TBC1D1/14-3-3相互作用在四型葡萄糖转运体细胞质膜转移过程中的功能研究

项目名称： TBC1D1/14-3-3相互作用在四型葡萄糖转运体细胞质膜转移过程中的功能研究

项目编号： No.31271498

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 陈帅

作者单位： 南京大学

项目金额： 80万元

中文摘要： 胰岛素和AMPK信号通路均可促进肌肉中四型葡萄糖转运体（GLUT4）从细胞内转移到细胞表面，从而诱导葡萄糖吸收。两种类似的RabGAP蛋白AS160和TBC1D1可能介导这两种通路对GLUT4细胞质膜转移的调控。申请人发现14-3-3蛋白会结合AS160和TBC1D1，而这分别受胰岛素和AMPK通路的调控。申请人最近证明了AS160/14-3-3的结合调控胰岛素诱导的GLUT4的细胞质膜转移，这填补了胰岛素调控的GLUT4质膜转移分子机制中的一个重要环节。关于TBC1D1/14-3-3相互作用的功能，申请人提出如下工作假设：TBC1D1/14-3-3的结合介导AMPK依赖的GLUT4细胞质膜转移，进而调控肌肉糖吸收和机体糖平衡。本申请拟利用基因敲入小鼠技术结合分子生理学手段研究这一假设，并阐明其分子机制。本项研究预期将填补AMPK通路调控的GLUT4细胞质膜转移分子机制中的一个关键环节。

中文关键词： 肥胖；2型糖尿病；TBC1D1；胰岛素样生长因子－1；4型葡萄糖转运体

英文摘要： Insulin stimulates uptake of glucose into skeletal muscle mainly through glucose transporter 4 (GLUT4) that translocates from its intracellular storage vesicles (GSVs) onto the plasma membrane upon insulin. Deregulation of this process is directly linked to the pathogenesis of type II diabetes. Besides insulin, other signals such as exercise and pharmaceutical AMPK activators (i.e. metformin，a drug for treatment of type II diabetes) can also stimulate GLUT4 translocation in an insulin-independent manner, which requires LKB1/AMPK pathway instead. Recent studies show that two related RabGAPs, AS160 and TBC1D1, may play important roles in regulating GLUT4 trafficking. AS160 and TBC1D1 are both regulated by protein phosphorylation and interaction with regulatory proteins named as 14-3-3 although some key regulatory details for these two RabGAPs are distinct. Insulin stimulates AS160 Thr642 phosphorylation and subsequently increases its interaction with 14-3-3 proteins while AMPK activators induce TBC1D1 Ser237 phosphorylation and up-regulate its binding to 14-3-3 proteins. The applicant has recently generated a kockin mouse model in which AS160 Thr642 is substituted by a non-phosphorylatable alanine, and showed that AS160 Thr642 phosphorylation and/or its binding to 14-3-3s play an important role in regulating insul

英文关键词： obesity；type 2 diabetes；TBC1D1；IGF-1；GLUT4