Akt mediates Rac/Cdc42-regulated cell motility in growth factor-stimulated cells and in invasive PTEN knockout cells.
Growth factors promote cell survival and cell motility, presumably through the activation of Akt and the Rac and Cdc42 GTPases, respectively. 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. 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 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.
Higuchi
M
M
Institute of Molecular and Cellular Biosciences, Faculty of Agricultural and Life Science, University of Tokyo, Yayoi, Bunkyo-ku, 113-0032, Tokyo, Japan.
Masuyama
N
N
Fukui
Y
Y
Suzuki
A
A
Gotoh
Y
Y
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D004023:Dictyostelium; D006133:Growth Substances / Q000502:physiology*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000502:physiology*
D006133:Growth Substances; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins