Structure and Regulation of Type 1 Protein Phosphatases

描述(由申请人提供)：蛋白磷酸酶1型(PP 1)是一种 一种主要的丝氨酸/苏氨酸磷酸酶，参与了一种 基本细胞功能的多样性。一种常见的催化亚基 带有大量的PP1结合蛋白，其功能是靶向 酶与不同的亚细胞隔间结合，赋予底物专一性 并控制活动。糖原靶向亚基的一个子集吸引了 特别注意，因为它们在荷尔蒙控制中的潜在作用 通过胰岛素和肾上腺素进行糖原代谢。其中，RGL和PTG已经成为 与肌肉糖原合成酶(GS)的胰岛素控制有关。近期工作 从首席研究员的实验室中，利用基因敲除小鼠， 表明Rgl实际上不是胰岛素或肾上腺素所必需的。 控制骨骼肌中的GS，但通过以下方式激活GS是必不可少的 肌肉收缩。因此，分子机制是最好的机制之一 已建立的胰岛素在细胞内的作用仍不完全清楚。 首席研究人员检测到一种胰岛素激活的磷酸酶 在野生型和Rgl基因敲除小鼠中，表明一种明显的磷酸酶 参与了胰岛素的作用。因此，这项建议的具体目标是： (1)鉴定胰岛素刺激的糖原合成酶磷酸酶，并 阐明胰岛素激活磷酸酶的分子机制； (2)探讨糖原靶向亚基PTG在激素调控中的作用 通过使用肌肉特异性基因敲除小鼠来研究糖原代谢，以及(3) 阐明Rg1介导的分子机制 收缩/运动诱导糖原合成酶的激活。要解决这些问题 问题，首席研究员将结合生化和分子 利用基因工程动物进行活体研究的生物学方法 模特们。这些研究的完成将产生重要的新信息 关于几种主要形式的蛋白磷酸酶的调节机制。 了解糖原代谢的收缩控制机制是 与肌肉功能有很大的相关性。此外，我们对这一问题的认识不断进步 胰岛素的作用对了解全身葡萄糖至关重要 代谢及其损害，如在糖尿病中。

DESCRIPTION (provided by the applicant): Protein phosphatase type 1 (PP 1) is a major serine/threonine phosphatase that has been implicated in the control of a variety of fundamental cell functions. A common catalytic subunit associates with a large number of PP1-binding proteins whose function is to target the enzyme to different subcellular compartments, to confer substrate specificity and to control activity. A subset of glycogen-targeting subunits has attracted particular attention because of their potential role in the hormonal control of glycogen metabolism by insulin and epinephrine. Of these, RGL and PTG have been implicated in insulin control of muscle glycogen synthase (GS). Recent work from the principal investigator's laboratory, utilizing knockout mice, has shown that RGL is in fact not required for either insulin or epinephrine control of GS in skeletal muscle, but is essential for activation of GS by muscle contraction. Therefore, the molecular mechanism for one of the best established intracellular actions of insulin remains incompletely understood. The principal investigator has detected an insulin-activated phosphatase both in wild type and in RGL knockout mice, indicating that a distinct phosphatase is involved in insulin action. Thus, the specific aims of this proposal are: (1) To characterize the insulin-stimulated glycogen synthase phosphatase and to elucidate the molecular mechanism by which insulin activates the phosphatase; (2) To probe the role of the glycogen-targeting subunit PTG in hormonal control of glycogen metabolism, by the use of muscle specific-knockout mice, and (3) To elucidate the molecular mechanism by which RGL mediates contraction/exercise-induced activation of glycogen synthase. To address these issues, the principal investigator will combine biochemical and molecular biological approaches with in vivo studies using genetically engineered animal models. Completion of these studies will generate important new information about the regulatory mechanisms of some major forms of protein phosphatase. Understanding the mechanism of contraction control of glycogen metabolism is of great relevance to muscle function. Furthermore, advances in our knowledge of insulin action are of central importance to understanding whole body glucose metabolism and its impairment, as in diabetes.