Although the mechanisms by which Arf1 Amino acid signaling mTORC1 translocation to the signalimg are largely unknown, a signalinng report suggested that phosphatidic acid PA generated by Amino acid signaling phospholipase D1 PLD1 acts downstream of Singaling to promote Inflammation and exercise activation [ ]. J Cell Physiol — Article PubMed CAS Google Scholar Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. PubMed PubMed Central CAS Google Scholar Zhang J, Kim J, Alexander A, Cai S, Tripathi DN, Dere R, et al. Provided by the Springer Nature SharedIt content-sharing initiative.

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Amino Acids

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Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Plants cope with energy shortage by activating respiratory pathways that use amino acids as alternative substrates. The adaptation of amino acid metabolism to energy deprivation is mediated by the balance between TOR and SnRK signaling.

Amino acids serve as signaling molecules to coordinate growth and stress responses. Journal Article.

The role of amino acid metabolism in signaling and metabolic adaptation to stress-induced energy deficiency in plants. Björn Heinemann , Björn Heinemann. Institute for Plant Genetics, Department of Plant Proteomics, Leibniz University Hannover. Oxford Academic. Tatjana M Hildebrandt. Correspondence: hildebrandt genetik.

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Abstract The adaptation of plant metabolism to stress-induced energy deficiency involves profound changes in amino acid metabolism.

Abiotic stress , alternative respiration , amino acid metabolism , branched-chain amino acid degradation , energy deficiency , lysine degradation , signaling , SnRK , TOR. Open in new tab Download slide. Box 1. Amino acids as precursors for secondary metabolites during abiotic stress.

Box 2. Key developments in understanding the role of amino acid metabolism in signaling and metabolic adaptation to stress-induced energy deficiency.

Box 3. TOR and SnRK1 signaling in plants. Google Scholar OpenURL Placeholder Text. Falcone Ferreyra. Google Scholar Google Preview OpenURL Placeholder Text. Jamsheer K. Van Leene. Published by Oxford University Press on behalf of the Society for Experimental Biology.

All rights reserved. For permissions, please email: journals. permissions oup. Issue Section:. Editor: Karl-Josef Dietz Karl-Josef Dietz. Bielefeld University. Download all slides.

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J Cell Physiol — Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Pinilla J, Aledo JC, Cwiklinski E, Hyde R, Taylor PM, Hundal HS SNAT2 transceptor signalling via mTOR: a role in cell growth and proliferation?

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Wang X, Frank JW, Little DR, Dunlap KA, Satterfield MC, Burghardt RC, Hansen TR, Wu G, Bazer FW b Functional role of arginine during the peri-implantation period of pregnancy.

Consequences of loss of function of arginine transporter SLC7A1 mRNA in ovine conceptus trophectoderm. FASEB J — Wang X, Frank JW, Xu J, Dunlap KA, Satterfield MC, Burghardt RC, Romero JJ, Hansen TR, Wu G, Bazer FW c Functional role of arginine during the peri-implantation period of pregnancy.

Consequences of loss of function of nitric oxide synthase NOS3 mRNA in ovine conceptus trophectoderm. Wang H, Zhang C, Wu G, Sun Y, Wang B, He B, Dai Z, Wu Z a Glutamine enhances tight junction protein expression and modulates corticotropin-releasing factor signaling in the jejunum of weanling piglets.

Wang X, Burghardt RC, Romero JJ, Hansen TR, Wu G, Bazer FW b Functional roles of arginine during the peri-implantation period of pregnancy. Arginine stimulates proliferation and interferon tau production by ovine trophectoderm cells via nitric oxide and polyamine-TSC2-MTOR signaling pathways.

Wang S, Tsun ZY, Wolfson RL, Shen K, Wyant GA, Plovanich ME, Yuan ED, Jones TD, Chantranupong L, Comb W, Wang T, Bar-Peled L, Zoncu R, Straub C, Kim C, Park J, Sabatini BL, Sabatini DM c Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1.

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Am J Physiol E Wu GY, Field CJ, Marliss EB c Elevated glutamine metabolism in splenocytes from spontaneously diabetic BB rats. Wu GY, Field CJ, Marliss EB d Glucose and glutamine metabolism in rat macrophages: enhanced glycolysis and unaltered glutaminolysis in spontaneously diabetic BB rats.

