Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.56 (insulin-degrading enzyme)
 737 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin receptor kinase (IRK) is a tyrosine kinase whose activation, subsequent to insulin binding, is essential for insulin-signalling in target tissues. Insulin binding to its cell surface receptor is rapidly followed by internalization of insulin-IRK complexes into the endosomal apparatus (EN) of the cell. Internalization of insulin into target organs, especially liver, is implicated in effecting insulin clearance from the circulation. Internalization mediates IRK downregulation and hence attenuation of insulin sensitivity although most internalized IRKs readily recycle to the plasma membrane at physiological levels of insulin. A role for internalization in insulin signalling is indicated by the accumulation of activated IRKs in ENs. Furthermore, the maximal level of IRK activation has been shown to exceed that attained at the cell surface. Using an in vivo rat liver model in which endosomal IRKs are exclusively activated has revealed that IRKs at this intracellular locus are able by themselves to promote IRS-1 tyrosine phosphorylation and induce hypoglycemia. Furthermore, studies with isolated rat adipocytes reveal the EN to be the principle site of insulin-stimulated IRS-1 tyrosine phosphorylation and associated PI3K activation. Key steps in the termination of the insulin signal are also operative in ENs. Thus, an endosomal acidic insulinase has been identified which limits the extent of IRK activation. Furthermore, IRK dephosphorylation is effected in ENs by an intimately associated phosphotyrosine phosphatase(s) which, in rat liver, appears to regulate IRK activity in both a positive and negative fashion. Thus, insulin-mediated internalization of IRKs into ENs plays a crucial role in effecting and regulating signal transduction in addition to modulating the levels of circulating insulin and the cellular concentration of IRK in target tissues.
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PMID:Insulin receptor internalization and signalling. 960 14

Insulin binding to insulin receptor (IR) at the cell surface results in the activation of IR kinase and initiates the translocation of insulin-IR complexes to clathrin-coated pits and to early endosomes containing internalized but still active receptors. In liver parenchyma, several mechanisms are involved in the regulation of endosomal IR tyrosine kinase activity. Two of these regulatory mechanisms are at the level of intraendosomal ligand. First, a progressive decrease in endosomal pH mediated by the vacuolar H(+)-ATPase proton pump promotes dissociation of the insulin-IR complex. Second, free dissociated insulin is degraded by a soluble endosomal acidic insulinase, which has been identified as aspartic acid protease cathepsin D. This enzyme catalyzes the cleavage of insulin at the Phe(B24)-Phe(B25) bond, generating a major clipped molecule, A(1-21)-B(1-24) insulin, that can no longer bind to IR within endosomes. Concomitant with, or shortly after, the tyrosine-phosphorylated IR is deactivated by two independent processes: its rapid dephosphorylation by endosome-associated phosphotyrosine phosphatase(s) and its association with the molecular adaptor Grb14, with resulting inhibition of IR catalytic activity. By mediating the removal and degradation of circulating insulin, as well as the deactivation of the activated IR, internalization of the insulin-receptor complex into endosomes represents a major mechanism involved in the negative regulation of insulin signaling.
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PMID:Assessment of insulin proteolysis in rat liver endosomes: its relationship to intracellular insulin signaling. 2437 14