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: 8664367
• 负责人: KEYONG DU
• 金额: $ 32.66万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664367
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Cell Nucleus; Cells; Cellular Membrane; Clip; Complex; Cytosol; Development; Diabetes Mellitus; Drug Targeting; 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; 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.

描述（由申请人提供）：我们研究了 Akt，它是 PI3K 的直接效应物和胰岛素代谢作用的主要介质。在这些研究过程中，我们分离出了 ClipR-59，作为一种 Akt 相互作用蛋白，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。 ClipR-59 不涉及 Akt 激活。相反，它在 Akt 激活后调节 Akt 细胞区室化，特别是 Akt 膜关联。 ClipR-59 对 Akt 膜关联的调节对于葡萄糖转运至关重要，这一发现表明，ClipR-59 的强制表达可促进脂肪细胞葡萄糖转运，而沉默 ClipR-59 则会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至关重要。由于肥胖的流行，II型糖尿病已成为流行病并成为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发挥作用； b) ClipR-59 的棕榈酰化（可能由蛋白质棕榈酰转移酶 DHHC17 介导）对于 ClipR-59 调节 Akt 细胞膜关联至关重要，这意味着 DHHC17 对 ClipR-59 棕榈酰化的调节构成了 ClipR-59 调节 Akt 信号转导的重要机制； c) ClipR-59 与 AS160 复合，AS160 是一种连接胰岛素信号传导和 Glut4 囊泡的 Rab-GAP 蛋白。由于 ClipR-59 还直接与 Akt 相互作用，因此 ClipR-59 可能充当支架蛋白，将 Akt 信号传导连接到 AS160。为了进一步研究ClipR-59的功能和调控，我们提出实验来解决以下具体问题： 1.确定ClipR-59在脂肪组织中的强制表达对全身葡萄糖稳态以及对肥胖、胰岛素抵抗和糖尿病发生和进展的影响； 2. 通过调节ClipR-59棕榈酰化确定蛋白质棕榈酰转移酶DHHC17在Akt信号传导和脂肪细胞葡萄糖转运中的作用； 3. 确定 ClipR-59 和 AS160 之间相互作用在脂肪细胞葡萄糖转运中的功能重要性。总的来说，这里提出的研究将证明 ClipR-59 的特定 Akt 胰岛素信号传导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 信号传导在胰岛素作用中的重要性。

项目成果

ClipR-59 interacts with Elmo2 and modulates myoblast fusion.

ClipR-59 与 Elmo2 相互作用并调节成肌细胞融合。

• DOI: 10.1074/jbc.m114.616680
• 发表时间: 2015
• 期刊: The Journal of biological chemistry
• 作者: Sun,Yingmin;Ren,Wenying;Côté,Jean-François;Hinds,PhilipW;Hu,Xiaoxiang;Du,Keyong
• 通讯作者: Du,Keyong

Glut4 palmitoylation at Cys223 plays a critical role in Glut4 membrane trafficking.

• DOI: 10.1016/j.bbrc.2015.03.094
• 发表时间: 2015-05-08
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Ren, Wenying;Sun, Yingmin;Du, Keyong
• 通讯作者: Du, Keyong

Proteomic analysis of protein palmitoylation in adipocytes.

脂肪细胞中蛋白质棕榈酰化的蛋白质组学分析。

• DOI: 10.4161/adip.22117
• 发表时间: 2013
• 期刊: Adipocyte
• 影响因子: 3.3
• 作者: Ren W;Jhala US;Du K
• 通讯作者: Du K