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rdf:type |
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lifeskim:mentions |
umls-concept:C0011860,
umls-concept:C0021641,
umls-concept:C0037083,
umls-concept:C0123658,
umls-concept:C0205314,
umls-concept:C0205396,
umls-concept:C0311400,
umls-concept:C0332307,
umls-concept:C0599155,
umls-concept:C0679622,
umls-concept:C0681850,
umls-concept:C1550501,
umls-concept:C1706203,
umls-concept:C1710082,
umls-concept:C2349001,
umls-concept:C2697811
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pubmed:issue |
4
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pubmed:dateCreated |
2003-4-7
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pubmed:abstractText |
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:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Glucose Transporter Type 4,
http://linkedlifedata.com/resource/pubmed/chemical/IRS1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin Receptor Substrate Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Irs1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Irs1 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Monosaccharide Transport Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Muscle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/SLC2A4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Slc2a4 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Slc2a4 protein, rat
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0021-972X
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
88
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1468-75
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:12679424-3T3 Cells,
pubmed-meshheading:12679424-Adipocytes,
pubmed-meshheading:12679424-Amino Acid Sequence,
pubmed-meshheading:12679424-Animals,
pubmed-meshheading:12679424-Diabetes Mellitus, Type 2,
pubmed-meshheading:12679424-Glucose Transporter Type 4,
pubmed-meshheading:12679424-Humans,
pubmed-meshheading:12679424-Immunosorbent Techniques,
pubmed-meshheading:12679424-Insulin,
pubmed-meshheading:12679424-Insulin Receptor Substrate Proteins,
pubmed-meshheading:12679424-Insulin Resistance,
pubmed-meshheading:12679424-Male,
pubmed-meshheading:12679424-Mice,
pubmed-meshheading:12679424-Middle Aged,
pubmed-meshheading:12679424-Monosaccharide Transport Proteins,
pubmed-meshheading:12679424-Muscle Proteins,
pubmed-meshheading:12679424-Mutation, Missense,
pubmed-meshheading:12679424-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:12679424-Phosphoproteins,
pubmed-meshheading:12679424-Polymorphism, Single-Stranded Conformational,
pubmed-meshheading:12679424-Rats,
pubmed-meshheading:12679424-Signal Transduction,
pubmed-meshheading:12679424-Transfection
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pubmed:year |
2003
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pubmed:articleTitle |
A novel T608R missense mutation in insulin receptor substrate-1 identified in a subject with type 2 diabetes impairs metabolic insulin signaling.
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pubmed:affiliation |
Department of Oncology and Neurosciences, Section of Molecular Pathology, University Gabriele D'Annunzio, 66013 Chieti, Italy.
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pubmed:publicationType |
Journal Article,
Case Reports,
Research Support, Non-U.S. Gov't
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