Regulation of the small GTPase Rheb by amino acids
- 19 September 2005
- journal article
- Published by Springer Nature in Oncogene
- Vol. 25 (5) , 657-664
- https://doi.org/10.1038/sj.onc.1209106
Abstract
The mTOR/S6K/4E-BP1 pathway integrates extracellular signals derived from growth factors, and intracellular signals, determined by the availability of nutrients like amino acids and glucose. Activation of this pathway requires inhibition of the tumor suppressor complex TSC1/2. TSC2 is a GTPase-activating protein for the small GTPase Ras homologue enriched in brain (Rheb), GTP loading of which activates mTOR by a yet unidentified mechanism. The level at which this pathway senses the availability of amino acids is unknown but is suggested to be at the level of TSC2. Here, we show that amino-acid depletion completely blocks insulin- and TPA-induced Rheb activation. This indicates that amino-acid sensing occurs upstream of Rheb. Despite this, amino-acid depletion can still inhibit mTOR/S6 kinase signaling in TSC2-/- fibroblasts. Since under these conditions Rheb-GTP levels remain high, a second level of amino-acid sensing exists, affecting mTOR activity in a Rheb-independent fashion.Keywords
This publication has 39 references indexed in Scilit:
- Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progressionOncogene, 2004
- Insulin Activation of Rheb, a Mediator of mTOR/S6K/4E-BP Signaling, Is Inhibited by TSC1 and 2Molecular Cell, 2003
- Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular amino acid availabilityBiochemical Journal, 2003
- Tsc tumour suppressor proteins antagonize amino-acid–TOR signallingNature Cell Biology, 2002
- Mammalian TOR: A Homeostatic ATP SensorScience, 2001
- p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BADProceedings of the National Academy of Sciences, 2001
- Regulation of 4E-BP1 phosphorylation: a novel two-step mechanismGenes & Development, 1999
- Amino Acid Sufficiency and mTOR Regulate p70 S6 Kinase and eIF-4E BP1 through a Common Effector MechanismJournal of Biological Chemistry, 1998
- The Serine Protease Inhibitors, Tosylphenylalanine Chloromethyl Ketone and Tosyllysine Chloromethyl Ketone, Potently Inhibit pp70 ActivationPublished by Elsevier ,1996
- Phosphorylation of initiation factor 2α by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeastPublished by Elsevier ,1992