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Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site

Siraj M Ali1, David M Sabatini

  • 1Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Cambridge, 02142, USA.

The Journal of Biological Chemistry
|April 6, 2005
PubMed

Insights

The mechanistic target of rapamycin (mTOR) pathway regulates cell growth. This study shows distinct mTOR complexes, raptor-mTOR and rictor-mTOR, differentially phosphorylate S6 kinase 1 (S6K1), clarifying mTOR signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The mechanistic target of rapamycin (mTOR) is a key regulator of cell growth.
  • S6 kinase 1 (S6K1) is a well-studied mTOR effector, and its phosphorylation at threonine 389 (Thr389) is a model for mTOR signaling.
  • Rapamycin sensitivity of Thr389 phosphorylation suggests mTOR is the kinase, but rapamycin-resistant S6K1 mutants challenge this.

Purpose of the Study:

  • To investigate the roles of distinct mTOR complexes in S6K1 phosphorylation.
  • To elucidate the mechanisms underlying rapamycin-sensitive and rapamycin-resistant S6K1 phosphorylation.
  • To determine if rictor-mTOR phosphorylates other kinases.

Main Methods:

  • Utilized rapamycin-sensitive and rapamycin-resistant S6K1 mutants.
  • Investigated phosphorylation by raptor-mTOR and rictor-mTOR complexes.
  • Analyzed the role of the carboxyl-terminal domain in rictor-mTOR phosphorylation.

Main Results:

  • The raptor-mTOR complex phosphorylates rapamycin-sensitive S6K1.
  • The rictor-mTOR complex phosphorylates rapamycin-resistant S6K1 mutants.
  • Rictor-mTOR phosphorylation of Thr389 is independent of the TOR signaling motif and requires carboxyl-terminal domain removal.

Conclusions:

  • Distinct mTOR complexes (raptor-mTOR and rictor-mTOR) have specific roles in S6K1 regulation.
  • Rictor-mTOR may phosphorylate hydrophobic motifs in other AGC family kinases.
  • This research clarifies mTOR signaling pathways and their regulation.

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