Abstract
Glutamine and leucine are important mTORC1 modulators, although their roles are not precisely defined. In HepG2 and HeLa cells glutamine-free incubation lowers mTORC1 activity, although cell leucine is not decreased. mTORC1 activity, suppressed by amino acid-free incubation, is completely rescued only if essential amino acids (EAA) and glutamine are simultaneously restored, although cell leucine is higher in the absence than in the presence of glutamine. Thus, glutamine stimulates mTORC1 independent of cell leucine, suggesting the existence of two distinct stimulatory signals from either glutamine or EAA.
References
Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A, Dai N (2009) Amino acid regulation of tor complex 1. Am J Physiol Endocrinol Metab 296:E592–E602
Baird FE, Bett KJ, MacLean C, Tee AR, Hundal HS, Taylor PM (2009) Tertiary active transport of amino acids reconstituted by coexpression of system a and l transporters in Xenopus oocytes. Am J Physiol Endocrinol Metab 297:E822–E829
Bauchart-Thevret C, Cui L, Wu G, Burrin DG (2010) Arginine-induced stimulation of protein synthesis and survival in ipec-j2 cells is mediated by mtor but not nitric oxide. Am J Physiol Endocrinol Metab 299:E899–E909
Bussolati O, Dall’Asta V, Franchi-Gazzola R, Sala R, Rotoli BM, Visigalli R, Casado J, Lopez-Fontanals M, Pastor-Anglada M, Gazzola GC (2001) The role of system a for neutral amino acid transport in the regulation of cell volume. Mol Membr Biol 18:27–38
Dall’Asta V, Bussolati O, Sala R, Parolari A, Alamanni F, Biglioli P, Gazzola GC (1999) Amino acids are compatible osmolytes for volume recovery after hypertonic shrinkage in vascular endothelial cells. Am J Physiol 276:C865–C872
Deldicque L, Sanchez Canedo C, Horman S, De Potter I, Bertrand L, Hue L, Francaux M (2008) Antagonistic effects of leucine and glutamine on the mtor pathway in myogenic c2c12 cells. Amino Acids 35:147–155
Evans K, Nasim Z, Brown J, Butler H, Kauser S, Varoqui H, Erickson JD, Herbert TP, Bevington A (2007) Acidosis-sensing glutamine pump snat2 determines amino acid levels and mammalian target of rapamycin signalling to protein synthesis in l6 muscle cells. J Am Soc Nephrol 18:1426–1436
Evans K, Nasim Z, Brown J, Clapp E, Amin A, Yang B, Herbert TP, Bevington A (2008) Inhibition of snat2 by metabolic acidosis enhances proteolysis in skeletal muscle. J Am Soc Nephrol 19:2119–2129
Feng B, Shiber SK, Max SR (1990) Glutamine regulates glutamine synthetase expression in skeletal muscle cells in culture. J Cell Physiol 145:376–380
Fox HL, Pham PT, Kimball SR, Jefferson LS, Lynch CJ (1998) Amino acid effects on translational repressor 4e-bp1 are mediated primarily by l-leucine in isolated adipocytes. Am J Physiol 275:C1232–C1238
Gleason CE, Lu D, Witters LA, Newgard CB, Birnbaum MJ (2007) The role of ampk and mtor in nutrient sensing in pancreatic beta-cells. J Biol Chem 282:10341–10351
Goberdhan DC (2010) Intracellular amino acid sensing and mtorc1-regulated growth: new ways to block an old target? Curr Opin Investig Drugs 11:1360–1367
Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, Kim HK, Ha SH, Ryu SH, Kim S (2012) Leucyl-trna synthetase is an intracellular leucine sensor for the mtorc1-signaling pathway. Cell. doi:10.1016/j.cell.2012.02.044
Hundal HS, Taylor PM (2009) Amino acid transceptors: gate keepers of nutrient exchange and regulators of nutrient signaling. Am J Physiol Endocrinol Metab 296:E603–E613
Karunakaran S, Ramachandran S, Coothankandaswamy V, Elangovan S, Babu E, Periyasamy-Thandavan S, Gurav A, Gnanaprakasam JP, Singh N, Schoenlein PV, Prasad PD, Thangaraju M, Ganapathy V (2011) Slc6a14 (atb0,+) protein, a highly concentrative and broad specific amino acid transporter, is a novel and effective drug target for treatment of estrogen receptor-positive breast cancer. J Biol Chem 286:31830–31838
