Assessment of Insulin Proteolysis in Rat Liver Endosomes

摘要: Insulin binding to insulin receptor (IR) at the cell surface results in activation of IR kinase and initiates translocation insulin-IR complexes clathrin-coated pits early endosomes containing internalized but still active receptors. In liver parenchyma, several mechanisms are involved regulation endosomal tyrosine activity. Two these regulatory level intraendosomal ligand. First, a progressive decrease pH mediated by vacuolar H(+)-ATPase proton pump promotes dissociation complex. Second, free dissociated is degraded soluble acidic insulinase, which has been identified as aspartic acid protease cathepsin D. This enzyme catalyzes cleavage Phe(B24)-Phe(B25) bond, generating major clipped molecule, A(1-21)-B(1-24) insulin, that can no longer bind within endosomes. Concomitant with, or shortly after, tyrosine-phosphorylated deactivated two independent processes: its rapid dephosphorylation endosome-associated phosphotyrosine phosphatase(s) association with molecular adaptor Grb14, resulting inhibition catalytic By mediating removal degradation circulating well deactivation activated IR, internalization insulin-receptor complex into represents mechanism negative signaling.