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mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events.

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.

Pubmed ID: 16286006


  • Holz MK
  • Ballif BA
  • Gygi SP
  • Blenis J



Publication Data

November 18, 2005

Associated Grants

  • Agency: NCI NIH HHS, Id: CA046595
  • Agency: NIGMS NIH HHS, Id: GM051405
  • Agency: NHGRI NIH HHS, Id: HG00041

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acids
  • Cell Line
  • Cell Line, Tumor
  • Eukaryotic Initiation Factor-3
  • Eukaryotic Initiation Factors
  • Gene Expression Regulation
  • HeLa Cells
  • Hormones
  • Humans
  • Insulin
  • Kinetics
  • Mitogens
  • Models, Biological
  • Multiprotein Complexes
  • Mutation
  • Peptide Chain Initiation, Translational
  • Phorbol Esters
  • Phosphorylation
  • Protein Binding
  • Protein Kinases
  • Protein Subunits
  • Proteins
  • RNA Cap Analogs
  • Ribosomal Protein S6 Kinases
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Sirolimus
  • TOR Serine-Threonine Kinases