Release of insulin receptor substrate proteins from an intracellular complex coincides with the development of insulin resistance
Release of insulin receptor substrate proteins from an intracellular complex coincides with the development of insulin resistance
复制标题
DOI：
10.1074/jbc.275.6.3819
复制
发表时间：
2000-02-11
影响因子：
4.8
通讯作者：
James, DE
中科院分区：
文献类型：
--
作者：
Clark, SF;Molero, JC;James, DE
胰岛素受体底物 (IRS) 蛋白是胰岛素受体 (IR) 的主要底物，IRS-1 与脂肪细胞中的不溶性多蛋白复合物（可能是细胞骨架）结合。这种定位可能有助于与细胞表面的红外相互作用。在本研究中，我们检验了这样的假设：IRS 蛋白从该位置的释放可能是胰岛素脱敏的机制。我们发现第二种 IRS 蛋白 IRS-2 与脂肪细胞中的多蛋白复合物相关，其特征与 IRS-1 复合物相似。胰岛素处理（15-60 分钟）导致 IRS-1 和 IRS-2 从该复合物（高速沉淀；HSP）释放到细胞质中，而酪氨酸磷酸化 IRS 蛋白的水平保持恒定。长期胰岛素治疗导致 HSP 中 IRS-1 和 IRS-2 急剧减少，最终（>2 小时）导致 IRS 蛋白降解和酪氨酰磷酸化 IRS 蛋白水平降低。冈田酸可快速诱导脂肪细胞中的胰岛素抵抗，与 TR 功能无关，导致 IRS-1 几乎定量地释放到细胞质中，与酪氨酰磷酸化 IRS 蛋白的显着减少相称。血小板衍生生长因子是一种已知会损害胰岛素信号传导的因子，它会导致 IRS 蛋白从 HSP 中更温和地释放。总的来说，这些结果表明，IRS-1/IRS-2 组装成多蛋白复合物有利于与 IR 的偶联，并且从该位置的调节释放可能代表了胰岛素抵抗的新机制。
Insulin receptor substrate (IRS) proteins are major substrates of the insulin receptor (IR), IRS-1 associates with an insoluble multiprotein complex, possibly the cytoskeleton, in adipocytes. This localization may facilitate interaction with the IR at the cell surface. In the present study, we examined the hypothesis that the release of IRS proteins from this location may be a mechanism for insulin desensitization. We show that a second IRS protein, IRS-2, is associated with a multiprotein complex in adipocytes with similar characteristics to the IRS-1 complex. Insulin treatment (15-60 min) caused the release of IRS-1 and IRS-2 from this complex (high speed pellet; HSP) into the cytosol, whereas the level of tyrpsyl-phosphorylated IRS proteins remained constant. Chronic insulin treatment resulted in a dramatic reduction in IRS-1 and IRS-2 in the HSP, eventually (>2 h) leading to IRS protein degradation and decreased levels of tyrosyl-phosphorylated IRS proteins. Okadaic acid, which rapidly induces insulin resistance in adipocytes independently of TR function, caused an almost quantitative release of IRS-1 into the cytosol commensurate with a significant reduction in tyrosyl-phosphorylated IRS proteins. Platelet-derived growth factor, a factor known to compromise insulin signaling, caused a more moderate release of IRS proteins from the HSP. Collectively, these results suggest that the assembly of IRS-1/IRS-2 into a multiprotein complex facilitates coupling to the IR and that the regulated release from this location may represent a novel mechanism of insulin resistance.