Receptor 'transactivation' in insulin signaling.

描述：（扫描自申请人摘要）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 代谢转变为合成代谢模式，脂质激酶产生抗凋亡 信号和酪氨酸激酶刺激细胞生长。目前的模型建议 胰岛素反应是由内在配体刺激的酪氨酸 受体的激酶活性作用于一小部分酪氨酸 磷蛋白衔接子然而，最近的工作已经开始揭示广泛的 胰岛素家族受体与其他信号之间的串扰网络 包括异源三聚体G蛋白和经典受体酪氨酸的转换器 激酶。在这项提案中，我们提供了初步数据，表明IGF-1 受体刺激抗凋亡IRS 1/磷脂酰肌醇3-激酶/Akt 通过不同的细胞周期调控机制， 机制等而IGF- 1受体介导的IRS蛋白磷酸化 控制抗凋亡途径，IGF-1诱导的促有丝分裂信号需要 表皮生长因子（EGF）样配体从细胞表面的释放 和EGF受体的旁分泌“反式激活”。IGF- 1与 EGF受体是通过基质金属蛋白酶依赖的切割介导的， 肝素结合（HB）-EGF，也涉及百日咳毒素敏感的过程 异源三聚体G蛋白。该提案的主要目标是， 胰岛素/IGF-1受体，EGF受体， 和异源三聚体G蛋白，并确定这些蛋白的贡献， 转录调控和细胞增殖控制的机制 通过胰岛素和IGF- 1受体。本提案的一个具体目的是确定 胰岛素和IGF- 1受体调节基质的机制 金属蛋白酶来控制EGF受体配体的胞外域脱落。 另一个目的是确定胰岛素/IGF- 1之间的串扰机制， 受体和异源三聚体G蛋白，并确定的作用 异源三聚体G蛋白在胰岛素和IGF- 1受体介导的 ERK 1/2 MAP激酶级联。第三个目标是确定贡献 胰岛素/IGF- 1受体、异源三聚体G蛋白和 表皮生长因子受体对转录调控和细胞凋亡的调控 在多种胰岛素敏感细胞类型中增殖。实验将 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 分离潜在有害增殖效应的方法 胰岛素家族受体的抗凋亡和代谢作用。

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.