.A. 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Yin H.L. Maruta H. Kohama K. G Proteins, Cytoskeleton and Cancer. R. G. Landes Company, Austin, TX1998: 19-35Google Scholar and 2Kwiatkowski D.J. Curr. Opin. Cell Biol. 1999; 11: 103-108Crossref PubMed Scopus (326) Google Scholar). They have as well as of which is consistent with M. Kwiatkowski D.J. 1999; PubMed Scopus Google Scholar). for Ca2+ regulation and actin binding are not into the of the a has a Ca2+-dependent R. J.E. Nature. 1985; PubMed Scopus Google Scholar), and CapG, a has in P.A. Yin H.L. Science. 1990; PubMed Scopus Google Scholar). with have also been I has an of T. C. N. de Proc. Natl. U. S. A. PubMed Scopus Google Scholar), which can binding include a family of proteins with Y.T. Yin H.L. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, K.S. de 1999; PubMed Scopus Google Scholar) and M. K. Y. T. M. F. E. T. Biochem. Biophys. 1999; PubMed Scopus Google Scholar). these I may the actin cytoskeleton to intracellular and membrane to signaling This review has on the intracellular of gelsolin and to a of how gelsolin the actin cytoskeleton in response to Ca2+ and phosphoinositide signaling. a of how actin regulatory proteins are to how they to actin dynamics within has been study that gelsolin and capping protein barbed ends during platelet activation M. K. Y. T. M. F. E. T. Biochem. Biophys. 1999; PubMed Scopus Google Scholar). study that filaments by gelsolin and Arp2/3 at the barbed and can in the of ADF/cofilin, and new barbed ends are K. Witke W. Kwiatkowski D.J. Hartwig J.H. J. Cell Biol. 1996; PubMed Scopus Google Scholar). Therefore, gelsolin severing and capping can novo by Arp2/3 by the number of filament ends and the actin F. D. C. Pantaloni D. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). These findings the of the involvement of gelsolin in actin dynamics.