The insulin-regulated aminopeptidase a companion and regulator of GLUT4

Abstract

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.

Fxna, a novel gene differentially expressed in the rat ovary at the time of folliculogenesis, is required for normal ovarian histogenesis

“…Peptidases bound to intracellular membranes may have fascinating functional properties as shown by the insulin-regulated aminopeptidase (IRAP), which is bound to intracellular membranes under basal conditions, but redistributes to the cell membrane in response to insulin stimulation (Keller, 2003). In type 2 diabetes, insulin action is impaired and the translocation of IRAP to the cell membrane fails to occur, suggesting that the absence of IRAPmediated peptide processing on the cell membrane is an intrinsic component of this pathology.…”

Human Leukocyte-derived Arginine Aminopeptidase

“…P-LAP is located in some intracellular vesicles, and stimulus-dependent translocation of the enzyme into the plasma membrane was observed in several biological systems (39 -43). It is generally believed that the physiological significance of P-LAP translocation is to enhance the cleavage of peptide hormone substrates at the cell surface (44). A-LAP/ ERAP1 is the first aminopeptidase localized and functions as an antigen-trimming enzyme in the lumenal side of the ER (9, 16).…”

Recycling of IRAP from the plasma membrane back to the insulin-responsive compartment requires the Q-SNARE syntaxin 6 but not the GGA clathrin adaptors

“…By contrast, IRAP shows broad tissue distribution (Keller, 2003). However, IRAP displays subcellular compartmentalization and insulin-stimulated trafficking properties that are indistinguishable from those of GLUT4 in both adipocytes and muscle cells (Kandror and Pilch, 1994a;Kandror and Pilch, 1994b;Kandror et al, 1994;Ueyama et al, 1999).…”

“…In addition to a short cytoplasmic tail region and a single transmembrane domain, IRAP has a large extracellular region that contains the catalytic and zinc-binding domains (Keller, 2004). IRAP is known to cleave a number of small peptides, including vasopressin, angiotensins III and IV, and oxytocin, among others, under in vitro conditions (Keller, 2003). Thus, IRAP could function in the processing of circulating peptide hormones, although its in vivo substrates remain unknown.…”

“…Subsequently identified as the placental leucine aminopeptidase (P-LAP), IRAP is a member of the zinc-dependent membrane aminopeptidase family (Keller, 2003). In addition to a short cytoplasmic tail region and a single transmembrane domain, IRAP has a large extracellular region that contains the catalytic and zinc-binding domains (Keller, 2004).…”