INSULIN-INDUCED TRANSLOCATION OF GLUCOSE TRANSPORTER

胰岛素诱导的葡萄糖转运蛋白易位

• 批准号: 6381929
• 负责人: NAI-WEN CHI
• 金额: $ 7.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381929
• 关键词: ADP ribosylation; CHO cells; SDS polyacrylamide gel electrophoresis; aminopeptidase; autoradiography; biological signal transduction; enzyme activity; enzyme substrate; glucose transporter; green fluorescent proteins; hormone binding protein; hormone regulation /control mechanism; immunoprecipitation; insulin; insulin sensitivity /resistance; mitogen activated protein kinase; phosphorylation; protein protein interaction; western blottings

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.

描述（摘自申请表） 糖尿病是影响数百万美国人的主要健康问题。在大多数 在某些情况下，这是由于胰岛素刺激葡萄糖的能力受损 吸收。了解糖尿病的发病机制对于其治疗至关重要 预防和管理。因此，原来K08项目的目标 （DK02540）是为了表征胰岛素如何刺激的分子机制 葡萄糖摄取。 刺激的摄取主要由葡萄糖转运蛋白介导 过剩4。在没有胰岛素的情况下，GLUT4被隔离在细胞内“GLUT4 囊泡。”这些囊泡还隔离跨膜蛋白 胰岛素反应性氨肽酶（IRAP）。在胰岛素刺激后，GLUT4 和 IRAP 被招募到质膜，GLUT4 可以在质膜上输入 细胞外葡萄糖。 GLUT4 和 IRAP 的靶向相似性 表明响应胰岛素信号的相同机制可以调节 他们的易位。 为了发现 IRAP/GLUT4 靶向机制的候选组件， 申请人已经鉴定出一个新的蛋白质家族，可以特异性结合 据推断，IRAP 与 GLUT4 间接相互作用。有趣的是，两者 IRAP 结合蛋白在胰岛素作用下按化学计量磷酸化 刺激。了解这些 IRAP 结合的生理作用 蛋白质，申请人建议破坏它们与 IRAP 的相互作用 体内。如果这影响胰岛素调节的 GLUT4/IRAP 靶向，那么 可以推断IRAP结合蛋白。 申请人已证明两种 IRAP 结合蛋白均具有内在的 聚（ADP-核糖）聚合酶活性。该活动是否受监管 将检查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其分子机制 IRAP/GLUT4 运输和胰岛素抵抗的发病机制。