The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses - PubMed (original) (raw)
. 2005 May 13;280(19):18717-27.
doi: 10.1074/jbc.M414499200. Epub 2005 Mar 16.
Affiliations
- PMID: 15772076
- DOI: 10.1074/jbc.M414499200
Free article
The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses
Ewan M Smith et al. J Biol Chem. 2005.
Free article
Abstract
Amino acids positively regulate signaling through the mammalian target of rapamycin (mTOR). Recent work demonstrated the importance of the tuberous sclerosis protein TSC2 for regulation of mTOR by insulin. TSC2 contains a GTPase-activator domain that promotes hydrolysis of GTP bound to Rheb, which positively regulates mTOR signaling. Some studies have suggested that TSC2 also mediates the control of mTOR by amino acids. In cells lacking TSC2, amino acid withdrawal still results in dephosphorylation of S6K1, ribosomal protein S6, the eukaryotic initiation factor 4E-binding protein, and elongation factor-2 kinase. The effects of amino acid withdrawal are diminished by inhibiting protein synthesis or adding back amino acids. These studies demonstrate that amino acid signaling to mTOR occurs independently of TSC2 and involves additional unidentified inputs. Although TSC2 is not required for amino acid control of mTOR, amino acid withdrawal does decrease the proportion of Rheb in the active GTP-bound state. Here we also show that Rheb and mTOR form stable complexes, which are not, however, disrupted by amino acid withdrawal. Mutants of Rheb that cannot bind GTP or GDP can interact with mTOR complexes. We also show that the effects of hydrogen peroxide and sorbitol, cell stresses that impair mTOR signaling, are independent of TSC2. Finally, we show that the ability of energy depletion (which impairs mTOR signaling in TSC2+/+ cells) to increase the phosphorylation of eukaryotic elongation factor 2 is also independent of TSC2. This likely involves the phosphorylation of the elongation factor-2 kinase by the AMP-activated protein kinase.
Similar articles
- Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb.
Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tee AR, et al. Curr Biol. 2003 Aug 5;13(15):1259-68. doi: 10.1016/s0960-9822(03)00506-2. Curr Biol. 2003. PMID: 12906785 - Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling.
Inoki K, Li Y, Xu T, Guan KL. Inoki K, et al. Genes Dev. 2003 Aug 1;17(15):1829-34. doi: 10.1101/gad.1110003. Epub 2003 Jul 17. Genes Dev. 2003. PMID: 12869586 Free PMC article. - Structural basis for the unique biological function of small GTPase RHEB.
Yu Y, Li S, Xu X, Li Y, Guan K, Arnold E, Ding J. Yu Y, et al. J Biol Chem. 2005 Apr 29;280(17):17093-100. doi: 10.1074/jbc.M501253200. Epub 2005 Feb 23. J Biol Chem. 2005. PMID: 15728574 - Molecular mechanisms through which amino acids mediate signaling through the mammalian target of rapamycin.
Kimball SR, Jefferson LS. Kimball SR, et al. Curr Opin Clin Nutr Metab Care. 2004 Jan;7(1):39-44. doi: 10.1097/00075197-200401000-00008. Curr Opin Clin Nutr Metab Care. 2004. PMID: 15090902 Review. - Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis.
Kwiatkowski DJ. Kwiatkowski DJ. Cancer Biol Ther. 2003 Sep-Oct;2(5):471-6. doi: 10.4161/cbt.2.5.446. Cancer Biol Ther. 2003. PMID: 14614311 Review.
Cited by
- MAP4K3 inhibits Sirtuin-1 to repress the LKB1-AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex.
Branch MR, Hsu CL, Ohnishi K, Shen WC, Lee E, Meisenhelder J, Winborn B, Sopher BL, Taylor JP, Hunter T, La Spada AR. Branch MR, et al. Life Sci Alliance. 2023 May 23;6(8):e202201525. doi: 10.26508/lsa.202201525. Print 2023 Aug. Life Sci Alliance. 2023. PMID: 37221017 Free PMC article. - Alcohol, Resistance Exercise, and mTOR Pathway Signaling: An Evidence-Based Narrative Review.
Levitt DE, Luk HY, Vingren JL. Levitt DE, et al. Biomolecules. 2022 Dec 20;13(1):2. doi: 10.3390/biom13010002. Biomolecules. 2022. PMID: 36671386 Free PMC article. Review. - Tryptophan promoted β-defensin-2 expression via the mTOR pathway and its metabolites: kynurenine banding to aryl hydrocarbon receptor in rat intestine.
Tang Z, Shi B, Sun W, Yin Y, Chen Q, Mohamed T, Lu C, Sun Z. Tang Z, et al. RSC Adv. 2020 Jan 21;10(6):3371-3379. doi: 10.1039/c9ra10477a. eCollection 2020 Jan 16. RSC Adv. 2020. PMID: 35497743 Free PMC article. - SLC38A10 Regulate Glutamate Homeostasis and Modulate the AKT/TSC2/mTOR Pathway in Mouse Primary Cortex Cells.
Tripathi R, Aggarwal T, Lindberg FA, Klemm AH, Fredriksson R. Tripathi R, et al. Front Cell Dev Biol. 2022 Apr 5;10:854397. doi: 10.3389/fcell.2022.854397. eCollection 2022. Front Cell Dev Biol. 2022. PMID: 35450293 Free PMC article. - G-Protein Coupled Receptor Signaling and Mammalian Target of Rapamycin Complex 1 Regulation.
Melick CH, Lama-Sherpa TD, Curukovic A, Jewell JL. Melick CH, et al. Mol Pharmacol. 2022 Apr;101(4):181-190. doi: 10.1124/molpharm.121.000302. Epub 2021 Dec 28. Mol Pharmacol. 2022. PMID: 34965982 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous