Activation and functions of the PDK1-Akt pathway in regulation of cell motility
| Project/Area Number |
16370085
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cell biology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
GOTOH Yukiko The University of Tokyo, Institute of Molecular and Cellular Biosciences, Professor, 分子細胞生物学研究所, 教授 (70252525)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥15,700,000 (Direct Cost: ¥15,700,000)
Fiscal Year 2005: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2004: ¥9,700,000 (Direct Cost: ¥9,700,000)
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| Keywords | Akt / PDK1 / cell motility / actin / Rac / Cdc42 / PAK / Rho / 細胞運動 / 増殖因子 / 細胞極性 |
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| Research Abstract |
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 co-localization 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. We then studied the mechanisms by which Akt regulates cell motility. We found that the PDK1-Akt pathway plays an essential role in the positive feedback loop of phosphatidyl inositol 3-phosphate accumulation.
In doing so, antagonistic interaction between the PDK1-Akt pathway and the small G protein Rho appears to be crucial. This mechanism contributes to the establishment of cell polarity, which is essential for the directional movement.
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Report
(3 results)
Research Products
(28 results)
