CAP Isoforms in Insulin Action

胰岛素作用中的 CAP 异构体

• 批准号: 6859383
• 负责人: MEI ZHANG
• 金额: $ 5.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6859383
• 关键词: biological signal transduction; carbohydrate biosynthesis; complementary DNA; confocal scanning microscopy; genetic library; glucose metabolism; glucose transport; glucose transporter; glycogen; insulin; lipolysis; postdoctoral investigator; protein isoforms; protein localization; protein protein interaction; yeast two hybrid system

DESCRIPTION (provided by applicant): Insulin stimulates glucose uptake into muscle and adipose tissue through the translocation of the insulin-responsive glucose transporter type 4 (GLUT4) from an intracellular compartment to the cell surface. This laboratory has identified a novel pathway that plays a crucial role in the regulation of glucose uptake by insulin [Baumann et al., Nature 2000]. This pathway involves the insulin-stimulated tyrosine phosphorylation of the Cbl protooncogene, and its translocation to lipid raft microdomains of the plasma membrane via the multidomain adaptor protein CAP. Although CAP was cloned in the Saltiel laboratory several years ago, I have recently identified several CAP splicing isoforms from mouse adipose tissue with additional potential functional domains including a coiled-coil domain and a proline-rich region. I will examine the role of these domains in protein interactions, as well as the subcellular localization of the isoforms. I will explore the role of CAP isoforms in the CAPICbl pathway of insulin signal transduction, and examine the effects of mutant forms of these proteins on the regulation of glucose transport, glycogen synthesis and lipolysis by insulin. Finally, I will search for novel CAP-interacting proteins. This approach may lead to new insights into the molecular mechanisms of insulin action, and ultimately to therapeutic approaches to insulin resistance and diabetes.

描述（由申请人提供）：胰岛素通过胰岛素反应性葡萄糖转运蛋白4型（GLUT4）从细胞内室向细胞表面刺激葡萄糖吸收到肌肉和脂肪组织中。该实验室已经确定了一种新的途径，在胰岛素对葡萄糖摄取的调节中起着至关重要的作用[Baumann等人，Nature 2000]。该途径涉及CBL原子元的胰岛素刺激的酪氨酸磷酸化，以及通过多域适配器蛋白帽的易位到质膜的脂质筏微区。尽管几年前将CAP克隆在Saltiel实验室中，但最近我发现了来自小鼠脂肪组织的几种瓶盖剪接同工型，其中包括其他潜在的功能域，包括卷曲螺旋型结构域和富含脯氨酸的区域。我将研究这些结构域在蛋白质相互作用中的作用，以及同工型的亚细胞定位。我将探讨帽同工型在胰岛素信号转导的Capicbl途径中的作用，并检查这些蛋白质突变形式对葡萄糖转运，糖原合成和胰岛素脂溶性的调节的影响。最后，我将搜索新型的帽相互作用蛋白。这种方法可能会导致对胰岛素作用的分子机制的新见解，并最终导致胰岛素抵抗和糖尿病的治疗方法。