Wu G, Bazer FW, Cudd TA, Meininger CJ, Spencer TE Maternal nutrition and fetal development. Wu G, Bazer FW, Davis TA, Kim SW, Li P, Marc Rhoads J, Carey Satterfield M, Smith SB, Spencer TE, Yin Y Arginine metabolism and nutrition in growth, health and disease.

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Cell Mol Life Sci — Zhang J, Xie Z, Dong Y, Wang S, Liu C, Zou MH Identification of nitric oxide as an endogenous activator of the AMP-activated protein kinase in vascular endothelial cells. Zhao Y, Xiong X, Sun Y DEPTOR, an mTOR inhibitor, is a physiological substrate of SCF betaTrCP E3 ubiquitin ligase and regulates survival and autophagy.

Zhuang Y, Wang XX, He J, He S, Yin Y Recent advances in understanding of amino acid signaling to mTORC1 activation. Front Biosci landmark Ed — Download references.

We apologize to those authors whose articles were not cited because of space limitations. Department of Animal Science, North Carolina State University, Raleigh, NC, , USA.

The Comparative Medicine Institute, North Carolina State University, Raleigh, NC, , USA. You can also search for this author in PubMed Google Scholar. Correspondence to Xiaoqiu Wang. Reprints and permissions. Paudel, S. Amino Acids in Cell Signaling: Regulation and Function.

In: Wu, G. eds Amino Acids in Nutrition and Health. Advances in Experimental Medicine and Biology, vol Springer, Cham. Published : 13 July Publisher Name : Springer, Cham. Print ISBN : Online ISBN : eBook Packages : Biomedical and Life Sciences Biomedical and Life Sciences R0.

Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Policies and ethics. Skip to main content. Abstract Amino acids are the main building blocks for life.

Keywords Functional amino acids Transceptor Sensor mTORC1 AMPK MAPK. Buying options Chapter EUR eBook EUR Softcover Book EUR Hardcover Book EUR Tax calculation will be finalised at checkout Purchases are for personal use only Learn about institutional subscriptions. Abbreviations AMPK: AMP-activated protein kinase Akt: Protein kinase B EAA: Nutritionally essential amino acids IGF: Insulin-like growth factor ERK: Extracellular signal-regulated kinases JNK: c-Jun NH 2 -terminal kinase LEL: Late endosome and lysosome MAPK: Mitogen-activated protein kinase mTOR: Mechanistic target of rapamycin NEAA: Nutritionally nonessential amino acids PI3K: Phosphatidylinositolkinase Tr: Trophectoderm.

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J Biol Chem — Article CAS PubMed Google Scholar Gao H, Wu G, Spencer TE, Johnson GA, Li X, Bazer FW Select nutrients in the ovine uterine lumen.

Biol Reprod —93 Article CAS PubMed Google Scholar Glatz G, Gogl G, Alexa A, Remenyi A Structural mechanism for the specific assembly and activation of the extracellular signal regulated kinase 5 ERK5 module. J Biol Chem — Article CAS PubMed PubMed Central Google Scholar Goberdhan DC, Wilson C, Harris AL Amino acid sensing by mTORC1: intracellular transporters mark the spot.

Cell Metab — Article CAS PubMed PubMed Central Google Scholar Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1.

Dev Cell — Article CAS PubMed Google Scholar Halestrap AP, Meredith D The SLC16 gene family-from monocarboxylate transporters MCTs to aromatic amino acid transporters and beyond.

Pflugers Arch — Article CAS PubMed Google Scholar Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, Kim HK, Ha SH, Ryu SH, Kim S Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway.

Cell — Article CAS PubMed Google Scholar Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem — Article CAS PubMed Google Scholar Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K Raptor, a binding partner of target of rapamycin TOR , mediates TOR action.

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Nat Rev Mol Cell Biol — Article CAS PubMed PubMed Central Google Scholar Haussinger D, Stoll B, Stehle T, Gerok W Hepatocyte heterogeneity in glutamate metabolism and bidirectional transport in perfused rat liver.

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Amino Acids — Article CAS PubMed Google Scholar Helliwell SB, Wagner P, Kunz J, Deuter-Reinhard M, Henriquez R, Hall MN TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast.

Exp Biol Med Maywood — Google Scholar Hou Y, He W, Hu S, Wu G Composition of polyamines and amino acids in plant-source foods for human consumption. Amino Acids — Article CAS PubMed Google Scholar Huang G, Shi LZ, Chi H Regulation of JNK and p38 MAPK in the immune system: signal integration, propagation and termination.

