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

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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.

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Figure 1: SWAP-70 binds PtdIns(3,4,5)P3.
Figure 2: SWAP-70 translocates to membrane ruffles.
Figure 3: SWAP-70 is a PtdIns(3,4,5)P3-dependent Rac specific GEF.
Figure 4: Impaired membrane ruffling in SWAP-70-deficient primary fibroblasts.

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Acknowledgements

We thank B. Mayer and M. Matsuda for useful suggestions and critical reading of the manuscript, and T. Nagase (Kazusa DNA Research Institute) for supplying the KIAA0640 clone. This work was supported by grants-in-aid for scientific research to Y.F. from the Ministry of Education, Science, Sports, and Culture of Japan, and by an NIH grant to R.J.

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Correspondence to Yasuhisa Fukui.

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Shinohara, M., Terada, Y., Iwamatsu, A. et al. SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane ruffling. Nature 416, 759–763 (2002) doi:10.1038/416759a

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