Insulin stimulated ubiquitin-like modification

胰岛素刺激的泛素样修饰

• 批准号: 8066936
• 负责人: JONATHAN BOGAN
• 金额: $ 29.41万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066936
• 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; 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; lipid metabolism; novel; programs; protein complex; protein degradation; receptor; response; rho; small hairpin RNA; soluble NSF attachment protein; syntaxin 16; syntaxin 6; trafficking; trans-Golgi Network

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物化学机制，被细胞用于各种目的。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，还没有描述泛素样修饰在胰岛素信号传导中发挥重要作用。TUG被鉴定为胰岛素信号传导的靶点，并且涉及调节脂肪细胞中的GLUT 4葡萄糖转运蛋白运输和葡萄糖摄取。根据所提出的模型，TUG通过在不存在胰岛素的情况下在细胞内“拴系”GLUT 4转运蛋白而起作用，将它们从质膜排除并限制葡萄糖摄取。胰岛素“解开”转运蛋白的束缚，重新分配GLUT 4并增强葡萄糖转运到细胞中。胰岛素作用于TUG和GLUT 4的机制尚不清楚。目前的建议将测试的假设，胰岛素刺激快速和位点特异性切割的TUG释放的氨基末端片段，TUGUL，这是一个新的泛素样修饰剂。使用培养的3 T3-L1脂肪细胞，将在目的1中使用几种生物化学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GLUT 4所需的。目的2将检验TUGUL作为泛素样修饰剂的假设，并将研究推定的TUG C末端切割产物的作用。目的3研究胰岛素信号如何作用于TUG，引起TUG的加工。预期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，预计这些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能力的缺陷。预计胰岛素作用和葡萄糖摄取的拟议研究将导致对可能导致2型糖尿病发展的机制的更好理解。

项目成果

A proteolytic pathway that controls glucose uptake in fat and muscle.

• DOI: 10.1007/s11154-013-9276-2
• 发表时间: 2014-03
• 期刊: Reviews in endocrine & metabolic disorders
• 影响因子: 8.2
• 作者: Belman JP;Habtemichael EN;Bogan JS
• 通讯作者: Bogan JS

Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet.

• DOI: 10.1016/j.cmet.2013.09.004
• 发表时间: 2013-10-01
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Jimenez-Gomez Y;Mattison JA;Pearson KJ;Martin-Montalvo A;Palacios HH;Sossong AM;Ward TM;Younts CM;Lewis K;Allard JS;Longo DL;Belman JP;Malagon MM;Navas P;Sanghvi M;Moaddel R;Tilmont EM;Herbert RL;Morrell CH;Egan JM;Baur JA;Ferrucci L;Bogan JS;Bernier M;de Cabo R
• 通讯作者: de Cabo R