INSULIN-INDUCED TRANSLOCATION OF GLUCOSE TRANSPORTER

描述（取自应用程序） 糖尿病是影响数百万美国人的主要健康问题。在大多数 例，这是由于胰岛素刺激葡萄糖的能力受损 摄取。了解糖尿病的发病机制对糖尿病的治疗至关重要。 预防和管理。因此，最初K 08项目的目标 （DK 02540）是为了表征胰岛素如何刺激 葡萄糖摄取 刺激摄取主要由葡萄糖转运蛋白介导 GLUT 4。在不存在胰岛素的情况下，GLUT 4被隔离在细胞内的“GLUT 4 囊泡“这些囊泡还能隔离一种跨膜蛋白 胰岛素反应性氨肽酶（IRAP）。在胰岛素刺激后，GLUT 4 和IRAP被募集到质膜上，GLUT 4可以在质膜上输入 胞外葡萄糖GLUT 4和IRAP靶向的相似性 表明对胰岛素信号做出反应的机制 他们的易位。 为了揭示IRAP/GLUT 4靶向机制的候选组分， 申请人已经鉴定了一个新的蛋白质家族，其特异性结合 IRAP和，通过推断，与GLUT 4间接相互作用。有趣的是，两者 IRAP结合蛋白在胰岛素作用下化学计量磷酸化 刺激.为了了解这些IRAP结合的生理作用， 对于蛋白质，申请人提出破坏它们与IRAP的相互作用， vivo.如果这影响了胰岛素调节的GLUT 4/IRAP靶向，那么 可以推断IRAP结合蛋白。 申请人已经表明，两种IRAP结合蛋白都具有内在的 聚（ADP-核糖）聚合酶活性。这项活动是否受到 将检测胰岛素刺激的磷酸化。拟议的实验 可能有助于揭示聚（ADP-核糖基）化作为一种新的信号机制 转导更重要的是，它们可能有助于确定 IRAP/GLUT 4运输和胰岛素抵抗的发病机制。

DESCRIPTION (taken from the application) Diabetes is a major health problem affecting millions of Americans. In most cases, it is due to the impaired ability of insulin to stimulate glucose uptake. Understanding the pathogenesis of diabetes is essential to its prevention and management. Therefore, the goal of the original K08 project (DK02540) is to characterize the molecular mechanism of how insulin stimulates glucose uptake. The stimulated uptake is predominantly mediated by the glucose transporter GLUT4. In the absence of insulin, GLUT4 is sequestered intracellular in "GLUT4 vesicles." These vesicles also sequester a transmembrane protein insulin-responsive aminopeptidase (IRAP). Upon insulin stimulation, both GLUT4 and IRAP are recruited to the plasma membrane, where GLUT4 can import extracellular glucose. The similarity in the targeting of GLUT4 and IRAP suggests that the same machinery that responds to insulin signaling regulates their translocation. To uncover candidate components of the targeting machinery for IRAP/GLUT4, the applicant has identified a novel family of proteins that specifically bind to IRAP and, by inference, interact with GLUT4 indirectly. Interestingly, both IRAP-binding proteins are phosphorylated stoichiometrically upon insulin stimulation. To understand the physiological role of these IRAP-binding proteins, the applicant proposes to disrupt their interaction with IRAP in vivo. If this affects insulin regulated GLUT4/IRAP targeting, then the role of the IRAP-binding proteins can be inferred. The applicant has shown that both IRAP-binding proteins have an intrinsic poly(ADP-ribose) polymerase activity. Whether this activity is regulated by insulin-stimulated phosphorylation will be examined. The proposed experiments may help uncover poly(ADP-ribosyl)ation as a novel mechanism of signal transduction. More importantly, they may help define the molecular mechanism of IRAP/GLUT4 trafficking and the pathogenesis of insulin resistance.