Regulation of the small GTPase Rheb by amino acids - PubMed (original) (raw)
. 2006 Feb 2;25(5):657-64.
doi: 10.1038/sj.onc.1209106.
Affiliations
- PMID: 16170341
- DOI: 10.1038/sj.onc.1209106
Regulation of the small GTPase Rheb by amino acids
M Roccio et al. Oncogene. 2006.
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.
Similar articles
- The mTOR/S6K signalling pathway: the role of the TSC1/2 tumour suppressor complex and the proto-oncogene Rheb.
Nobukini T, Thomas G. Nobukini T, et al. Novartis Found Symp. 2004;262:148-54; discussion 154-9, 265-8. Novartis Found Symp. 2004. PMID: 15562827 Review. - Rheb activation of mTOR and S6K1 signaling.
Hanrahan J, Blenis J. Hanrahan J, et al. Methods Enzymol. 2006;407:542-55. doi: 10.1016/S0076-6879(05)07044-8. Methods Enzymol. 2006. PMID: 16757352 - Selective inhibition of growth of tuberous sclerosis complex 2 null cells by atorvastatin is associated with impaired Rheb and Rho GTPase function and reduced mTOR/S6 kinase activity.
Finlay GA, Malhowski AJ, Liu Y, Fanburg BL, Kwiatkowski DJ, Toksoz D. Finlay GA, et al. Cancer Res. 2007 Oct 15;67(20):9878-86. doi: 10.1158/0008-5472.CAN-07-1394. Cancer Res. 2007. PMID: 17942919 - Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase.
Avruch J, Hara K, Lin Y, Liu M, Long X, Ortiz-Vega S, Yonezawa K. Avruch J, et al. Oncogene. 2006 Oct 16;25(48):6361-72. doi: 10.1038/sj.onc.1209882. Oncogene. 2006. PMID: 17041622 Review. - Measurements of TSC2 GAP activity toward Rheb.
Li Y, Inoki K, Vikis H, Guan KL. Li Y, et al. Methods Enzymol. 2006;407:46-54. doi: 10.1016/S0076-6879(05)07005-9. Methods Enzymol. 2006. PMID: 16757313
Cited by
- mTORC1 and Nutrient Homeostasis: The Central Role of the Lysosome.
Rabanal-Ruiz Y, Korolchuk VI. Rabanal-Ruiz Y, et al. Int J Mol Sci. 2018 Mar 12;19(3):818. doi: 10.3390/ijms19030818. Int J Mol Sci. 2018. PMID: 29534520 Free PMC article. Review. - A genome-wide siRNA screen in mammalian cells for regulators of S6 phosphorylation.
Papageorgiou A, Rapley J, Mesirov JP, Tamayo P, Avruch J. Papageorgiou A, et al. PLoS One. 2015 Mar 19;10(3):e0116096. doi: 10.1371/journal.pone.0116096. eCollection 2015. PLoS One. 2015. PMID: 25790369 Free PMC article. - Growing knowledge of the mTOR signaling network.
Huang K, Fingar DC. Huang K, et al. Semin Cell Dev Biol. 2014 Dec;36:79-90. doi: 10.1016/j.semcdb.2014.09.011. Epub 2014 Sep 19. Semin Cell Dev Biol. 2014. PMID: 25242279 Free PMC article. Review. - Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1.
Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM. Bar-Peled L, et al. Cell. 2012 Sep 14;150(6):1196-208. doi: 10.1016/j.cell.2012.07.032. Cell. 2012. PMID: 22980980 Free PMC article. - Rheb1 is required for mTORC1 and myelination in postnatal brain development.
Zou J, Zhou L, Du XX, Ji Y, Xu J, Tian J, Jiang W, Zou Y, Yu S, Gan L, Luo M, Yang Q, Cui Y, Yang W, Xia X, Chen M, Zhao X, Shen Y, Chen PY, Worley PF, Xiao B. Zou J, et al. Dev Cell. 2011 Jan 18;20(1):97-108. doi: 10.1016/j.devcel.2010.11.020. Dev Cell. 2011. PMID: 21238928 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous