Insulin stimulates phosphatidylinositol 3-phosphate production via the activation of Rab5
Insulin stimulates phosphatidylinositol 3-phosphate production via the activation of Rab5
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DOI：
10.1091/mbc.e08-01-0105
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发表时间：
2008-07-01
影响因子：
3.3
通讯作者：
Saltiel, Alan R.
中科院分区：
文献类型：
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作者：
Lodhi, Irfan J.;Bridges, Dave;Saltiel, Alan R.
磷脂酰肌醇3-磷酸（PI（3）P）在胰岛素刺激的葡萄糖摄取中起重要作用。胰岛素通过依赖于TC 10活化的过程促进PI（3）P在质膜上的产生。在这里，我们报告说，胰岛素刺激PI（3）P的生产需要Rab 5的激活，Rab 5是一个小的GT 4，在磷酸肌醇合成和营业额中起着关键作用。这种激活发生在质膜上，位于TC 10的下游。TC 10通过募集GAPEX-5刺激Rab 5活性，GAPEX-5是一种含有VPS 9结构域的鸟苷酸交换因子，与TC 10形成复合物。尽管质膜定位的GAPEX-5或组成型活性Rab 5的过表达促进PI（3）P形成，但GAPEX-5的敲除或显性负性Rab 5突变体的过表达阻断了胰岛素或TC 10对该过程的影响。伴随着其对PI（3）P水平的影响，GAPEX-5的敲低阻断胰岛素刺激的Glut 4易位和葡萄糖摄取。总之，这些研究表明TC 10/GAPEX-5/Rab 5轴介导胰岛素刺激的PI（3）P的产生，PI（3）P调节Glut 4囊泡的运输。
Phosphatidylinositol 3-phosphate (PI(3) P) plays an important role in insulin-stimulated glucose uptake. Insulin promotes the production of PI(3) P at the plasma membrane by a process dependent on TC10 activation. Here, we report that insulin-stimulated PI(3) P production requires the activation of Rab5, a small GTPase that plays a critical role in phosphoinositide synthesis and turnover. This activation occurs at the plasma membrane and is downstream of TC10. TC10 stimulates Rab5 activity via the recruitment of GAPEX-5, a VPS9 domain-containing guanyl nucleotide exchange factor that forms a complex with TC10. Although overexpression of plasma membrane-localized GAPEX-5 or constitutively active Rab5 promotes PI(3) P formation, knockdown of GAPEX-5 or overexpression of a dominant negative Rab5 mutant blocks the effects of insulin or TC10 on this process. Concomitant with its effect on PI(3) P levels, the knockdown of GAPEX-5 blocks insulin-stimulated Glut4 translocation and glucose uptake. Together, these studies suggest that the TC10/GAPEX-5/Rab5 axis mediates insulin-stimulated production of PI(3) P, which regulates trafficking of Glut4 vesicles.