mTOR and S6K1 Mediate Assembly of the Translation Preinitiation Complex through Dynamic Protein Interchange and Ordered Phosphorylation Events
Open accessAbstract
In response to nutrients, energy sufficiency, hormones, and mitogenic agents, S6K1 phosphorylates several targets linked to translation. However, the molecular mechanisms whereby S6K1 is activated, encounters substrate, and contributes to translation initiation are poorly understood. We show that mTOR and S6K1 maneuver on and off the eukaryotic initiation factor 3 (eIF3) translation initiation complex in a signal-dependent, choreographed fashion. When inactive, S6K1 associates with the eIF3 complex, while the S6K1 activator mTOR/raptor does not. Cell stimulation promotes mTOR/raptor binding to the eIF3 complex and phosphorylation of S6K1 at its hydrophobic motif. Phosphorylation results in S6K1 dissociation, activation, and subsequent phosphorylation of its translational targets, including eIF4B, which is then recruited into the complex in a phosphorylation-dependent manner. Thus, the eIF3 preinitiation complex acts as a scaffold to coordinate a dynamic sequence of events in response to stimuli that promote efficient protein synthesis.
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mTOR can phosphorylate eIF4G and ribosomal S6 kinases such as p70S6K, which phosphorylate eIF4B, enhancing its interaction with eIF3 and stimulating protein synthesis.
“mTOR can also phosphorylate eIF4G, the ribosomal S6 kinases (RS6K) such as p70S6K which phosphorylate eIF4B, enhancing its interaction with eIF3 and stimulate protein synthesis [75–77] (Fig. 1).”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [76]
The Discussion reports that mTOR/raptor phosphorylates S6K1, after which activated S6K1 phosphorylates eIF4B and phosphorylated eIF4B is recruited to the eIF3 preinitiation complex. The Results link this sequence to translation initiation. The paper describes mTOR phosphorylating 4E-BP1, followed by recruitment of eIF4G; it does not support the claim that mTOR phosphorylates eIF4G. (LLM, conf=0.88)
Experimental — accuracy not yet measuredS6K phosphorylation by mTOR is linked to translation activation.
“Since S6K phosphorylation by mTOR is linked to translation activation (19), we explored the possibility of whether specific inhibition of S6K could rescue PD pathology and neurodegeneration in the pathologic α-syn model (Syb-QF2> α-syn) (16).”
From Enhanced mTORC1 signaling and Protein Synthesis in Parkinson’s Disease Pathogenesis Disease Pathogenesis (2022) · cites this paper as [19]
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- Authors
- Holz, M. K., Ballif, B. A., Gygi, S. P., & Blenis, J.
- Affiliations
- Harvard University (US)
- Corresponding author
- Blenis, John
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2005-11
- Volume
- 123
- Issue
- 4
- Pages
- 569-580
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2041308494
- Cited by
- 1,262
- References
- 1
- Citations by year
- 2026: 38 · 2025: 47 · 2024: 65 · 2023: 68 · 2022: 69 · 2021: 88 · 2020: 56 · 2019: 54 · 2018: 77 · 2017: 53 · 2016: 57 · 2015: 66 · 2014: 60 · 2013: 59 · 2012: 60
- FWCI
- 19.52
- Type
- journal article
- Language
- en
- Update notices
- addendum (2021-04-15)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Human Genome Research Institute (HG000 41)
- National Cancer Institute (CA046595)
- National Institute of General Medical Sciences (GM051405, R01GM051405)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- mTOR, S6K1, eIF3, translation initiation complex, protein phosphorylation, hydrophobic motif, eIF4B, raptors, protein complex formation, translational regulation, nutrient signaling, protein synthesis
- MeSH terms
- Regulatory-Associated Protein of mTOR, Amino Acids, Cell Line, Gene Expression Regulation, HeLa Cells, Hormones, Humans, Insulin, Kinetics, Mitogens, Models, Biological, Mutation, Peptide Chain Initiation, Translational, Phorbol Esters, Phosphorylation, Protein Binding, Protein Kinases, Proteins, RNA Cap Analogs, Ribosomal Protein S6 Kinases, Sirolimus, Protein Subunits, Ribosomal Protein S6 Kinases, 90-kDa, Eukaryotic Initiation Factor-3, Eukaryotic Initiation Factors, Cell Line, Tumor, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, TOR Serine-Threonine Kinases
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