Receptor 'transactivation' in insulin signaling.

描述：(摘自申请人的摘要)对胰岛素的反应， 葡萄糖转运蛋白重新分布到质膜、葡萄糖和脂质 新陈代谢进入合成代谢模式，脂蛋白激酶产生抗细胞凋亡 信号和酪氨酸激酶刺激细胞生长。当前的模型建议 胰岛素反应来自内源性配体刺激的酪氨酸 作用于一小部分酪氨酸的受体的激酶活性 磷酸蛋白适配器。然而，最近的研究开始揭示出广泛的 胰岛素家族受体与其他信号之间的串扰网络 包括异三聚体G蛋白和经典受体酪氨酸在内的转导分子 激活剂。在这项提案中，我们提供了初步数据，证明IGF-1 受体激活抗细胞凋亡的IRS1/磷脂酰肌醇3-激酶/Akt Shc/Grb2-SOS/RAS/ERK1/2信号通路与细胞增殖的差异 机械装置。而IGF-1受体介导的IRS蛋白的磷酸化 控制抗凋亡途径，IGF-1诱导的有丝分裂信号需要 表皮生长因子(EGF)样配体从细胞表面释放 和旁分泌“反式激活”的EGF受体。IGF-1和IGF-1之间的串扰 EGF受体由基质金属蛋白酶依赖的裂解介导 肝素结合(HB)-EGF，也涉及百日咳毒素敏感的过程 异三聚体G蛋白。这项提案的广泛目标是将 胰岛素/胰岛素样生长因子-1受体、表皮生长因子受体、 和异三聚体G蛋白，并确定这些蛋白的贡献 转录调控机制与细胞增殖控制 通过胰岛素和IGF-1受体。这项提案的一个具体目标是确定 胰岛素和胰岛素样生长因子-1受体调节基质的机制 金属蛋白水解酶控制EGF受体配体的胞外区脱落。 另一个目的是确定胰岛素/LGF-1之间的串扰机制 受体和异源三聚体G蛋白的作用及确定 胰岛素中异三聚体G蛋白和IGF-1受体介导的激活 ERK1/2的MAPK级联反应。第三个目标是确定贡献 胰岛素/LGF-1受体、异源三聚体G蛋白和胰岛素/LGF-1受体之间的相互作用 EGF受体对转录调控和细胞调控的作用 在各种类型的胰岛素敏感细胞中增殖。实验将会 使用永生化细胞系以及培养的肝细胞、脂肪细胞和 肌肉细胞。了解这些机制可能会导致药理学上的 解除核糖核酸潜在有害扩散影响的方法 胰岛素家族受体的抗细胞凋亡和代谢作用。

DESCRIPTION: (Scanned from the applicant's abstract) In response to insulin, glucose transporters redistribute to the plasma membrane, glucose and lipid metabolism shifts into an anabolic mode, lipid kinases generate anti-apoptotic signals, and tyrosine kinases stimulate cell growth. Current models propose that insulin responses arise from the intrinsic ligand-stimulated tyrosine kinase activity of the receptor acting upon a small subset of tyrosine phosphoprotein adapters. Recent work, however, has begun to reveal extensive networks of cross talk between insulin family receptors and other signal transducers including heterotrimeric G proteins and classical receptor tyrosine kinases. In this proposal, we provide preliminary data demonstrating that IGF-1 receptors stimulate the anti-apoptotic IRS1/Phosphatidylinositol 3-kinase/Akt pathway and the proliferative Shc/Grb2-Sos/Ras/ERK1/2 pathway by distinct mechanisms. Whereas IGF- 1 receptor-mediated phosphorylation of IRS proteins controls the antiapoptotic pathway, IGF-1-induced mitogenic signaling requires the release of epidermal growth factor (EGF)like ligands from the cell surface and paracrine "transactivation" of EGF receptors. Cross talk between IGF- 1 and EGF receptors is mediated by matrix metalloprotease-dependent cleavage of heparin-binding (HB)-EGF, process which also involves pertussis toxin-sensitive heterotrimeric G proteins. The broad goals of this proposal are to characterize the mechanisms of cross talk between insulin/IGF-1 receptors, EGF receptors, and heterotrimeric G proteins, and to determine contribution of these mechanisms to transcriptional regulation and the control of cell proliferation by insulin and IGF- 1 receptors. One specific aim of this proposal to determine the mechanism whereby insulin and IGF- 1 receptors regulate matrix metalloproteases to control ectodomain shedding of EGF receptor ligands. Another aim is to determine the mechanism of cross talk between insulin/lGF- 1 receptors and heterotrimeric G proteins and to define the role of heterotrimeric G proteins in insulin and IGF- 1 receptor-mediated activation of the ERK1/2 MAP kinase cascade. The third aim is to determine the contribution of cross talk between insulin/lGF- 1 receptors, heterotrimeric G proteins and EGF receptors to transcriptional regulation and the control of cell proliferation in a variety of insulin-sensitive cell types. Experiments will employ immortalized cell lines, as well as cultured hepatocyte, adipocyte and muscle cells. Understanding these mechanisms may lead to pharmacologic approaches to dissociate the potentially harmful proliferative effects of insulin family receptors from their anti-apoptotic and metabolic effects.