Structure and Regulation of Type 1 Protein Phosphatases

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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.