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(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，以及信号转导。除了泛素本身调节胰岛素受体和IRS蛋白的作用外，泛素样修饰还没有被描述为在胰岛素信号转导中发挥显著作用。TUG被认为是胰岛素信号转导的靶点，并参与调节GLUT4葡萄糖转运体的运输和脂肪细胞对葡萄糖的摄取。根据提出的模型，在没有胰岛素的情况下，TUG通过将GLUT4转运体“拴在”细胞内，将它们排除在质膜之外，限制葡萄糖的摄取。胰岛素“解开”转运蛋白，重新分配GLUT4，加强葡萄糖向细胞的转运。胰岛素作用于TUG和GLUT4的机制尚不清楚。目前的提议将检验这一假设，即胰岛素刺激TRAG的快速和位点特异性切割以释放氨基末端片段TUGUL，这是一种新的泛素样修饰物。使用培养的3T3-L1脂肪细胞，目标1将使用几种生化和细胞生物学方法来测试胰岛素是否刺激TUG切割，以及这是否是胰岛素动员GLUT4所必需的。目的2将验证TUGUL作为泛素样修饰物的假设，并将研究假定的TUG C末端切割产物的作用。目标3将研究胰岛素信号如何作用于TUG以导致其处理。预计，这些目标的实现将开始定义一条胰岛素调节的泛素样修饰的新途径。此外，预计这一结果将对理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健康问题，部分原因是胰岛素刺激葡萄糖摄取的能力存在缺陷。预计对胰岛素作用和葡萄糖摄取的拟议研究将使人们更好地理解可能有助于2型糖尿病发展的机制。

项目成果

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

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