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Nature 416, 759-763 (18 April 2002) | doi:10.1038/416759a; Received 9 October 2001; Accepted 11 February 2002

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SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane ruffling

Masahiro Shinohara1, Yoh Terada1,1, Akihiro Iwamatsu2, Azusa Shinohara2, Naoki Mochizuki3,1, Maiko Higuchi4, Yukiko Gotoh4, Sayoko Ihara1, Satoshi Nagata1,1, Hiroshi Itoh1, Yasuhisa Fukui1 & Rolf Jessberger5

  1. Department of Applied Biological Chemistry, Faculty of Agricultural and Life Science, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan
  2. Central Laboratories for Key Technology, Kirin Brewery, 1-13-5 Fukuura, Kanazawa-ku, Yokohama City, Kanagawa 236-0004, Japan
  3. Department of Pathology, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
  4. Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
  5. Mount Sinai School of Medicine, The Carl C. Icahn Institute for Gene Therapy and Molecular Medicine, 1425 Madison Avenue, Box 1496, New York, New York 10029-6574, USA
  6. Present addresses: Molecular Medicine Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd, Tsukuba, Ibaraki 305-8585, Japan (Y.T.); Department of Structure Analysis, National Cardiovascular Center Research Institute, 5-7-4 Fujishirodai, Suita, Osaka 565-8565, Japan (N.M.); Laboratory of Molecular Biology, National Cancer Institute, National Institute of Health, Bethesda, Maryland 20892-4255, USA (S.N.).

Correspondence to: Yasuhisa Fukui1 Correspondence and requests for materials should be addressed to Y.F. (e-mail: Email: ayfukui@mail.ecc.u-tokyo.ac.jp).

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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)1, 2, 3, 4, 5. PtdIns(3,4,5)P3 is instrumantal 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 discovered1, 2, 3, 4, 5, 6, 7. We demonstrate that SWAP-70, a unique signalling protein8, 9, 10, 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.