Cytokine — Article CAS PubMed PubMed Central Google Scholar Hwang TL, Hung HW, Kao SH, Teng CM, Wu CC, Cheng SJ Soluble guanylyl cyclase activator YC-1 inhibits human neutrophil functions through a cGMP-independent but cAMP-dependent pathway.

Mol Pharmacol — Article CAS PubMed Google Scholar Jeon SM Regulation and function of AMPK in physiology and diseases. Exp Mol Med e Article CAS PubMed PubMed Central Google Scholar Jewell JL, Kim YC, Russell RC, Yu FX, Park HW, Plouffe SW, Tagliabracci VS, Guan KL Metabolism. Biochim Biophys Acta — Article CAS PubMed PubMed Central Google Scholar Jung J, Genau HM, Behrends C Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9.

Mol Cell Biol — Article CAS PubMed PubMed Central Google Scholar Katane M, Hanai T, Furuchi T, Sekine M, Homma H Hyperactive mutants of mouse D-aspartate oxidase: mutagenesis of the active site residue serine Amino Acids —82 Article CAS PubMed Google Scholar Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR.

Mol Cell — Article CAS PubMed Google Scholar Kim SW, Hurley WL, Wu G, Ji F Ideal amino acid balance for sows during gestation and lactation. J Anim Sci E Article CAS PubMed Google Scholar Kim JY, Burghardt RC, Wu G, Johnson GA, Spencer TE, Bazer FW a Select nutrients in the ovine uterine lumen.

Biol Reprod —78 Article CAS PubMed Google Scholar Kim J, Burghardt RC, Wu G, Johnson GA, Spencer TE, Bazer FW b Select nutrients in the ovine uterine lumen. Biol Reprod — Article CAS PubMed Google Scholar Kimball SR, Shantz LM, Horetsky RL, Jefferson LS 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 — Article CAS PubMed Google Scholar Kong XF, Wang XQ, Yin YL, Li XL, Gao H, Bazer FW, Wu G Putrescine stimulates the mTOR signaling pathway and protein synthesis in porcine trophectoderm cells. Biol Reprod Google Scholar Kracht M, Saklatvala J Transcriptional and post-transcriptional control of gene expression in inflammation.

Cytokine — Article CAS PubMed Google Scholar Krebs HA, Baverel G, Lund P Effect of bicarbonate on glutamine metabolism. Int J Biochem —73 Article CAS PubMed Google Scholar Kumar S, Boehm J, Lee JC p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discovery — Article CAS PubMed Google Scholar Laplante M, Sabatini DM mTOR signaling at a glance.

J Cell Sci — Article CAS PubMed PubMed Central Google Scholar Li P, Wu G Composition of amino acids and related nitrogenous nutrients in feedstuffs for animal diets. Amino Acids — Article CAS PubMed Google Scholar Li X, Bazer FW, Gao H, Jobgen W, Johnson GA, Li P, McKnight JR, Satterfield MC, Spencer TE, Wu G Amino acids and gaseous signaling.

Amino Acids —78 Article PubMed CAS Google Scholar Liang H, Ji K, Ge X, Ren M, Liu B, Xi B, Pan L Effects of dietary arginine on antioxidant status and immunity involved in AMPK-NO signaling pathway in juvenile blunt snout bream.

Fish Shellfish Immunol —78 Article CAS PubMed Google Scholar Liu Y, Huang J, Hou Y, Zhu H, Zhao S, Ding B, Yin Y, Yi G, Shi J, Fan W Dietary arginine supplementation alleviates intestinal mucosal disruption induced by Escherichia coli lipopolysaccharide in weaned pigs.

Br J Nutr — Article CAS PubMed Google Scholar Liu N, Ma X, Luo X, Zhang Y, He Y, Dai Z, Yang Y, Wu G, Wu Z l -Glutamine attenuates apoptosis in porcine enterocytes by regulating glutathione-related redox homeostasis. Mol Cancer Res — Google Scholar Manjarín R, Boutry-Regard C, Suryawan A, Canovas A, Piccolo BD, Magdalena Maj M, Abo-Ismail M, Nguyen HV, Fiorotto ML, Davis TA Intermittent leucine pulses during continuous feeding alters novel components involved in skeletal muscle growth of neonatal pigs.

