Impact of Natural IRS-1 Mutations on Insulin Signals: Mutations of IRS-1 in the PTB Domain and Near SH2 Protein Binding Sites Result in Impaired Function at Different Steps of IRS-1 Signaling

Yoshimura, Ryohei; Araki, Eiichi; Ura, S.; Todaka, Mikio; Tsuruzoe, Kaku; Furukawa, Noboru; Motoshima, Hiroyuki; Yoshizato, Kazuaki; Kaneko, Katsuya; Matsuda, Kouki; Kishikawa, Hiroki; Shichiri, Motoaki

doi:10.2337/diab.46.6.929

Cited by 44 publications

(21 citation statements)

References 38 publications

(72 reference statements)

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“…We identified 44 articles published until January 2002 on the Gly972Arg polymorphism in Type 2 diabetic patients and control subjects. We excluded five studies because they examined the expression of the mutation instead of the prevalence [29,30,31,32,33]. We excluded seven studies because case subjects were relatives of Type 2 diabetic patients [34,35,36,37] or were obese subjects [27,38,39] instead of Type 2 diabetic patients.…”

Section: Methodsmentioning

confidence: 99%

Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies

et al. 2003

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Aims/hypothesis. Several case-control studies have examined the association between the Gly972Arg variant in the IRS-1 gene and Type 2 diabetes, but most had limited power and results could therefore be conflicting. Methods. We systematically reviewed the literature by means of a meta-analysis and investigated sources of heterogeneity in results of different studies.Results. The summary risk ratio, based on 3408 cases and 5419 control cases from 27 studies, was 1.25 (95% CI 1.05-1.48). The results, however, differed according to the type of study, method of verifying non-diabetic status of the control subjects, and age of the case subjects. Population-based studies reported lower odds ratios than hospital-based studies (OR 0.98, 95% CI 0.74-1.30 vs OR 1.43, 95% CI 1.17-1.74). Also, the diagnostic test to exclude diabetes amongst control subjects interacted with the association between the IRS-1 Gly972Arg variant and Type 2 diabetes (p=0.03). Finally, the odds ratio reduced with increasing age (p=0.03). Conclusion/interpretation. Overall, carriers of the 972Arg variant of the IRS-1 gene are at a 25% increased risk of having Type 2 diabetes compared with non-carriers. The odds ratios are generally higher in hospital-based studies, including relatively young, symptomatic, cases. [Diabetologia (2003) 46:990-995]

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Section: Methodsmentioning

confidence: 99%

Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies

et al. 2003

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“…While the prevalence of each of these polymorphisms alone is not different between patients and healthy controls, the combined prevalence of these polymorphisms, along with the G972R polymorphism, is threefold greater compared with healthy controls (29.5 vs. 8.5%; P < 0.05). In vitro, 32D cells expressing these variants also show reduced PI3-kinase activation (87). In a euglycemic, hyperinsulinemic clamp, the insulin sensitivity in the carriers versus noncarriers of these polymorphism carriers is decreased 29.5% in type 2 diabetics and 22% in healthy subjects…”

Section: Genetic Alterations In the Insulin Signaling Proteinsmentioning

confidence: 99%

Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance

Virkamäki

Ueki²,

Kahn³

1999

J. Clin. Invest.

773

527

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Insulin is an anabolic hormone with powerful metabolic effects. The events after insulin binds to its receptor are highly regulated and specific. Defining the key steps that lead to the specificity in insulin signaling presents a major challenge to biochemical research, but the outcome should offer new therapeutic approaches for treatment of patients suffering from insulin-resistant states, including type 2 diabetes.The insulin receptor belongs to the large family of growth factor receptors with intrinsic tyrosine kinase activity. Following insulin binding, the receptor undergoes autophosphorylation on multiple tyrosine residues. This results in activation of the receptor kinase and tyrosine phosphorylation of a family of insulin receptor substrate (IRS) proteins. These substrates are commonly referred to as docking proteins, since several other intracellular proteins bind to the phosphorylated substrates, thereby transmitting the signal downstream. Like other growth factors, insulin uses phosphorylation and the resultant protein-protein interactions as essential tools to transmit and compartmentalize its signal. These intracellular protein-protein interactions are pivotal in transmitting the signal from the receptor to the final cellular effect, such as translocation of vesicles containing GLUT4 glucose transporters from the intracellular pool to the plasma membrane, activation of glycogen or protein synthesis, and initiation of specific gene transcription ( Figure 1). In this article, we review some of our current understanding about early insulin signal transduction through the network of IRS interacting proteins and the mechanisms that may modify insulin signal transduction in insulinresistant states, especially obesity and type 2 diabetes. Protein-protein interactionsSome of the best-characterized protein interaction domains involved in insulin signaling are the PH (pleckstrin homology), PTB (phosphotyrosine binding), SH2, and SH3 domains (1) ( Table 1). Other, less-characterized domains (e.g., LIM, PDZ, NOTCH, and WW) may also prove to be relevant (2).These interaction domains exist in the natural tertiary structure of proteins. In other cases, the domains for interaction are created by posttranslational covalent modification of the protein. The most common examples of the latter are the effects of phosphorylation of proteins on tyrosine or serine/threonine residues and the lipid modification by prenylation or fatty acid acylation Figure 2 illustrates how signal transduction is transmitted from the receptor downstream using different types of domains. PH domains, which are found in most of the proteins that interact with the insulin receptor, bind to charged headgroups of specific phosphatidylinositides and are thereby targeted preferentially to membrane structures. PH domains in the IRS proteins target the proteins to the membrane adjacent to the insulin receptor (3). PTB domains, also found in IRS proteins, recognize the phosphotyrosine in the amino acid sequence asparagine-proline-any amino acid-phospho...

