University of Virginia Health System

My major research interests are signaling from the insulin receptor, the regulation of membrane trafficking to the plasma membrane by insulin, and the subsequent modification of cell surface function. The present research in my laboratory focuses on the characterization of the insulin-regulated membrane aminopeptidase (IRAP). IRAP is a member of the family of zinc-dependent membrane aminopeptidases. It was originally identified as a major protein in the intracellular vesicles of fat and muscle cells which also harbor the insulin-responsive glucose transporter GLUT4. IRAP, like GLUT4, redistributes from this intracellular location to the cell surface in response to insulin. It is well known that the insulin-induced redistribution of GLUT4 in fat and muscle cells is the major mechanism responsible for the disposal of glucose after a meal and thus the maintenance of glucose homeostasis. The physiological function of IRAP and the role it plays in insulin action are unknown. My hypothesis is that IRAP processes peptide hormones and that insulin through eliciting the translocation of IRAP to the cell surface increases the processing of extracellular substrates. In support of this hypothesis, we have shown that IRAP cleaves several peptide hormones in vitro, and that in insulin-treated isolated fat cells, concomitant with IRAP’s appearance at the cell surface, aminopeptidase activity toward extracellular substrates increases. However, the in vivo substrates for IRAP are not known. To address the question of the function of IRAP in a physiological context, we have generated mice lacking IRAP (referred to as IRAP KO mice). The initial analysis has revealed several abnormalities in these mice. The ongoing research aims at elucidating the molecular basis for the observed changes in the IRAP KO mice and at determining the specific role of IRAP in these effects. A second project addresses the question of the insulin-regulated trafficking of IRAP. IRAP has been well characterized in muscle (both skeletal muscle and heart) and fat cells with regard to its subcellular localization and regulation by insulin. IRAP, in contrast to GLUT4, is not restricted to these tissues, but is also expressed at comparable levels in most major tissues. We are in the process of examining where IRAP is localized in these tissues and whether insulin affects the subcellular distribution of IRAP. Research in this area has direct implications for diseases characterized by insulin resistance (non-insulin dependent diabetes mellitus, hypertension, obesity). The insulin-induced translocation of GLUT4 and IRAP are impaired in insulin-resistant individuals. The defect in the translocation of GLUT4 is most likely responsible for the decrease in glucose disposal present in these diseases. The elucidation of the physiological role of IRAP in insulin action may thus provide novel insights at the molecular level into the primary cause of other defects present concomitant with insulin resistance.