The ultimate objective of this research is to develop a novel treatment for diabetes based on the enhancement of insulin action through the inhibition of an insulin receptor-specific phosphotyrosine phosphatase (PTPase). Phosphorylation of the insulin receptor beta-subunit, in response to insuli binding, has been correlated with activation of the pleiotrophic intra- cellular insulin signal. Modulation of the phosphorylation state of the insulin receptor could affect post-receptor signalling events. The specifi aims of this proposal are to identify and purify as insulin receptor PTPase(s). During Phase I, we propose to identify and partially purify an insulin receptor-specific PTPase. The specificity of the phosphatase will be examined comparing dephosphorylation of the insulin receptor to other phosphotyrosine, phosphoserine, and phosphothreonine-containing substrates. During Phase II, we will continue purification, generate monoclonal antibodies, and identify the cDNA encoding the insulin receptor PTPase activity.