Abstract
Insulin receptor substrate (IRS) proteins are docking proteins that couple growth factor receptors to various effector molecules, including phosphoinositide-3 kinase, Grb-2, Syp, and Nck. Here we show that IRS-1 associates with the loop domain of Bcl-2 and synergistically up-regulates antiapoptotic function of Bcl-2. IRS-2 but not IRS-3 binds to Bcl-2, and IRS-1 associates with Bcl-XL but not with Bax or Bik. Overexpression of IRS-1 suppresses phosphorylation of Bcl-2 induced by stimulation with insulin, and the hypophosphorylation may lead to its enhanced antiapoptotic activity. The binding site for Bcl-2 is located on the carboxyl half-domain of IRS-1. IRS-3, which lacks the corresponding region, dominant-negatively abrogates the survival effects of IRS-1 and Bcl-2. For the antiapoptotic activity of IRS-1, binding to Bcl-2 is more critical than activating phosphoinositide-3 kinase. Our results indicate that IRS proteins transmit signals from the insulin receptor to Bcl-2, thus regulating cell survival probably through regulating phosphorylation of Bcl-2.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins
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Apoptosis* / drug effects
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Binding Sites
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Cell Line
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Humans
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Insulin / pharmacology
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins*
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Mitochondrial Proteins
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Models, Biological
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Molecular Weight
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / chemistry
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Phosphorylation / drug effects
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Phosphotyrosine / metabolism
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Protein Binding
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Protein Structure, Tertiary
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Proteins / genetics
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Proteins / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / chemistry
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Signal Transduction / drug effects
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Transfection
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bcl-2-Associated X Protein
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bcl-X Protein
Substances
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Apoptosis Regulatory Proteins
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BAX protein, human
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BCL2L1 protein, human
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BIK protein, human
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IRS1 protein, human
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IRS2 protein, human
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IRS3P protein, human
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Insulin
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Mitochondrial Proteins
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Phosphoproteins
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Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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bcl-2-Associated X Protein
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bcl-X Protein
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Phosphotyrosine