The insulin-regulated aminopeptidase: a companion and regulator of GLUT4.
The insulin-regulated membrane aminopeptidase (IRAP) was originally identified in fat and muscle cells as a major protein in intracellular vesicles that also harbor the insulin-responsive glucose transporter GLUT4. IRAP, like GLUT4, predominantly localizes to these intracellular vesicles under basal conditions. In response to insulin IRAP, like GLUT4, translocates to the plasma membrane. Purification and cloning of IRAP revealed that it was a novel member of the family of zinc-dependent membrane aminopeptidases. Upon the cloning of the human placental oxytocinase (P-LAP) it was discovered that IRAP and P-LAP were the rat and human homologues of the same protein. The expression of IRAP/P-LAP is not limited to fat and muscle cells, and the subcellular distribution of IRAP/P-LAP is regulated by different peptide hormones and exercise. IRAP/P-LAP cleaves several peptide hormones in vitro. In insulin- and oxytocin-treated cells, concomitant with the appearance of IRAP/P-LAP at the cell surface, aminopeptidase activity toward extracellular substrates increases. A physiological function for IRAP/P-LAP may thus be the processing of circulating peptide hormones. These extracellular substrates, however, would be processed efficiently only when IRAP/P-LAP gets access to them after translocation to the cell surface upon stimulation of cells with insulin or other factors. The in vivo substrates for IRAP/P-LAP remain to be determined. The initial characterization of mice in which IRAP/P-LAP was deleted (IRAP -/- mice) revealed that GLUT4 protein levels were dramatically decreased in all fat and muscle tissues. This finding suggests a function for IRAP/P-LAP in the regulation of GLUT4 levels. Further characterization of the IRAP -/- mice is required to elucidate the role IRAP/P-LAP may play in the control of peptide hormone metabolism.
Keller
Susanna R
SR
University of Virginia, Department of Internal Medicine-Division of Endocrinology, PO Box 801409, Charlottesville VA 22908, USA. srk4b@virginia.edu
D000818:Animals; D010122:Cystinyl Aminopeptidase / Q000378:metabolism* / Q000502:physiology; D051275:Glucose Transporter Type 4; D006801:Humans; D007328:Insulin / Q000502:physiology*; D009004:Monosaccharide Transport Proteins / Q000378:metabolism* / Q000502:physiology; D009124:Muscle Proteins
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495692:SLC2A4 protein, human; D010122:Cystinyl Aminopeptidase