Insulin signaling diverges into Akt-dependent and -independent signals to regulate the recruitment/docking and the fusion of GLUT4 vesicles to the plasma membrane
Insulin signaling diverges into Akt-dependent and -independent signals to regulate the recruitment/docking and the fusion of GLUT4 vesicles to the plasma membrane
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DOI：
10.1091/mbc.e06-07-0585
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发表时间：
2006-10-01
影响因子：
3.3
通讯作者：
McGraw, Timothy E.
中科院分区：
文献类型：
--
作者：
Gonzalez, Eva;McGraw, Timothy E.
胰岛素通过调节GLUT 4葡萄糖转运蛋白的细胞再分布来调节肌肉和脂肪组织中的葡萄糖处置。蛋白激酶Akt/PKB是胰岛素调节的GLUT 4易位的中心介质;然而，Akt调节的GLUT 4转运步骤尚不清楚。在这里，我们使用急性药理学Akt抑制表明，Akt是胰岛素刺激的GLUT 4胞吐到质膜所必需的。我们的数据还表明，AS 160 Rab GAP不是胰岛素刺激的GLUT 4易位所需的唯一Akt靶点。使用全内反射显微镜分析，我们表明，Akt活性是胰岛素介导的预融合步骤，涉及招聘和/或对接GLUT 4囊泡到质膜250 nm内的具体要求。此外，胰岛素刺激的GLUT 4囊泡与质膜的融合可以独立于Akt活性发生，尽管基于渥曼青霉素的抑制，它依赖于磷脂酰肌醇3'激酶活性。因此，为了实现GLUT 4完全重新分布到质膜中，胰岛素信号传导分叉以独立地调节融合和融合前步骤。
Insulin modulates glucose disposal in muscle and adipose tissue by regulating the cellular redistribution of the GLUT4 glucose transporter. Protein kinase Akt/PKB is a central mediator of insulin-regulated translocation of GLUT4; however, the GLUT4 trafficking step(s) regulated by Akt is not known. Here, we use acute pharmacological Akt inhibition to show that Akt is required for insulin-stimulated exocytosis of GLUT4 to the plasma membrane. Our data also suggest that the AS160 Rab GAP is not the only Akt target required for insulin-stimulated GLUT4 translocation. Using a total internal reflection microscopy assay, we show that Akt activity is specifically required for an insulin-mediated prefusion step involving the recruitment and/or docking of GLUT4 vesicles to within 250 nm of the plasma membrane. Moreover, the insulin-stimulated fusion of GLUT4 vesicles with the plasma membrane can occur independently of Akt activity, although based on inhibition by wortmannin, it is dependent on phosphatidylinositol 3' kinase activity. Hence, to achieve full redistribution of GLUT4 into the plasma membrane, insulin signaling bifurcates to independently regulate both fusion and a prefusion step(s).