SWAP-70 Is a Guanine-Nucleotide-Exchange Factor That Mediates Signalling of Membrane Ruffling

Nature. 2002 Apr 18;416(6882):759-63. doi: 10.1038/416759a.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • COS Cells
  • Cattle
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism*
  • Cell Size / drug effects
  • Cell Surface Extensions / drug effects
  • Cell Surface Extensions / metabolism*
  • Cells, Cultured
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Epidermal Growth Factor / pharmacology
  • Fibroblasts
  • Guanine Nucleotide Exchange Factors / chemistry
  • Guanine Nucleotide Exchange Factors / deficiency
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Mice
  • Minor Histocompatibility Antigens
  • Mutation / genetics
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphatidylinositol Phosphates / metabolism
  • Platelet-Derived Growth Factor / pharmacology
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • Signal Transduction* / drug effects
  • rac1 GTP-Binding Protein / antagonists & inhibitors
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism

Substances

  • DNA-Binding Proteins
  • Guanine Nucleotide Exchange Factors
  • Minor Histocompatibility Antigens
  • Nuclear Proteins
  • Phosphatidylinositol Phosphates
  • Platelet-Derived Growth Factor
  • SWAP70 protein, human
  • Swap70 protein, mouse
  • phosphatidylinositol 3,4,5-triphosphate
  • Epidermal Growth Factor
  • rac1 GTP-Binding Protein