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“…Mutations in IRS-1 are uncommon in severe insulin resistance, although one person with a missense mutation in IRS-1 has been described [47]. The Gly 972 Arg IRS-1 polymorphism has been associated with Type II diabetes [48,49] as have mutations in the PTB domain of IRS-1 [50]. The evidence implicating the Arg 409 Gln mutation in the p85a subunit of PI 3K as a causative factor in the severe insulin resistance of the family described in this report is, however, arguably the strongest for the existence of an inherited post-receptor defect in human insulin action.…”

Section: Discussionmentioning

confidence: 99%

Natural variants of human p85α phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity

et al. 2000

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Severe insulin resistance is found in a heterogeneous group of uncommon disorders characterised by acanthosis nigricans, impaired glucose tolerance or diabetes mellitus and in women, features of hyperandrogenism such as oligomenorrhoea and hirsutism [1±3]. The mechanisms underlying severe insulin resistance in human disease remain poorly understood, but mutations in the insulin receptor gene or autoantibodies to the insulin receptor are responsible in only a small minority of cases [4±6]. The increasing knowledge of the complexity of intracellular insulin signalling path- Diabetologia (2000) AbstractAims/hypothesis. Phosphoinositide 3-kinase (PI 3K) plays a central part in the mediation of insulin-stimulated glucose disposal. No genetic studies of this enzyme in human syndromes of severe insulin resistance have been previously reported. Methods. Phosphoinositide 3-kinase p85a regulatory subunit cDNA was examined in 20 subjects with syndromes of severe insulin resistance by single strand conformational polymorphism and restriction fragment length polymorphism analyses. Insulin-stimulated phosphoinositide 3-kinase activity and recruitment into phosphotyrosine complexes of variants of p85a were studied in transiently transfected HEK293 cells. Phosphopeptide binding characteristics of wild-type and mutant p85a-GST fusion proteins were examined by surface plasmon resonance. Results. The common p85a variant, Met 326 I1e, was identified in 9 of the 20 subjects. Functional studies of the Met 326 Ile variant showed it to have equivalent insulin-stimulated lipid kinase activity and phosphotyrosine recruitment as wild-type p85a. A novel heterozygous mutation, Arg 409 Gln, was detected in one subject. Within the proband's family, carriers of the mutation had a higher median fasting plasma insulin (218 pmol/l) compared with wild-type relatives (72 mol/l) (n = 8 subjects, p = 0.06). The Arg 409 Gln p85a subunit was associated with lower insulin-stimulated phosphoinositide 3-kinase activity compared with wild-type (mean reduction 15 %, p < 0.05, n = 5). The recruitment of Arg 409 Gln p85a into phosphotyrosine complexes was not significantly impaired. GST fusion proteins of wild-type and mutant p85a showed identical binding to phosphopeptides in surface plasmon resonance studies. Conclusion/interpretation. Mutations in p85a are uncommon in subjects with syndromes of severe insulin resistance. The Met 326 Ile p85a variant appears to have no functional effect on the insulin-stimulated phosphoinositide 3-kinase activity. The impaired phosphoinositide 3-kinase activity of the Arg 409 Gln mutant suggests that it could contribute to the insulin resistance seen in this family. [Diabetologia (2000) 43: 321±331] Keywords Keywords Genetics, insulin signalling, phosphatidylinositol 3-kinase.

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Impact of Natural IRS-1 Mutations on Insulin Signals: Mutations of IRS-1 in the PTB Domain and Near SH2 Protein Binding Sites Result in Impaired Function at Different Steps of IRS-1 Signaling

Cited by 44 publications

References 38 publications

Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies

Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies

Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance

Natural variants of human p85α phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity

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