Insulin stimulated ubiquitin-like modification

胰岛素刺激的泛素样修饰

基本信息

批准号：
7260014
负责人：
JONATHAN BOGAN
金额：
$ 30.53万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7260014
关键词：
Abbreviations Adipocytes Affinity Chromatography Binding Biochemical Biological C-terminal Cell membrane Cell surface Cells Characteristics Cleaved cell Complex Coupled Data Defect Deubiquitinating Enzyme Development Endocytosis Enzymes Family Fatty acid glycerol esters GLUT4 gene GTP Binding GTP-Binding Proteins GTPase TC10 Glucose Transporter Goals Hormones Immunoprecipitation Insulin Insulin Receptor Insulin Resistance Interferons Lead Ligands Light Mediating Membrane Methods Microsomes Mitosis Modeling Modification Molecular Molecular Motors Muscle Mutation Analysis N-terminal Non-Insulin-Dependent Diabetes Mellitus Pathway interactions Phosphatidylinositols Phosphorylation Phosphotransferases Physiologic pulse Play Process Protein Binding Protein Biosynthesis Proteins Proteomics Public Health Pulse taking Purpose RNA Interference Regulation Research Personnel Role SNAP receptor Signal Pathway Signal Transduction Site Small Interfering RNA Techniques Testing Tissues Transferrin Receptor UBD protein Ubiquitin Ubiquitin Like Proteins Western Blotting Work blood glucose regulation carbohydrate metabolism cell type glucose transport glucose uptake insulin signaling intracellular protein transport novel programs protein degradation protein localization location receptor response rho small hairpin RNA soluble NSF attachment protein syntaxin 16 syntaxin 6 trafficking trans-Golgi Network

项目摘要

DESCRIPTION (provided by applicant): Ubiquitin-like modification is a conserved biochemical mechanism that is used by cells for various purposes. These include targeted degradation of proteins, endocytosis of receptors, regulation of protein localization, and signal transduction. Apart from a role of ubiquitin itself to modulate insulin receptors and IRS proteins, ubiquitin-like modifications have not been described to play a prominent role in insulin signaling. TUG was identified as a target of insulin signaling, and is implicated regulating GLUT4 glucose transporter trafficking and glucose uptake in adipocytes. According to the proposed model, TUG acts by "tethering" GLUT4 transporters intracellularly in the absence of insulin, excluding them from the plasma membrane and limiting glucose uptake. Insulin "untethers" the transporters to redistribute GLUT4 and to enhance glucose transport into cells. The mechanism by which insulin acts on TUG and GLUT4 is not well understood. The present proposal will test the hypothesis that insulin stimulates rapid and site-specific cleavage of TUG to liberate an amino terminal fragment, TUGUL, that is a new ubiquitin-like modifier. Using cultured 3T3-L1 adipocytes, several biochemical and cell biological approaches will be used in Aim 1 to test whether insulin stimulates TUG cleavage, and whether this is required for insulin to mobilize GLUT4. Aim 2 will test the hypothesis that TUGUL functions as a ubiquitin-like modifier, and will study the role of the putative TUG C terminal cleavage product. Aim 3 will study how the insulin signal may act on TUG to cause its processing. It is anticipated that, together, accomplishment of these aims will begin to define a novel pathway for insulin regulated ubiquitin-like modification. Furthermore, it is anticipated that the results will have importance for understanding how insulin stimulates glucose uptake. Type 2 diabetes is a major public health problem that results in part from a defect in the ability of insulin to stimulate glucose uptake. It is anticipated that the proposed studies of insulin action and glucose uptake will lead to a greater understanding of mechanisms that may contribute to the development of type 2 diabetes.

描述（由申请人提供）：泛素样修饰是一种保守的生化机制，被细胞用于多种目的。这些包括蛋白质的靶向降解、受体的内吞作用、蛋白质定位的调节和信号转导。除了泛素本身调节胰岛素受体和 IRS 蛋白的作用外，泛素样修饰尚未被描述在胰岛素信号传导中发挥重要作用。 TUG 被确定为胰岛素信号转导的靶标，并参与调节脂肪细胞中的 GLUT4 葡萄糖转运蛋白运输和葡萄糖摄取。根据提出的模型，TUG 在没有胰岛素的情况下通过在细胞内“束缚”GLUT4 转运蛋白来发挥作用，将它们排除在质膜之外并限制葡萄糖的摄取。胰岛素“解开”转运蛋白，重新分配 GLUT4 并增强葡萄糖转运到细胞中。胰岛素作用于 TUG 和 GLUT4 的机制尚不清楚。目前的提案将检验这样的假设：胰岛素刺激 TUG 快速且位点特异性的裂解，释放氨基末端片段 TUGUL，这是一种新的类泛素修饰剂。使用培养的 3T3-L1 脂肪细胞，目标 1 将使用多种生化和细胞生物学方法来测试胰岛素是否刺激 TUG 裂解，以及这是否是胰岛素动员 GLUT4 所必需的。目标 2 将检验 TUGUL 作为泛素样修饰剂的假设，并将研究假定的 TUG C 末端裂解产物的作用。目标 3 将研究胰岛素信号如何作用于 TUG 以引起其处理。预计这些目标的实现将开始定义胰岛素调节的泛素样修饰的新途径。此外，预计该结果对于了解胰岛素如何刺激葡萄糖摄取具有重要意义。 2 型糖尿病是一个主要的公共卫生问题，部分原因是胰岛素刺激葡萄糖摄取的能力缺陷造成的。预计拟议的胰岛素作用和葡萄糖摄取研究将有助于更好地了解可能导致 2 型糖尿病发生的机制。