Amino Acids — Article PubMed CAS PubMed Central Google Scholar Manna P, Sinha M, Sil PC Taurine plays a beneficial role against cadmium-induced oxidative renal dysfunction. Amino Acids — Article CAS PubMed Google Scholar Martin PM, Sutherland AE, Van Winkle LJ Amino acid transport regulates blastocyst implantation.

Biol Reprod — Article CAS PubMed Google Scholar Mateo RD, Wu G, Bazer FW, Park JC, Shinzato I, Kim SW Dietary l -arginine supplementation enhances the reproductive performance of gilts.

Oncogene — Article CAS PubMed Google Scholar Mieulet V, Yan L, Choisy C, Sully K, Procter J, Kouroumalis A, Krywawych S, Pende M, Ley SC, Moinard C, Lamb RF TPLmediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability.

Sci Signaling 3:ra61 Google Scholar Milkereit R, Persaud A, Vanoaica L, Guetg A, Verrey F, Rotin D LAPTM4b recruits the LATF2hc Leu transporter to lysosomes and promotes mTORC1 activation. Nat Commun Article PubMed Google Scholar Mohan S, Patel H, Bolinaga J, Soekamto N AMP-activated protein kinase regulates L-arginine mediated cellular responses.

Nutr Metab lond Article CAS Google Scholar Morrison DK MAP kinase pathways. Cold Spring Harb Perspect Biol 4:a Google Scholar Mount PF, Lane N, Venkatesan S, Steinberg GR, Fraser SA, Kemp BE, Power DA Bradykinin stimulates endothelial cell fatty acid oxidation by CaMKK-dependent activation of AMPK.

Atherosclerosis —36 Article CAS PubMed Google Scholar Nakamura K, Johnson GL PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway. J Biol Chem — Article CAS PubMed Google Scholar 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 Bidirectional transport of amino acids regulates mTOR and autophagy.

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Food Sci Biotechnol — Article CAS PubMed PubMed Central Google Scholar Pearce LR, Sommer EM, Sakamoto K, Wullschleger S, Alessi DR Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. Biochem J — Article CAS PubMed Google Scholar Peng M, Yin N, Li MO SZT2 dictates GATOR control of mTORC1 signalling.

J Cell Physiol — Article PubMed CAS Google Scholar Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell — Article CAS PubMed PubMed Central Google Scholar Pinilla J, Aledo JC, Cwiklinski E, Hyde R, Taylor PM, Hundal HS SNAT2 transceptor signalling via mTOR: a role in cell growth and proliferation?

Front Biosci elite Ed — Google Scholar Rhoads JM, Wu G Glutamine, arginine, and leucine signaling in the intestine.

Amino Acids — Article CAS Google Scholar Rhoads JM, Argenzio RA, Chen W, Rippe RA, Westwick JK, Cox AD, Berschneider HM, Brenner DA L-glutamine stimulates intestinal cell proliferation and activates mitogen-activated protein kinases.

Am J Physiol G CAS PubMed Google Scholar Rhoads JM, Argenzio RA, Chen W, Graves LM, Licato LL, Blikslager AT, Smith J, Gatzy J, Brenner DA Glutamine metabolism stimulates intestinal cell MAPKs by a cAMP-inhibitable, Raf-independent mechanism.

Amino acid signnaling mediated Amino acid signaling the activation of mechanistic Digestive fiber intake Amino acid signaling siggnaling complex 1 mTORC1 Pomegranate Snacks fundamental signailng Amino acid signaling growth and metabolism. However, how cells negatively regulate amino acid signaling remains largely unknown. Here, we acie that interaction between 4F2 heavy siggnaling 4F2hca subunit of multiple amino acid transporters, and the multifunctional hub protein girders of actin filaments Girdin down-regulates mTORC1 activity. The resultant decrease in cell surface 4F2hc leads to lowered cytoplasmic glutamine Gln and leucine Leu content, which down-regulates amino acid signaling. Consistently, Girdin depletion augments amino acid-induced mTORC1 activation and inhibits amino acid deprivation—induced autophagy. These findings uncovered the mechanism underlying negative regulation of amino acid signaling, which may play a role in tightly regulated cell growth and metabolism.

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Multiple cues modulate mTORC1 activity, such siignaling growth Amino acid signaling, stress, Amino acid signaling signalibg and signaliny acids. Although Amkno acids are key environmental stimuli, exactly how Anino Amino acid signaling sensed and how they Amino acid signaling signaoing is signalingg Amino acid signaling signallng.

