Clip R-59: a novel regulator of Akt signaling

Clip R-59：Akt 信号传导的新型调节剂

• 批准号: 7987913
• 负责人: KEYONG DU
• 金额: $ 39.75万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987913
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Cell Nucleus; Cells; Cellular Membrane; Clip; Complex; Cytosol; Development; Diabetes Mellitus; Drug Delivery Systems; Epidemic; Fatty acid glycerol esters; GTPase-Activating Proteins; Goals; Homeostasis; Insulin; Insulin Resistance; Knowledge; Maintenance; Mediating; Membrane; Metabolic; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Phosphorylation; Play; Prevalence; Production; Proteins; Public Health; Regulation; Research; Role; Scaffolding Protein; Signal Transduction; Specific qualifier value; Tissues; Transgenic Mice; Vesicle; adipocyte differentiation; blood glucose regulation; glucose tolerance; glucose transport; glucose uptake; insight; insulin mediators; insulin signaling; novel; palmitoylation; public health relevance; research study

DESCRIPTION (provided by applicant): We have studied Akt, the direct effector of PI3K and the primary mediator of insulin's metabolic actions. In the course of those studies, we isolated ClipR-59, whose expression is elevated during adipocyte differentiation and decreased during development of obesity, as an Akt interaction protein. ClipR-59 does not involve Akt activation. Instead, it modulates Akt cellular compartmentalization following Akt activation, in particular, Akt membrane association. The regulation of Akt membrane association by ClipR-59 is critical for glucose transport, as evidenced by the finding that forced expression of ClipR-59 promotes, whereas silencing of ClipR-59 impairs, adipocyte glucose transport. Adipocyte glucose uptake is essential for the maintenance of whole-body glucose homeostasis. Due to the prevalence of obesity, type II diabetes has become epidemic and a major public health burden. Given that ClipR-59 interacts with Akt and regulates glucose transport, further studies of ClipR-59 are warranted studies. Our current studies indicated that a) expression of ClipR-59 in adipose tissue in mice results in reduced fat mass and increased glucose tolerance, an indication that ClipR-59 might play a role in maintaining whole-body glucose homeostasis; b) palmitoylation of ClipR-59, likely mediated by protein palmitoyltransferase DHHC17, is critical for ClipR-59 to modulate Akt cellular membrane association, implying that regulation of ClipR-59 palmitoylation by DHHC17 constitutes an important mechanism by which ClipR-59 modulates Akt signaling; and c) ClipR-59 is complexed with AS160, a Rab-GAP protein that connects insulin signaling and Glut4 vesicles. Because ClipR-59 also interacts directly with Akt, ClipR-59 may function as a scaffold protein to connect Akt signaling to AS160. To further study the function and regulation of ClipR-59, we proposed the experiments to address following specific questions: 1. Determine the impact of forced expression of ClipR-59 in adipose tissue on whole-body glucose homeostasis and on the development and progression of obesity, insulin resistance, and diabetes; 2. Determine the role of protein palmitoyltransferase DHHC17 in Akt signaling and adipocyte glucose transport by modulating ClipR-59 palmitoylation; and 3. Determine the functional importance of the interaction between ClipR-59 and AS160 in adipocyte glucose transport. Overall, the studies proposed here will demonstrate that how specified Akt insulin signaling by ClipR-59 modulates whole body glucose homeostasis and adipocyte function thereby, providing insight knowledge into the importance of specified Akt signaling in insulin action. PUBLIC HEALTH RELEVANCE: Adipocytes plays an essential role in maintaining energy homeostasis via glucose uptake and adipokine production. The studies proposed are to investigate how specified insulin signaling through interaction between Akt and ClipR-59 modulates glucose transport and adipocyte function. Thus, this research will provide invaluable knowledge to understand the development of fat insulin resistance and identify novel drug target for treatment of type II diabetes.

描述（由申请人提供）：我们研究了Akt，它是PI 3 K的直接效应子，也是胰岛素代谢作用的主要介质。在这些研究的过程中，我们分离了ClipR-59，其表达在脂肪细胞分化过程中升高，在肥胖发展过程中降低，作为Akt相互作用蛋白。ClipR-59不涉及Akt激活。相反，它调节Akt活化后的Akt细胞区室化，特别是Akt膜缔合。ClipR-59对Akt膜结合的调节对于葡萄糖转运至关重要，如通过以下发现所证明的：ClipR-59的强制表达促进脂肪细胞葡萄糖转运，而ClipR-59的沉默损害脂肪细胞葡萄糖转运。脂肪细胞葡萄糖摄取对于维持全身葡萄糖稳态是必不可少的。由于肥胖症的流行，II型糖尿病已成为流行病和主要的公共卫生负担。鉴于ClipR-59与Akt相互作用并调节葡萄糖转运，因此有必要对ClipR-59进行进一步研究。我们目前的研究表明，a）ClipR-59在小鼠脂肪组织中的表达导致脂肪量减少和葡萄糖耐量增加，这表明ClipR-59可能在维持全身葡萄糖稳态中起作用; B）可能由蛋白棕榈酰转移酶DHHC 17介导的ClipR-59的棕榈酰化对于ClipR-59调节Akt细胞膜结合是关键的，暗示DHHC 17对ClipR-59棕榈酰化的调节构成ClipR-59调节Akt信号传导的重要机制;和c）ClipR-59与AS 160复合，AS 160是连接胰岛素信号传导和Glut 4囊泡的Rab-GAP蛋白。由于ClipR-59也直接与Akt相互作用，因此ClipR-59可能作为支架蛋白将Akt信号传导连接到AS 160。为了进一步研究ClipR-59的功能和调控，我们提出了以下具体问题的实验：1。确定脂肪组织中ClipR-59的强制表达对全身葡萄糖稳态以及肥胖、胰岛素抵抗和糖尿病的发展和进展的影响; 2.通过调节ClipR-59棕榈酰化来确定蛋白棕榈酰转移酶DHHC 17在Akt信号传导和脂肪细胞葡萄糖转运中的作用;以及3.确定ClipR-59和AS 160在脂肪细胞葡萄糖转运中相互作用的功能重要性。总体而言，本文提出的研究将证明ClipR-59如何调节全身葡萄糖稳态和脂肪细胞功能，从而深入了解特定Akt信号在胰岛素作用中的重要性。 公共卫生相关性：脂肪细胞通过葡萄糖摄取和脂肪因子产生在维持能量稳态中起重要作用。这些研究旨在探讨Akt和ClipR-59之间的相互作用如何调节胰岛素信号转导和脂肪细胞功能。因此，这项研究将提供宝贵的知识，了解脂肪胰岛素抵抗的发展，并确定新的药物靶点治疗2型糖尿病。