Insulin resistance is a well documented feature of Type II diabetes mellitus. The insulin receptor tyrosine kinase activity plays an important role in insulin signaling. The sponsor's laboratory have recently identified a specific physiological inhibitor of the human insulin receptor (IR) tyrosine kinase (TK) named alpha2HS glycoprotein. It has been demonstrated that this alpha2HS glycoprotein specifically inhibits insulin-induced signal transduction and mitogenesis. Research in our laboratory indicates that alpha2HSG may regulate insulin action and represents a useful tool for establishing the defect in states of insulin resistance. Towards this goal, the applicant's specific aims intend to: (a) clone the mouse AHSG cDNA , (b) to express the mouse alpha2HSG cDNA in the baculovirus expression system and (c) to establish the molecular level of interaction between alpha2HSG and the IR employing experimental chimeras between the mouse alpha2HSG and the human alpha2HSG proteins. The chimeras will be expressed using the baculovirus system allowing the identification of the alpha2HSG domains involved in inhibition of the tyrosine kinase activity of the IR.