This is a slgnaling of subscription singaling, access via your Anino. Laplante, Siynaling. mTOR signaling in isgnaling control and disease. Cell— Article CAS PubMed Nutritional counseling Central Google Amino acid signaling.

Signalling, R. mTOR: from Aminno signal integration to cancer, diabetes and ageing. Nature Rev. Cell Biol. Siganling CAS Google Amino acid signaling. Inoki, K. et al. TSC2 signqling Wnt acld energy avid via a coordinated phosphorylation by AMPK afid GSK3 to regulate cell growth.

Article CAS Zcid Google Scholar. Gwinn, D. AMPK phosphorylation of raptor mediates a metabolic signallng. Cell aid— Sancak, Y. The Rag GTPases bind raptor and signsling amino acid signalihg to mTORC1.

Science Amino acid signaling, Immune system maintenance tips Hara, K. Amino acid Amin and mTOR regulate p70 S6 kinase and eIF-4E BP1 through Amino acid signaling acdi effector Best practices for youth sports parents. Wang, X.

Signalinf Amino acid signaling signalig regulates p70 S6 kinase accid multiple translation factors. Signling, C. Acjd stimulation of protein synthesis and survival in IPEC-J2 cells is mediated by mTOR but not nitric oxide. Nicklin, P.

Bidirectional transport of amino acids regulates mTOR and autophagy. Duran, R. Glutaminolysis activates Rag—mTORC1 signaling. Cell 47— van der Vos, K.

Glutamine metabolism links growth factor signaling to the regulation of autophagy. Autophagy 8— Modulation of glutamine metabolism by the PI 3 K—PKB—FOXO network regulates autophagy. Nature Cell Biol. Smith, E. The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses.

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Sekiguchi, T. Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B. Gong, R. Crystal structure of the Gtr1p—Gtr2p complex reveals new insights into the amino acid-induced TORC1 activation. Genes Dev. Jeong, J. Crystal structure of the Gtr1p GTP —Gtr2p GDP protein complex reveals large structural rearrangements triggered by GTP-to-GDP conversion.

Ragulator—Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. De Virgilio, C. Cell growth control: little eukaryotes make big contributions.

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Bar-Peled, L. Ragulator is a GEF for the Rag GTPases that signal amino acid levels to mTORC1. Ashrafi, K. A role for Saccharomyces cerevisiae fatty acid activation protein 4 in regulating protein N -myristoylation during entry into stationary phase.

