title: SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane ruffling.
abstract: Phosphoinositide-3-OH kinase (PI(3)K), activated through growth factor stimulation, generates a lipid second messenger, phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). PtdIns(3,4,5)P3 is instrumental in signalling pathways that trigger cell activation, cytoskeletal rearrangement, survival and other reactions. However, some targets of PtdIns(3,4,5)P3 are yet to be discovered. We demonstrate that SWAP-70, a unique signalling protein, specifically binds PtdIns(3,4,5)P3. On stimulation by growth factors, cytoplasmic SWAP-70, which is dependent on PI(3)K but independent of Ras, moved to cell membrane rearrangements known as ruffles. However, mutant SWAP-70 lacking the ability to bind PtdIns(3,4,5)P3 blocked membrane ruffling induced by epidermal growth factor or platelet-derived growth factor. SWAP-70 shows low homology with Rac-guanine nucleotide exchange factors (GEFs), and catalyses PtdIns(3,4,5)P3-dependent guanine nucleotide exchange to Rac. SWAP-70-deficient fibroblasts showed impaired membrane ruffling after stimulation with epidermal growth factor, and failed to activate Rac fully. We conclude that SWAP-70 is a new type of Rac-GEF which, independently of Ras, transduces signals from tyrosine kinase receptors to Rac.
authors.affiliation: Department of Applied Biological Chemistry, Faculty of Agricultural and Life Science, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shinohara
authors.forename: Yoh
authors.initials: Y
authors.lastname: Terada
authors.forename: Akihiro
authors.initials: A
authors.lastname: Iwamatsu
authors.forename: Azusa
authors.initials: A
authors.lastname: Shinohara
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Maiko
authors.initials: M
authors.lastname: Higuchi
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Gotoh
authors.forename: Sayoko
authors.initials: S
authors.lastname: Ihara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fukui
authors.forename: Rolf
authors.initials: R
authors.lastname: Jessberger
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019556:COS Cells; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D048429:Cell Size / Q000187:drug effects; D022081:Cell Surface Extensions / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005347:Fibroblasts; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D015778:Minor Histocompatibility Antigens; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D018129:Phosphatidylinositol Phosphates; D010982:Platelet-Derived Growth Factor; C491873:SWAP70 protein, human; C113365:Swap70 protein, mouse; C060974:phosphatidylinositol 3,4,5-triphosphate; D004815:Epidermal Growth Factor; D020830:rac1 GTP-Binding Protein