Activation of translation initiation factor eIF2B by insulin requires phosphatidyl inositol 3-kinase

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. (C) 1997 Federation of European Biochemical Societies.