Serine / Threonine Phosphorylation and IRS1 Degradation

丝氨酸/苏氨酸磷酸化和 IRS1 降解

• 批准号: 7157682
• 负责人: Nancy Jeannette Fidyk
• 金额: $ 4.6万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7157682
• 关键词: insulin receptor; insulin sensitivity /resistance; molecular pathology; molecular site; noninsulin dependent diabetes mellitus; phosphorylation; postdoctoral investigator; posttranslational modifications; protein degradation; protein kinase; protein structure; protein structure function; serine; site directed mutagenesis; threonine

DESCRIPTION (provided by applicant): Type 2 diabetes is characterized by systemic insulin resistance that cannot be corrected by increased insulin secretion. IRS proteins, important insulin receptor-signaling propagators, represent a potential point of signal breakdown that could lead to insulin resistance. Low IRS protein expression has been observed in humans who have advanced T2 diabetes. Low expression could be due to a number of reasons including increased protein degradation by the 26S proteosome. This study aims at understanding the molecular cues needed to trigger IRS-1 degradation. MS analysis has revealed new S/T phosphorylation sites that are present in IRS-1, only when it is isolated in the presence of proteosome inhibitors (e.g. MG132). Using site- specific mutagenesis and phospho-specific mAbs, each of these sites will be examined for its impact on IRS- 1 protein degradation. Potential kinases that regulate IRS-1 degradation will be investigated using MS analysis as well. This work will highlight previously unappreciated regulatory sites among the numerous S/T residues contained within IRS-1, a key suspect in the development of insulin resistance, and it will identify new IRS-1 regulatory proteins that could be potential drug targets for the treatment of T2 diabetes.

描述（由申请人提供）：2型糖尿病的特点是全身胰岛素抵抗，不能通过增加胰岛素分泌来纠正。IRS蛋白是重要的胰岛素受体信号传导体，它代表了可能导致胰岛素抵抗的潜在信号分解点。在晚期T2糖尿病患者中观察到低IRS蛋白表达。低表达可能是由于多种原因，包括26S蛋白体的蛋白质降解增加。本研究旨在了解触发IRS-1降解所需的分子线索。质谱分析揭示了IRS-1中存在新的S/T磷酸化位点，只有当它在蛋白体抑制剂（例如MG132）存在的情况下分离时才存在。使用位点特异性诱变和磷酸化特异性单克隆抗体，这些位点中的每一个都将被检查其对IRS- 1蛋白降解的影响。调控IRS-1降解的潜在激酶也将使用质谱分析进行研究。这项工作将突出IRS-1中包含的众多S/T残基中先前未被认识的调控位点，这是胰岛素抵抗发展的关键怀疑，它将识别新的IRS-1调节蛋白，可能是治疗T2糖尿病的潜在药物靶点。