Qian Yong, Corum Linda, Meng Qiao, Blenis John, Zheng Jenny Z, Shi Xianglin, Flynn Daniel C, Jiang Bing-Hua
Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health/NIH, Morgantown, WV 26506, USA.
Am J Physiol Cell Physiol. 2004 Jan;286(1):C153-63. doi: 10.1152/ajpcell.00142.2003. Epub 2003 Sep 10.
This study was designed to identify the molecular mechanisms of phosphatidylinositol 3-kinase (PI3K)-induced actin filament remodeling and cell migration. Expression of active forms of PI3K, v-P3k or Myr-P3k, was sufficient to induce actin filament remodeling to lead to an increase in cell migration, as well as the activation of Akt in chicken embryo fibroblast (CEF) cells. Either the inhibition of PI3K activity using a PI3K-specific inhibitor, LY-294002, or the disruption of Akt activity restored the integrity of actin filaments in CEF cells and inhibited PI3K-induced cell migration. We also found that expression of an activated form of Akt (Myr-Akt) was sufficient to remodel actin filaments to lead to an increase in cell migration, which was unable to be inhibited by the presence of LY-294002. Furthermore, we found that p70S6K1 kinase was a downstream molecule that can mediate the effects of both PI3K and Akt on actin filaments and cell migration. Overexpression of an active form of p70S6K1 was sufficient to induce actin filament remodeling and cell migration in CEF cells, which requires Rac activity. These results demonstrate that activation of PI3K activity alone is sufficient to remodel actin filaments to increase cell migration through the activation of Akt and p70S6K1 in CEF cells.
本研究旨在确定磷脂酰肌醇3激酶（PI3K）诱导肌动蛋白丝重塑和细胞迁移的分子机制。PI3K的活性形式v-P3k或Myr-P3k的表达足以诱导肌动蛋白丝重塑，导致细胞迁移增加，以及鸡胚成纤维细胞（CEF）中Akt的激活。使用PI3K特异性抑制剂LY-294002抑制PI3K活性，或破坏Akt活性，均可恢复CEF细胞中肌动蛋白丝的完整性，并抑制PI3K诱导的细胞迁移。我们还发现，激活形式的Akt（Myr-Akt）的表达足以重塑肌动蛋白丝，导致细胞迁移增加，而LY-294002的存在无法抑制这种迁移。此外，我们发现p70S6K1激酶是一个下游分子，可介导PI3K和Akt对肌动蛋白丝和细胞迁移的影响。p70S6K1活性形式的过表达足以在CEF细胞中诱导肌动蛋白丝重塑和细胞迁移，这需要Rac活性。这些结果表明，单独激活PI3K活性足以通过激活CEF细胞中的Akt和p70S6K1来重塑肌动蛋白丝，从而增加细胞迁移。
