Glutaminolysis activates Rag-mTORC1 signaling
- PMID: 22749528
- DOI: 10.1016/j.molcel.2012.05.043
Glutaminolysis activates Rag-mTORC1 signaling
Abstract
Amino acids control cell growth via activation of the highly conserved kinase TORC1. Glutamine is a particularly important amino acid in cell growth control and metabolism. However, the role of glutamine in TORC1 activation remains poorly defined. Glutamine is metabolized through glutaminolysis to produce α-ketoglutarate. We demonstrate that glutamine in combination with leucine activates mammalian TORC1 (mTORC1) by enhancing glutaminolysis and α-ketoglutarate production. Inhibition of glutaminolysis prevented GTP loading of RagB and lysosomal translocation and subsequent activation of mTORC1. Constitutively active Rag heterodimer activated mTORC1 in the absence of glutaminolysis. Conversely, enhanced glutaminolysis or a cell-permeable α-ketoglutarate analog stimulated lysosomal translocation and activation of mTORC1. Finally, cell growth and autophagy, two processes controlled by mTORC1, were regulated by glutaminolysis. Thus, mTORC1 senses and is activated by glutamine and leucine via glutaminolysis and α-ketoglutarate production upstream of Rag. This may provide an explanation for glutamine addiction in cancer cells.
Copyright © 2012 Elsevier Inc. All rights reserved.
Similar articles
-
Metabolism. Differential regulation of mTORC1 by leucine and glutamine.Science. 2015 Jan 9;347(6218):194-8. doi: 10.1126/science.1259472. Epub 2015 Jan 7. Science. 2015. PMID: 25567907 Free PMC article.
-
Glutamine and asparagine activate mTORC1 independently of Rag GTPases.J Biol Chem. 2020 Mar 6;295(10):2890-2899. doi: 10.1074/jbc.AC119.011578. Epub 2020 Feb 4. J Biol Chem. 2020. PMID: 32019866 Free PMC article.
-
Nitrogen source activates TOR (target of rapamycin) complex 1 via glutamine and independently of Gtr/Rag proteins.J Biol Chem. 2014 Sep 5;289(36):25010-20. doi: 10.1074/jbc.M114.574335. Epub 2014 Jul 25. J Biol Chem. 2014. PMID: 25063813 Free PMC article.
-
Glutaminolysis and autophagy in cancer.Autophagy. 2015;11(8):1198-208. doi: 10.1080/15548627.2015.1053680. Autophagy. 2015. PMID: 26054373 Free PMC article. Review.
-
Key mediators of intracellular amino acids signaling to mTORC1 activation.Amino Acids. 2015 May;47(5):857-67. doi: 10.1007/s00726-015-1937-x. Epub 2015 Feb 21. Amino Acids. 2015. PMID: 25701492 Review.
Cited by
-
A prismatic view of the epigenetic-metabolic regulatory axis in breast cancer therapy resistance.Oncogene. 2024 Jun;43(23):1727-1741. doi: 10.1038/s41388-024-03054-9. Epub 2024 May 8. Oncogene. 2024. PMID: 38719949 Free PMC article. Review.
-
Uncharacterized yeast gene YBR238C, an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging via HAP4- and RMD9-dependent mechanisms.Elife. 2024 May 7;12:RP92178. doi: 10.7554/eLife.92178. Elife. 2024. PMID: 38713053 Free PMC article.
-
P4HA2 activates mTOR via hydroxylation and targeting P4HA2-mTOR inhibits lung adenocarcinoma cell growth.Oncogene. 2024 Jun;43(24):1813-1823. doi: 10.1038/s41388-024-03032-1. Epub 2024 Apr 23. Oncogene. 2024. PMID: 38654109 Free PMC article.
-
Metabolic Signaling in Cancer Metastasis.Cancer Discov. 2024 Jun 3;14(6):934-952. doi: 10.1158/2159-8290.CD-24-0174. Cancer Discov. 2024. PMID: 38592405 Review.
-
Nutrients: Signal 4 in T cell immunity.J Exp Med. 2024 Mar 4;221(3):e20221839. doi: 10.1084/jem.20221839. Epub 2024 Feb 27. J Exp Med. 2024. PMID: 38411744 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources