title: Dynamic regulation of the translation initiation helicase complex by mitogenic signal transduction to eukaryotic translation initiation factor 4G.
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.
authors.affiliation: Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Mikhail I
authors.initials: MI
authors.lastname: Dobrikov
authors.forename: Elena Y
authors.initials: EY
authors.lastname: Dobrikova
authors.forename: Matthias
authors.initials: M
authors.lastname: Gromeier
mesh_terms: D000595:Amino Acid Sequence; D047390:Casein Kinase II / Q000378:metabolism; D039621:Eukaryotic Initiation Factor-3 / Q000378:metabolism; D039601:Eukaryotic Initiation Factor-4A / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000737:chemistry* / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D039621:Eukaryotic Initiation Factor-3; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; D047908:Intracellular Signaling Peptides and Proteins; C031799:eIF-4B; C491395:MKNK1 protein, human; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D039601:Eukaryotic Initiation Factor-4A