ACTIVATION OF TRANSLATION INITIATION-FACTOR EIF2B BY INSULIN REQUIRESPHOSPHATIDYL-INOSITOL 3-KINASE

Eukaryotic initiation factor eIF2B mediates a key regulatory step in p eptide-chain initiation and is acutely activated by insulin, although it is not clear how, Inhibitors of phosphatidylinositide 3-kinase bloc ked activation of eIF2B, although rapamycin, which inhibits the p70 S6 kinase pathway, did not, Furthermore, a dominant negative mutant of P I 3-kinase also prevented activation of eIF2B, while a Sos-mutant, whi ch 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 al l cases, eIF2B and GSK-3 were regulated reciprocally, Dominant negativ e PI 3-kinase abolished the insulin-induced inhibition of GSK-3, These data strongly support the hypothesis that insulin activates eIF2B thr ough a signalling pathway involving PI 3-kinase and inhibition of GSK- 3. (C) 1997 Federation of European Biochemical Societies.