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mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and

Marina K Holz1, Bryan A Ballif, Steven P Gygi

  • 1Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Cell
|November 16, 2005
PubMed

Insights

The study reveals how the eukaryotic initiation factor 3 (eIF3) complex acts as a scaffold, orchestrating the dynamic activation of S6 kinase 1 (S6K1) to control protein synthesis in response to cellular signals.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Ribosomal protein S6 kinase 1 (S6K1) is a key regulator of translation, phosphorylating targets involved in protein synthesis.
  • The precise molecular mechanisms governing S6K1 activation, substrate interaction, and its role in translation initiation remain incompletely understood.

Purpose of the Study:

  • To elucidate the dynamic interplay between mTOR, S6K1, and the eukaryotic initiation factor 3 (eIF3) complex during signal-dependent translation initiation.
  • To investigate how cellular stimuli modulate the association and activation of S6K1 within the eIF3 complex.

Main Methods:

  • Utilized biochemical assays to track the association and dissociation of mTOR, raptor, and S6K1 with the eIF3 complex.
  • Investigated the phosphorylation status of S6K1 at its hydrophobic motif upon cellular stimulation.
  • Examined the phosphorylation-dependent recruitment of translation factors like eIF4B to the eIF3 complex.

Main Results:

  • Demonstrated that inactive S6K1 binds to the eIF3 complex, while its activator, mTOR/raptor, does not.
  • Showed that cell stimulation leads to mTOR/raptor binding to eIF3, promoting S6K1 phosphorylation and subsequent dissociation and activation.
  • Confirmed that activated S6K1 phosphorylates downstream targets such as eIF4B, facilitating its recruitment to the translation initiation complex.

Conclusions:

  • The eIF3 complex serves as a crucial scaffold, coordinating a dynamic sequence of molecular events for signal-responsive translation initiation.
  • This mechanism ensures efficient protein synthesis by precisely regulating S6K1 activation and substrate phosphorylation in response to cellular cues.

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