Amino acid regulation of TOR complex 1
- PMID: 18765678
- PMCID: PMC2670622
- DOI: 10.1152/ajpendo.90645.2008
Amino acid regulation of TOR complex 1
Abstract
TOR complex 1 (TORC1), an oligomer of the mTOR (mammalian target of rapamycin) protein kinase, its substrate binding subunit raptor, and the polypeptide Lst8/GbetaL, controls cell growth in all eukaryotes in response to nutrient availability and in metazoans to insulin and growth factors, energy status, and stress conditions. This review focuses on the biochemical mechanisms that regulate mTORC1 kinase activity, with special emphasis on mTORC1 regulation by amino acids. The dominant positive regulator of mTORC1 is the GTP-charged form of the ras-like GTPase Rheb. Insulin, growth factors, and a variety of cellular stressors regulate mTORC1 by controlling Rheb GTP charging through modulating the activity of the tuberous sclerosis complex, the Rheb GTPase activating protein. In contrast, amino acids, especially leucine, regulate mTORC1 by controlling the ability of Rheb-GTP to activate mTORC1. Rheb binds directly to mTOR, an interaction that appears to be essential for mTORC1 activation. In addition, Rheb-GTP stimulates phospholipase D1 to generate phosphatidic acid, a positive effector of mTORC1 activation, and binds to the mTOR inhibitor FKBP38, to displace it from mTOR. The contribution of Rheb's regulation of PL-D1 and FKBP38 to mTORC1 activation, relative to Rheb's direct binding to mTOR, remains to be fully defined. The rag GTPases, functioning as obligatory heterodimers, are also required for amino acid regulation of mTORC1. As with amino acid deficiency, however, the inhibitory effect of rag depletion on mTORC1 can be overcome by Rheb overexpression, whereas Rheb depletion obviates rag's ability to activate mTORC1. The rag heterodimer interacts directly with mTORC1 and may direct mTORC1 to the Rheb-containing vesicular compartment in response to amino acid sufficiency, enabling Rheb-GTP activation of mTORC1. The type III phosphatidylinositol kinase also participates in amino acid-dependent mTORC1 activation, although the site of action of its product, 3'OH-phosphatidylinositol, in this process is unclear.
Figures
Similar articles
-
Re-evaluating the roles of proposed modulators of mammalian target of rapamycin complex 1 (mTORC1) signaling.J Biol Chem. 2008 Nov 7;283(45):30482-92. doi: 10.1074/jbc.M803348200. Epub 2008 Aug 1. J Biol Chem. 2008. PMID: 18676370 Free PMC article.
-
Amino acids activate mammalian target of rapamycin (mTOR) complex 1 without changing Rag GTPase guanyl nucleotide charging.J Biol Chem. 2014 Jan 31;289(5):2658-74. doi: 10.1074/jbc.M113.528505. Epub 2013 Dec 11. J Biol Chem. 2014. PMID: 24337580 Free PMC article.
-
Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein.J Biol Chem. 2009 May 8;284(19):12783-91. doi: 10.1074/jbc.M809207200. Epub 2009 Mar 19. J Biol Chem. 2009. PMID: 19299511 Free PMC article.
-
Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase.Oncogene. 2006 Oct 16;25(48):6361-72. doi: 10.1038/sj.onc.1209882. Oncogene. 2006. PMID: 17041622 Review.
-
Rheb and Rags come together at the lysosome to activate mTORC1.Biochem Soc Trans. 2013 Aug;41(4):951-5. doi: 10.1042/BST20130037. Biochem Soc Trans. 2013. PMID: 23863162 Review.
Cited by
-
Sugar signals pedal the cell cycle!Front Plant Sci. 2024 Mar 18;15:1354561. doi: 10.3389/fpls.2024.1354561. eCollection 2024. Front Plant Sci. 2024. PMID: 38562561 Free PMC article. Review.
-
BCAA metabolism in pancreatic cancer affects lipid balance by regulating fatty acid import into mitochondria.Cancer Metab. 2024 Mar 26;12(1):10. doi: 10.1186/s40170-024-00335-5. Cancer Metab. 2024. PMID: 38532464 Free PMC article.
-
RNAi-Mediated Knockdown of Acidic Ribosomal Stalk Protein P1 Arrests Egg Development in Adult Female Yellow Fever Mosquitoes, Aedes aegypti.Insects. 2024 Jan 24;15(2):84. doi: 10.3390/insects15020084. Insects. 2024. PMID: 38392504 Free PMC article.
-
Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling.Int J Mol Sci. 2024 Jan 25;25(3):1489. doi: 10.3390/ijms25031489. Int J Mol Sci. 2024. PMID: 38338768 Free PMC article. Review.
-
Residual Feed Intake as an Efficiency Metric for Pre-Weaning Dairy Calves: What Do We Know?Life (Basel). 2023 Aug 11;13(8):1727. doi: 10.3390/life13081727. Life (Basel). 2023. PMID: 37629582 Free PMC article. Review.
References
-
- Ali SM, Sabatini DM. Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site. J Biol Chem 280: 19445–19448, 2005. - PubMed
-
- Anthony TG, McDaniel BJ, Byerley RL, McGrath BC, Cavener DR, McNurlan MA, Wek RC. Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. J Biol Chem 279: 36553–36561, 2004. - PubMed
-
- Aspuria PJ, Sato T, Tamanoi F. The TSC/Rheb/TOR signaling pathway in fission yeast and mammalian cells: temperature sensitive and constitutive active mutants of TOR. Cell Cycle 6: 1692–1695, 2007. - PubMed
-
- Backer JM The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem J 410: 1–17, 2008. - PubMed
-
- Bai X, Ma D, Liu A, Shen X, Wang QJ, Liu Y, Jiang Y. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 318: 977–980, 2007. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous