Abstract
Eukaryotic translation initiation factor 4F (eIF4F), comprising the cap-binding protein eIF4E, the helicase eIF4A, and the central scaffold eIF4G, is a convergence node for a complex signaling network that controls protein synthesis. Together with eIF3 and eIF4A/4B, eIF4G recruits ribosomal subunits to mRNAs and facilitates 5' untranslated region unwinding. Mammalian eIF4G contains three HEAT domains and unstructured regions involved in protein-protein interactions. Despite detailed eIF4G structure data, the mechanisms controlling initiation scaffold formation remain obscure. We found a new, highly regulated eIF4B/-3 binding site within the HEAT-1/-2 interdomain linker, harboring two phosphorylation sites that we identified as substrates for Erk1/2 and casein kinase 2. Phorbol ester-induced sequential phosphorylation of both sites detached HEAT-2 from the complex with eIF4A/-4B/-3 and stimulated the association of HEAT-3 with the mitogen-activated protein kinase signal integrating kinase Mnk1. Our results provide a mechanistic link between intracellular signal transduction and dynamic initiation complex formation coordinated by flexible eIF4G structure.