Serine / Threonine Phosphorylation and IRS1 Degradation

描述(申请人提供)：2型糖尿病的特征是全身性胰岛素抵抗，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播者，是导致胰岛素抵抗的潜在信号失调点。在患有晚期T2糖尿病的人中观察到低IRS蛋白表达。低表达可能是由于许多原因，包括26S蛋白小体加速蛋白质降解。本研究旨在了解触发IRS-1降解所需的分子信号。MS分析显示，只有在蛋白酶体抑制剂(如MG132)存在的情况下，IR-1中才存在新的S/T磷酸化位点。利用定点突变和磷酸特异性单抗，将检查这些位点中的每一个对IRS-1蛋白降解的影响。调节IRS-1降解的潜在激酶也将使用MS分析进行研究。这项工作将突出IRS-1中包含的众多S/T残基中以前未被识别的调控位点，IRS-1是胰岛素抵抗发生的关键嫌疑人，它将识别新的IRS-1调节蛋白，这些蛋白可能成为治疗T2糖尿病的潜在药物靶点。

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.