Akt mediates Rac/Cdc42-regulated cell motility in growth factor-stimulated cells and in invasive PTEN knockout cells
Akt mediates Rac/Cdc42-regulated cell motility in growth factor-stimulated cells and in invasive PTEN knockout cells
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DOI：
10.1016/s0960-9822(01)00599-1
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发表时间：
2001-12-11
期刊：
影响因子：
9.2
通讯作者：
Gotoh, Y
中科院分区：
文献类型：
--
作者：
Higuchi, M;Masuyama, N;Gotoh, Y
生长因子促进细胞存活和细胞运动，可能分别通过激活Akt和Rac和CDC42 GTP酶[1，2]。由于AM对于RAC/CDC42调节肌动蛋白重组是必不可少的，因此一直认为RAC和CDC42在哺乳动物细胞中刺激不依赖Akt的细胞运动[3-5]。然而，在这项研究中，我们证明Akt对于RAC/Cdc42调节的哺乳动物成纤维细胞的细胞运动是必不可少的。显性负性Akt抑制RAC/CDC42或PDGF刺激的细胞运动，但不影响褶皱膜型肌动蛋白的重组。我们已经证实了先前的报道，即Akt是由Rac和CDc42[6]的表达激活的，并且还观察到内源性磷酸化Akt与Rac和CDc42在成纤维细胞的前沿共定位。重要的是，活性Akt的表达而不是密切相关的激酶SGK的表达足以增加细胞的运动性。Akt的这种作用是细胞自主的，不是通过抑制GSK3介导的。最后，我们发现，显性负的Akt而不是SGK逆转了缺乏PTEN抑癌基因的成纤维细胞增加的细胞运动表型。综上所述，这些结果表明，在生长因子刺激的细胞和侵袭性PTEN缺陷的细胞中，Akt促进RAC/CDC42下游的细胞运动。
Growth factors promote cell survival and cell: motility, presumably through the activation of Akt and the Rac and Cdc42 GTPases, respectively [1, 2]. Because AM 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 [3-5]. 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 [6] 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.