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Related Experiment Videos

Regulation of the small GTPase Rheb by amino acids.

M Roccio1, J L Bos, F J T Zwartkruis

  • 1Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.

Oncogene
|September 20, 2005
PubMed
Summary

Nutrient sensing by the mTOR pathway involves two levels. Amino acid levels regulate Rheb activation and also impact mTOR signaling independently of Rheb.

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Area of Science:

  • Cellular signaling
  • Molecular biology
  • Metabolic regulation

Background:

  • The mechanistic target of rapamycin (mTOR)/S6K/4E-BP1 pathway integrates growth factor and nutrient signals.
  • Activation of mTOR requires TSC1/2 complex inhibition, which regulates Rheb GTP loading.
  • The precise mechanism of amino acid sensing within this pathway remains unclear.

Purpose of the Study:

  • To investigate the level at which amino acid availability is sensed in the mTOR pathway.
  • To determine if amino acid sensing occurs upstream or downstream of Rheb GTP loading.
  • To elucidate the mechanism of mTOR regulation by amino acids in a Rheb-independent manner.

Main Methods:

  • Utilized insulin and TPA stimulation in cell culture models.
  • Assessed Rheb activation and GTP loading under varying amino acid conditions.

Related Experiment Videos

  • Examined mTOR/S6 kinase signaling in TSC2-deficient fibroblasts.

    • Main Results:

    • Amino acid depletion abolished insulin- and TPA-induced Rheb activation, indicating upstream sensing.
    • mTOR/S6 kinase signaling was inhibited by amino acid depletion even when Rheb-GTP levels remained high.
    • This demonstrates a second, Rheb-independent amino acid sensing mechanism affecting mTOR.

    Conclusions:

    • Amino acid sensing occurs at least at two distinct levels within the mTOR pathway.
    • One level involves regulation upstream of Rheb activation.
    • A second, Rheb-independent mechanism directly influences mTOR activity based on amino acid availability.