Dynamic regulation of the translation initiation helicase complex by mitogenic signal transduction to eukaryotic translation initiation factor 4G.
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.
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Related Subject Headings
- Protein Structure, Tertiary
- Protein Serine-Threonine Kinases
- Protein Interaction Mapping
- Protein Binding
- Phosphorylation
- Molecular Sequence Data
- Mitogen-Activated Protein Kinase 3
- Mitogen-Activated Protein Kinase 1
- Intracellular Signaling Peptides and Proteins
- Humans
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Protein Structure, Tertiary
- Protein Serine-Threonine Kinases
- Protein Interaction Mapping
- Protein Binding
- Phosphorylation
- Molecular Sequence Data
- Mitogen-Activated Protein Kinase 3
- Mitogen-Activated Protein Kinase 1
- Intracellular Signaling Peptides and Proteins
- Humans