Abstract
Eukaryotic initiation factor eIF2B mediates a key regulatory step in peptide-chain initiation and is acutely activated by insulin, although, it is not clear how. Inhibitors of phosphatidylinositide 3-kinase blocked activation of eIF2B, although rapamycin, which inhibits the p70 S6 kinase pathway, did not. Furthermore, a dominant negative mutant of PI 3-kinase also prevented activation of eIF2B, while a Sos-mutant, which blocks MAP kinase activation, did not. The data demonstrate that a pathway distinct from MAP and p70 S6 kinases regulates eIF2B. Glycogen synthase kinase-3 (GSK-3) phosphorylates and inactivates eIF2B. In all cases, eIF2B and GSK-3 were regulated reciprocally. Dominant negative PI 3-kinase abolished the insulin-induced inhibition of GSK-3. These data strongly support the hypothesis that insulin activates eIF2B through a signalling pathway involving PI 3-kinase and inhibition of GSK-3.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Animals
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CHO Cells
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cricetinae
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Enzyme Inhibitors / pharmacology
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Eukaryotic Initiation Factor-2 / metabolism*
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Eukaryotic Initiation Factor-2B
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Glycogen Synthase Kinase 3
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Glycogen Synthase Kinases
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Guanine Nucleotide Exchange Factors
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Humans
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Insulin / physiology*
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Phosphatidylinositol 3-Kinases
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
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Phosphotransferases (Alcohol Group Acceptor) / metabolism*
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Proteins / metabolism*
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Signal Transduction
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Wortmannin
Substances
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Androstadienes
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Enzyme Inhibitors
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Eukaryotic Initiation Factor-2
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Eukaryotic Initiation Factor-2B
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Guanine Nucleotide Exchange Factors
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Insulin
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Proteins
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Phosphatidylinositol 3-Kinases
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Phosphotransferases (Alcohol Group Acceptor)
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Glycogen Synthase Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3
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Wortmannin