Kimball SR, Shantz LM, Horetsky RL, Jefferson LS (1999) Leucine regulates translation of specific mrnas in l6 myoblasts through mtor-mediated changes in availability of eif4e and phosphorylation of ribosomal protein s6. J Biol Chem 274:11647–11652
Krause U, Bertrand L, Maisin L, Rosa M, Hue L (2002) Signalling pathways and combinatory effects of insulin and amino acids in isolated rat hepatocytes. Eur J Biochem 269:3742–3750
Labow BI, Abcouwer SF, Lin CM, Souba WW (1998) Glutamine synthetase expression in rat lung is regulated by protein stability. Am J Physiol 275:L877–L886
Labow BI, Souba WW, Abcouwer SF (1999) Glutamine synthetase expression in muscle is regulated by transcriptional and posttranscriptional mechanisms. Am J Physiol 276:E1136–E1145
Ma XM, Blenis J (2009) Molecular mechanisms of mtor-mediated translational control. Nat Rev Mol Cell Biol 10:307–318
Nakajo T, Yamatsuji T, Ban H, Shigemitsu K, Haisa M, Motoki T, Noma K, Nobuhisa T, Matsuoka J, Gunduz M, Yonezawa K, Tanaka N, Naomoto Y (2005) Glutamine is a key regulator for amino acid-controlled cell growth through the mtor signaling pathway in rat intestinal epithelial cells. Biochem Biophys Res Commun 326:174–180
Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO (2009) Bidirectional transport of amino acids regulates mtor and autophagy. Cell 136:521–534
Rotoli BM, Uggeri J, Dall’Asta V, Visigalli R, Barilli A, Gatti R, Orlandini G, Gazzola GC, Bussolati O (2005) Inhibition of glutamine synthetase triggers apoptosis in asparaginase-resistant cells. Cell Physiol Biochem 15:281–292
Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The rag gtpases bind raptor and mediate amino acid signaling to mtorc1. Science 320:1496–1501
Sancak Y, Sabatini DM (2009) Rag proteins regulate amino-acid-induced mtorc1 signalling. Biochem Soc Trans 37:289–290
Sengupta S, Peterson TR, Sabatini DM (2010) Regulation of the mtor complex 1 pathway by nutrients, growth factors, and stress. Mol Cell 40:310–322
Tardito S, Chiu M, Franchi-Gazzola R, Dall’asta V, Comi P, Bussolati O (2011a) The non-proteinogenic amino acids l: methionine sulfoximine and dl: phosphinothricin activate mtor. Amino Acids. doi:10.1007/s00726-011-0981-4
Tardito S, Chiu M, Uggeri J, Zerbini A, Da Ros F, Dall’asta V, Missale G, Bussolati O (2011b) L-asparaginase and inhibitors of glutamine synthetase disclose glutamine addiction of beta-catenin-mutated human hepatocellular carcinoma cells. Curr Cancer Drug Targets 11:929–943
Wang X, Proud CG (2011) Mtorc1 signaling: What we still don’t know. J Mol Cell Biol 3:206–220
Wen HY, Abbasi S, Kellems RE, Xia Y (2005) Mtor: A placental growth signaling sensor. Placenta 26 Suppl A, S63–69
Xia Y, Wen HY, Young ME, Guthrie PH, Taegtmeyer H, Kellems RE (2003) Mammalian target of rapamycin and protein kinase a signaling mediate the cardiac transcriptional response to glutamine. J Biol Chem 278:13143–13150
Xu G, Kwon G, Cruz WS, Marshall CA, McDaniel ML (2001) Metabolic regulation by leucine of translation initiation through the mtor-signaling pathway by pancreatic beta-cells. Diabetes 50:353–360
Zoncu R, Efeyan A, Sabatini DM (2011) Mtor: From growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21–35
Acknowledgments
M.C. is supported by a fellowship of the Doctorate School of Molecular Medicine, University of Milan. A.B. and M.G.B. are supported by research scholarships of the University of Parma Medical School.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
M. Chiu and S. Tardito contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Chiu, M., Tardito, S., Barilli, A. et al. Glutamine stimulates mTORC1 independent of the cell content of essential amino acids. Amino Acids 43, 2561–2567 (2012). https://doi.org/10.1007/s00726-012-1312-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-012-1312-0