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PMID:12679424

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Citation

Esposito, DL, Li, Y, Vanni, C, Mammarella, S, Veschi, S, Della Loggia, F, Mariani-Costantini, R, Battista, P, Quon, MJ and Cama, A (2003) A novel T608R missense mutation in insulin receptor substrate-1 identified in a subject with type 2 diabetes impairs metabolic insulin signaling. J. Clin. Endocrinol. Metab. 88:1468-75

Abstract

Naturally occurring mutations in insulin receptor substrate-1 (IRS-1) have previously been implicated in impaired insulin action. We now report a novel mutation in IRS-1 with substitution of Arg for Thr(608) that was identified in a patient with type 2 diabetes mellitus. We detected the T608R mutation in 1 of 136 chromosomes from diabetic patients and in 0 of 120 chromosomes from nondiabetic controls, suggesting that this is a rare IRS-1 variant. Conservation of Thr(608) in human, monkey, rat, mouse, and chicken IRS-1 sequences is consistent with a crucial function for this residue. Moreover, Thr(608) is located near the YMXM motif containing Tyr(612) that is important for binding and activation of phosphoinositol 3-kinase (PI 3-kinase). To investigate whether the T608R mutation impairs insulin signaling, we transiently transfected NIH-3T3(IR) cells with hemagglutinin-tagged wild-type or T608R mutant IRS-1 constructs. Recombinant IRS-1 immunoprecipitated from transfected cells treated with or without insulin was subjected to immunoblotting for the p85 regulatory subunit of PI 3-kinase as well as a PI 3-kinase assay. As expected, in control cells transfected with wild-type IRS-1, insulin stimulation caused an increase in p85 coimmunoprecipitated with IRS-1 as well as a 10-fold increase in IRS-1-associated PI 3-kinase activity. Interestingly, when cells transfected with IRS1-T608R were stimulated with insulin, both the amount of p85 coimmunoprecipitated with IRS1-T608R as well as the associated PI 3-kinase activity were approximately 50% less than those observed with wild-type IRS-1. Moreover, in rat adipose cells, overexpression of IRS1-T608R resulted in significantly less translocation of GLUT4 to the cell surface than comparable overexpression of wild-type IRS-1. We conclude that a naturally occurring substitution of Arg for Thr(608) in IRS-1 is a rare human mutation that may contribute to insulin resistance by impairing metabolic signaling through PI 3-kinase-dependent pathways.

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PubMed

Keywords

3T3 Cells; Adipocytes/metabolism; Amino Acid Sequence; Animals; Diabetes Mellitus, Type 2/genetics; Glucose Transporter Type 4; Humans; Immunosorbent Techniques; Insulin/metabolism; Insulin/pharmacology; Insulin Receptor Substrate Proteins; Insulin Resistance/genetics; Male; Mice; Middle Aged; Monosaccharide Transport Proteins/metabolism; Muscle Proteins; Mutation, Missense; Phosphatidylinositol 3-Kinases/metabolism; Phosphoproteins/chemistry; Phosphoproteins/genetics; Polymorphism, Single-Stranded Conformational; Rats; Signal Transduction; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status


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