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

Masahiro Shinohara, Yoh Terada, Akihiro Iwamatsu, Azusa Shinohara, Naoki Mochizuki, Maiko Higuchi, Yukiko Gotoh, Sayoko Ihara, Satoshi Nagata, Hiroshi Itoh, Yasuhisa Fukui () and Rolf Jessberger
Additional contact information
Masahiro Shinohara: University of Tokyo
Yoh Terada: University of Tokyo
Akihiro Iwamatsu: Kirin Brewery
Azusa Shinohara: Kirin Brewery
Naoki Mochizuki: International Medical Center of Japan
Maiko Higuchi: University of Tokyo
Yukiko Gotoh: University of Tokyo
Sayoko Ihara: University of Tokyo
Satoshi Nagata: University of Tokyo
Hiroshi Itoh: University of Tokyo
Yasuhisa Fukui: University of Tokyo
Rolf Jessberger: The Carl C. Icahn Institute for Gene Therapy and Molecular Medicine

Nature, 2002, vol. 416, issue 6882, 759-763

Abstract: 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)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.

Date: 2002
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DOI: 10.1038/416759a

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