Insulin Action and Its Disturbances in Disease - part 1 ppsx

[...]... both in terminating the insulin signal and in insulin degradation (this being the major mechanism by which insulin is cleared from the circulation, particularly by the liver) The Figure 1. 4 CARBOXYL-TERMINAL REGION TYROSINE KINASE DOMAIN JUXTAMEMBRANE REGION EXTRACELLULAR REGION Substrate binding (IRS, Shc) Insulin receptor intracellular domain Adaptor binding ?? Y 115 8 Y 116 2 Y 116 3 Y1328 Y1334 Tyrosine... substrate kinase activity.68 CR L1 L2 e1 e2 L2′ CR′ insulin Fn Figure 1. 3 Insulin receptor ligand binding model (adapted from reference 15 ) Fn L1′ 10 THE INSULIN RECEPTOR AND DOWNSTREAM SIGNALLING INSULIN RECEPTOR STRUCTURE AND FUNCTION 11 Within the intracellular portion of the IR, the tyrosine kinase domain proper, of approximately 250 amino acids, is flanked by a juxtamembrane (JM) domain of approximately... kinase activation Substrate binding (APS) Adaptor binding (Grb10) K1030 S1037 S1305 S1327 T1348 ATP binding Y972 S967 12 THE INSULIN RECEPTOR AND DOWNSTREAM SIGNALLING INSULIN RECEPTOR STRUCTURE AND FUNCTION 13 endocytic machinery recognizes β-turn tyrosine motifs and/ or dileucine motifs in the receptor juxtamembrane domain. 81 – 83 Phosphorylation of the juxtamembrane tyrosines is not required for internalization,... reduction in IRS expression further impairs insulin signalling Several different kinases have been implicated in phosphorylating serine 307 of IRS -1 , including mTOR (activated by insulin itself) ,18 6, 18 7 JNK (activated by cytokines such as TNFα )18 8, 18 9 and IKKβ (activated by lipids, probably acting via PKC) .19 0 – 19 2 Interestingly, serine 307 is IRS -1 specific and is not conserved in IRS-2, although... domain interaction with membrane phospholipids144, 14 8 and/ or specific proteins ,14 9, 15 0 and is in uenced by phosphorylation of IRSs on serine residues .15 1, 15 2 Membrane targeting of IRSs may be important in bringing associated proteins such as PI 3-kinase and Grb2/Sos into proximity with their substrates, PtdIns(4,5)bisphosphate and Ras Following termination of insulin stimulation, phosphotyrosine... phosphorylation and/ or SH2 domain binding so that specific downstream signalling pathways are not engaged For instance, serines 612 and 632 are adjacent to tyrosines 608 and 628, which are known to be important in binding PI 3-kinase .13 5, 17 8 Phosphorylation of serine 612 apparently underlies the inhibition of IRS -1 - dependent PI 3-kinase signalling by PKC/MAPK .17 9 – 18 1 Second, serine phosphorylation may inhibit... PTB IR-JM Grb2-SH2 pY ?? pY Shc p52/p46 PTB ?? SH2 ?? IR-TK IR-TK Cbl-SH2 pY APS Pro PH BPS SH2 APS-pY CAP-SH3 Crk-SH2 pY pY c-Cbl SH2 Ring Pro Figure 1. 5 Insulin receptor substrates: schematic representation of insulin receptor substrates, their tyrosine phosphorylation sites (pY), and their interactions with other proteins 16 THE INSULIN RECEPTOR AND DOWNSTREAM SIGNALLING The so-called insulin receptor... characterized and binding sites have been identified for a number of transcription factors Such studies have provided some insights into mechanisms that may be responsible for the almost ubiquitous expression of IR ,10 8 – 11 1 the abundant expression in muscle, liver and fat ,10 9, 11 0, 11 2 – 11 5 the 14 THE INSULIN RECEPTOR AND DOWNSTREAM SIGNALLING regulatory effects of hormones ,11 6, 11 7 and increased expression in. .. are β-helical domains; CR is the cysteine-rich domain; Fn0, Fn1 and Fn2 are fibronectin type III repeats; the inserted region within Fn1 includes the site of cleavage between - and β-subunits; JM is the juxtamembrane region; TK is the tyrosine kinase domain; CT is the carboxyl-terminal domain Positions of inter-subunit disulphide links and ligand binding epitopes are as indicated The corresponding portion... in mediating the major actions of insulin. 5, 13 5 IRS proteins were first identified by anti-phosphotyrosine blotting of insulin- treated cells and tissues, and the original name pp185 reflected their apparent mass of 18 0 19 0 kDa as seen on polyacrylamide gels .13 6 pp185 was shown to be widely distributed but especially prominent in muscle and liver, and to be rapidly phosphorylated in response to insulin/ IGF . Glucocorticoid metabolism and obesity 217 8 .17 11 β-hydroxysteroid dehydrogenase (11 β-HSD) 218 8 .18 Isoenzymes of 11 β-HSD 218 8 .19 11 β-HSD and obesity 219 8.20 Sex steroid metabolism and obesity: oestrogen. 13 4 5.3 Candidate genes involved in the mechanisms of insulin resistance 13 4 5.4 Insulin signalling network 13 6 5.5 Factors leading to insulin resistance 13 7 5.6 Defining the function of the insulin. Data Insulin resistance : insulin action and its disturbances in disease / editors, Sudhesh Kumar, Stephen O’Rahilly. p. cm. Includes bibliographical references and index. ISBN 0-4 7 0-8 500 8-6 1. Insulin