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Akt mediates Rac/Cdc42-regulated cell motility in growth factor-stimulated cells and in invasive PTEN knockout cells

2001; Elsevier BV; Volume: 11; Issue: 24 Linguagem: Inglês

10.1016/s0960-9822(01)00599-1

1879-0445

Maiko Higuchi, Norihisa Masuyama, Yasuhisa Fukui, Akira Suzuki, Yukiko Gotoh,

Mast cells and histamine

Growth factors promote cell survival and cell motility, presumably through the activation of Akt and the Rac and Cdc42 GTPases, respectively [1Datta S.R. Brunet A. Greenberg M.E. Cellular survival a play in three Akts.Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3718) Google Scholar, 2Nobes C.D. Hawkins P. Stephens L. Hall A. Activation of the small GTP-binding proteins rho and rac by growth factor receptors.J Cell Sci. 1995; 108: 225-233Crossref PubMed Google Scholar]. Because Akt is dispensable for Rac/Cdc42 regulation of actin reorganization, it has been assumed that Rac and Cdc42 stimulate cell motility independent of Akt in mammalian cells [3Welch H. Eguinoa A. Stephens L.R. Hawkins P.T. Protein kinase B and rac are activated in parallel within a phosphatidylinositide 3OH-kinase-controlled signaling pathway.J Biol Chem. 1998; 273: 11248-11256Crossref PubMed Scopus (86) Google Scholar, 4van Weering D.H. de Rooij J. Marte B. Downward J. Bos J.L. Burgering B.M. Protein kinase B activation and lamellipodium formation are independent phosphoinositide 3-kinase-mediated events differentially regulated by endogenous Ras.Mol Cell Biol. 1998; 18: 1802-1811Crossref PubMed Scopus (93) Google Scholar, 5Klippel A. Kavanaugh W.M. Pot D. Williams L.T. A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain.Mol Cell Biol. 1997; 17: 338-344Crossref PubMed Scopus (446) Google Scholar]. However, in this study we demonstrate that Akt is essential for Rac/Cdc42-regulated cell motility in mammalian fibroblasts. A dominant-negative Akt inhibits cell motility stimulated by Rac/Cdc42 or by PDGF treatment, without affecting ruffling membrane-type actin reorganization. We have confirmed a previous report that Akt is activated by expression of Rac and Cdc42 [6Genot E.M. Arrieumerlou C. Ku G. Burgering B.M. Weiss A. Kramer I.M. The T-cell receptor regulates Akt (protein kinase B) via a pathway involving Rac1 and phosphatidylinositide 3-kinase.Mol Cell Biol. 2000; 20: 5469-5478Crossref PubMed Scopus (108) Google Scholar] and also observed colocalization of endogenous phosphorylated Akt with Rac and Cdc42 at the leading edge of fibroblasts. Importantly, expression of active Akt but not the closely related kinase SGK is sufficient for increasing cell motility. This effect of Akt is cell autonomous and not mediated by inhibition of GSK3. Finally, we found that dominant-negative Akt but not SGK reverses the increased cell motility phenotype of fibroblasts lacking the PTEN tumor suppressor gene. Taken together, these results suggest that Akt promotes cell motility downstream of Rac/Cdc42 in growth factor-stimulated cells and in invasive PTEN-deficient cells.