MOLECULAR MECHANISMS FOR THE CONTROL OF TRANSLATION BY INSULIN

Insulin acutely stimulates protein synthesis in mammalian cells, and t his involves activation of the process of mRNA translation. mRNA trans lation is a complex multi-step process mediated by proteins termed tra nslation factors. Several translation factors are regulated in respons e to insulin, often as a consequence of changes in their states of pho sphorylation. The initiation factor eIF4E binds to the cap structure a t the 5'-end of the mRNA and mediates assembly of an initiation-factor complex termed eIF4F. Assembly of this complex can be regulated by eI F4E-binding proteins (4E-BPs), which inhibit eIF4F complex assembly. I nsulin induces phosphorylation of the 4E-BPs, resulting in alleviation of the inhibition. This regulatory mechanism is likely to be especial ly important for the control of the translation of specific mRNAs whos e 5'-untranslated regions (5'-UTRs) are rich in secondary structure. T ranslation of another class of mRNAs, those with 5'-UTRs containing po lypyrimidine tracts is also activated by insulin and this, like phosph orylation of the 4E-BPs, appears to involve the rapamycin-sensitive si gnalling pathway which leads to activation of the 70 kDa ribosomal pro tein S6 kinase (p70 S6 kinase) and the phosphorylation of the ribosoma l protein S6. Overall stimulation of translation may involve activatio n of initiation factor eIF2B, which is required for all initiation eve nts. This effect is dependent upon phosphatidylinositol 3-kinase and m ay involve the inactivation of glycogen synthase kinase-3 and conseque nt dephosphorylation of eIF2B, leading to its activation. Peptide-chai n elongation can also be activated by insulin, and this is associated with the dephosphorylation and activation of elongation factor eEF2, p robably as a consequence of the insulin-induced reduction in eEF2 kina se activity. Thus multiple signalling pathways acting on different ste ps in translation are involved in the activation of this process by in sulin and lead both to general activation of translation and to the se lective regulation of specific mRNAs.