The aim of the project is a better understanding of the role of protein phosphorylation in the mechanisms of action of hormones such as insulin, glucagon and catecholamines. The initial target of hormonal control to be studied is glycogen metabolism, and in particular, the multiply phosphorylated enzyme, glycogen synthase, in liver and muscle. What is the detailed relationship between covalent phosphorylation and glycogen synthase activity? Which phosphorylation sites are linked to the actions of different hormones? What are the different protein kinases and phosphatases involved? Can mechanisms of regulating the converting enzymes be identified? How does the potential regulation in liver and muscle differ, and can differences be related to the distinct roles of glycogen in these two tissues? Experimental approaches will combine the study of isolated enzymes with investigations of intact muscle and isolated hepatocytes. A long term objective is to improve knowledge of the diversity of protein kinases present in cells and of their potential roles in different cellular processes. In this way, it may be possible to build a wider and more coordinated view of the regulatory role of protein phosphorylation, and hopefully link this with the action of hormones and other extracellular agents. The thrust of the whole program is to analyze hormonal and cellular controls at a biochemical level. Of course, we believe that advancements in the knowledge of the mechanisms of action of insulin, glucagon and catecholamines can have important implications for pathological situations, notably in the case of impaired insulin function, for insulin-dependent and insulin-independent diabetes.
