Gelsolin, a Multifunctional Actin Regulatory Protein

Abstract

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.