REGULATION OF EUKARYOTIC INITIATION-FACTOR EIF2B - GLYCOGEN-SYNTHASE KINASE-3 PHOSPHORYLATES A CONSERVED SERINE WHICH UNDERGOES DEPHOSPHORYLATION IN RESPONSE TO INSULIN

Eukaryotic initiation factor eIF2B catalyses a key regulatory step in mRNA translation, eIF2B and total protein synthesis are acutely activa ted by insulin, and this requires phosphatidylinositol 3-kinase (PI 3- kinase). The epsilon-subunit of eIF2B is phosphorylated by glycogen sy nthase kinase-3 (GSK-3), which is inactivated-by insulin in a PI 3-kin ase-dependent manner, Here we identify the phosphorylation site in eIF 2B epsilon as Ser(540) and show that treatment of eIF2B with GSK-3 inh ibits its activity. Ser(540) is phosphorylated in intact cells and und ergoes dephosphorylation in response to insulin, This is blocked by PI 3-kinase inhibitors, Insulin-induced dephosphorylation of this inhibi tory site in eIF2B seems likely to be important in the overall activat ion of translation by this hormone, (C) 1998 Federation of European Bi ochemical Societies.