A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action.
A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action.
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DOI：
10.1091/mbc.e10-08-0665
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发表时间：
2011-01-01
影响因子：
3.3
通讯作者：
Saltiel AR
中科院分区：
文献类型：
--
作者：
Chen XW;Leto D;Xiong T;Yu G;Cheng A;Decker S;Saltiel AR
研究表明，RalA在胰岛素作用中受ralgap复合物（RGC 1/2）的调控，并将PI 3-激酶信号通路与RalA的激活联系起来。Akt磷酸化该复合物并抑制其功能，导致RalA活性和葡萄糖摄取增加。胰岛素通过葡萄糖转运蛋白4 （GLUT4）转运到质膜，刺激葡萄糖在肌肉和脂肪组织中的转运。我们之前报道过PI 3-激酶下游小GTPase RalA的激活在这一过程中发挥了关键作用，通过动员脂肪细胞内的囊泡复合物来靶向GLUT4囊泡。在这里，我们报道了一个Ral GAP复合物（RGC）的鉴定和表征，该复合物介导PI 3-激酶/Akt通路下游RalA的激活。该复合物由RGC1调控亚基和RGC2催化亚基（先前鉴定为AS250）组成，直接刺激RalA的鸟苷三磷酸水解。RGC蛋白的敲低导致脂肪细胞中RalA活性和葡萄糖摄取增加。在体外和体内，胰岛素通过akt2催化的RGC2磷酸化抑制GAP复合物，而激活的Akt则缓解了RGC蛋白对RalA活性的抑制作用。因此，RGC复合物将PI 3-激酶/Akt活性与负责GLUT4易位的转运机制联系起来。
It is shown that RalA is regulated by a Ral GAP complex (RGC 1/2) in insulin action and links PI 3-kinase signaling to RalA activation. Akt phosphorylates the complex and inhibits its function, resulting in increased RalA activity and glucose uptake. Insulin stimulates glucose transport in muscle and adipose tissue by translocation of glucose transporter 4 (GLUT4) to the plasma membrane. We previously reported that activation of the small GTPase RalA downstream of PI 3-kinase plays a critical role in this process by mobilizing the exocyst complex for GLUT4 vesicle targeting in adipocytes. Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. Knockdown of RGC proteins leads to increased RalA activity and glucose uptake in adipocytes. Insulin inhibits the GAP complex through Akt2-catalyzed phosphorylation of RGC2 in vitro and in vivo, while activated Akt relieves the inhibitory effect of RGC proteins on RalA activity. The RGC complex thus connects PI 3-kinase/Akt activity to the transport machineries responsible for GLUT4 translocation.