Ras-mediated activation of the TORC2-PKB pathway is critical for chemotaxis.
Ras-mediated activation of the TORC2-PKB pathway is critical for chemotaxis.
复制标题
DOI：
10.1083/jcb.201001129
复制
发表时间：
2010-07-26
期刊：
影响因子：
--
通讯作者：
Devreotes PN
中科院分区：
文献类型：
--
作者：
Cai H;Das S;Kamimura Y;Long Y;Parent CA;Devreotes PN
RASC调控TORC2的空间和时间活性，调节细胞定向迁移。在趋化细胞中，G蛋白偶联受体激活RAS蛋白，但RAS相关通路如何将细胞外信号与细胞迁移联系起来尚不清楚。我们发现，在盘基网柄菌中，RASC的激活形式延长了TORC2(雷帕霉素[Tor]复合体2的靶标)介导的肉豆蔻酰化蛋白激酶B(PKB；PKBR1)的激活和PKB底物的磷酸化的时间进程，而不依赖于磷脂酰肌醇-(3，4，5)-三磷酸。与这些变化相平行的是，趋化剂诱导的腺苷环化酶激活和肌动蛋白聚合的动力学延长，伪足活性增加和错位，趋化性受损。TORC2亚基PIAA的缺失抑制了激活的RASC的作用。在体外，依赖RasCQ62L的PKB的磷酸化可以通过将PIAA相关的免疫复合体添加到TORC2缺陷细胞膜上而迅速启动，并被TOR特异性抑制剂pp242阻断。此外，TORC2与激活形式的RASC特异性结合。这些结果表明，RASC是TORC2的上游调节因子，TORC2-PKB信号介导了激活的RAS蛋白对细胞骨架和细胞迁移的影响。
RasC controls the spatial and temporal activity of TORC2 to regulate directional cell migration. In chemotactic cells, G protein–coupled receptors activate Ras proteins, but it is unclear how Ras-associated pathways link extracellular signaling to cell migration. We show that, in Dictyostelium discoideum, activated forms of RasC prolong the time course of TORC2 (target of rapamycin [Tor] complex 2)-mediated activation of a myristoylated protein kinase B (PKB; PKBR1) and the phosphorylation of PKB substrates, independently of phosphatidylinositol-(3,4,5)-trisphosphate. Paralleling these changes, the kinetics of chemoattractant-induced adenylyl cyclase activation and actin polymerization are extended, pseudopodial activity is increased and mislocalized, and chemotaxis is impaired. The effects of activated RasC are suppressed by deletion of the TORC2 subunit PiaA. In vitro RasCQ62L-dependent PKB phosphorylation can be rapidly initiated by the addition of a PiaA-associated immunocomplex to membranes of TORC2-deficient cells and blocked by TOR-specific inhibitor PP242. Furthermore, TORC2 binds specifically to the activated form of RasC. These results demonstrate that RasC is an upstream regulator of TORC2 and that the TORC2–PKB signaling mediates effects of activated Ras proteins on the cytoskeleton and cell migration.
登录
查看更多内容
影响因子：
14.9
作者：
Faix, J;Kreppel, L;Kimmel, AR
通讯作者：
Kimmel, AR
影响因子：
9.2
作者：
Meili, R;Ellsworth, C;Firtel, RA
通讯作者：
Firtel, RA
影响因子：
3.3
作者：
Lee, S;Parent, CA;Firtel, RA
通讯作者：
Firtel, RA
影响因子：
5.3
作者：
Kamada, Y;Fujioka, Y;Ohsumi, Y
通讯作者：
Ohsumi, Y
影响因子：
3.3
作者：
Lee, S;Comer, FI;Firtel, RA
通讯作者：
Firtel, RA