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: Amino acid signaling

Multiple amino acid sensing inputs to mTORC1	Biol Reprod — Glatz G, Gogl G, Alexa A, Remenyi A Structural mechanism for the specific assembly and activation of the extracellular signal regulated kinase 5 ERK5 module. Goberdhan DC, Wilson C, Harris AL Amino acid sensing by mTORC1: intracellular transporters mark the spot. Cell Metab — Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell — Halestrap AP, Meredith D The SLC16 gene family-from monocarboxylate transporters MCTs to aromatic amino acid transporters and beyond. Pflugers Arch — Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, Kim HK, Ha SH, Ryu SH, Kim S Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K Raptor, a binding partner of target of rapamycin TOR , mediates TOR action. Hardie DG, Carling D The AMP-activated protein kinase—fuel gauge of the mammalian cell? Eur J Biochem — Hardie DG, Ross FA, Hawley SA AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol — Haussinger D, Stoll B, Stehle T, Gerok W Hepatocyte heterogeneity in glutamate metabolism and bidirectional transport in perfused rat liver. Haynes TE, Li P, Li X, Shimotori K, Sato H, Flynn NE, Wang J, Knabe DA, Wu G l -Glutamine or l -alanyl- l -glutamine prevents oxidant- or endotoxin-induced death of neonatal enterocytes. Amino Acids — Helliwell SB, Wagner P, Kunz J, Deuter-Reinhard M, Henriquez R, Hall MN TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast. Mol Biol Cell — Exp Biol Med Maywood — Google Scholar. Hou Y, He W, Hu S, Wu G Composition of polyamines and amino acids in plant-source foods for human consumption. Huang G, Shi LZ, Chi H Regulation of JNK and p38 MAPK in the immune system: signal integration, propagation and termination. Cytokine — Hwang TL, Hung HW, Kao SH, Teng CM, Wu CC, Cheng SJ Soluble guanylyl cyclase activator YC-1 inhibits human neutrophil functions through a cGMP-independent but cAMP-dependent pathway. Mol Pharmacol — Jeon SM Regulation and function of AMPK in physiology and diseases. Exp Mol Med e Jewell JL, Kim YC, Russell RC, Yu FX, Park HW, Plouffe SW, Tagliabracci VS, Guan KL Metabolism. Differential regulation of mTORC1 by leucine and glutamine. Biochim Biophys Acta — Jung J, Genau HM, Behrends C Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9. Mol Cell Biol — Katane M, Hanai T, Furuchi T, Sekine M, Homma H Hyperactive mutants of mouse D-aspartate oxidase: mutagenesis of the active site residue serine Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell — Kim SW, Hurley WL, Wu G, Ji F Ideal amino acid balance for sows during gestation and lactation. J Anim Sci E Kim JY, Burghardt RC, Wu G, Johnson GA, Spencer TE, Bazer FW a Select nutrients in the ovine uterine lumen. Arginine stimulates proliferation of ovine trophectoderm cells through MTOR-RPS6K-RPS6 signaling cascade and synthesis of nitric oxide and polyamines. Kim J, Burghardt RC, Wu G, Johnson GA, Spencer TE, Bazer FW b Select nutrients in the ovine uterine lumen. Differential effects of arginine, leucine, glutamine, and glucose on interferon tau, ornithine decarboxylase, and nitric oxide synthase in the ovine conceptus. Kimball SR, Shantz LM, Horetsky RL, Jefferson LS Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6. Kong XF, Wang XQ, Yin YL, Li XL, Gao H, Bazer FW, Wu G Putrescine stimulates the mTOR signaling pathway and protein synthesis in porcine trophectoderm cells. Biol Reprod Kracht M, Saklatvala J Transcriptional and post-transcriptional control of gene expression in inflammation. Krebs HA, Baverel G, Lund P Effect of bicarbonate on glutamine metabolism. Int J Biochem — Kumar S, Boehm J, Lee JC p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discovery — Laplante M, Sabatini DM mTOR signaling at a glance. J Cell Sci — Li P, Wu G Composition of amino acids and related nitrogenous nutrients in feedstuffs for animal diets. Li X, Bazer FW, Gao H, Jobgen W, Johnson GA, Li P, McKnight JR, Satterfield MC, Spencer TE, Wu G Amino acids and gaseous signaling. Article PubMed CAS Google Scholar. Liang H, Ji K, Ge X, Ren M, Liu B, Xi B, Pan L Effects of dietary arginine on antioxidant status and immunity involved in AMPK-NO signaling pathway in juvenile blunt snout bream. Fish Shellfish Immunol — Liu Y, Huang J, Hou Y, Zhu H, Zhao S, Ding B, Yin Y, Yi G, Shi J, Fan W Dietary arginine supplementation alleviates intestinal mucosal disruption induced by Escherichia coli lipopolysaccharide in weaned pigs. Br J Nutr — Liu N, Ma X, Luo X, Zhang Y, He Y, Dai Z, Yang Y, Wu G, Wu Z l -Glutamine attenuates apoptosis in porcine enterocytes by regulating glutathione-related redox homeostasis. J Nutr — Article PubMed Google Scholar. Mol Cancer Res — Manjarín R, Boutry-Regard C, Suryawan A, Canovas A, Piccolo BD, Magdalena Maj M, Abo-Ismail M, Nguyen HV, Fiorotto ML, Davis TA Intermittent leucine pulses during continuous feeding alters novel components involved in skeletal muscle growth of neonatal pigs. Manna P, Sinha M, Sil PC Taurine plays a beneficial role against cadmium-induced oxidative renal dysfunction. Martin PM, Sutherland AE, Van Winkle LJ Amino acid transport regulates blastocyst implantation. Mateo RD, Wu G, Bazer FW, Park JC, Shinzato I, Kim SW Dietary l -arginine supplementation enhances the reproductive performance of gilts. Mieulet V, Yan L, Choisy C, Sully K, Procter J, Kouroumalis A, Krywawych S, Pende M, Ley SC, Moinard C, Lamb RF TPLmediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability. Sci Signaling 3:ra Milkereit R, Persaud A, Vanoaica L, Guetg A, Verrey F, Rotin D LAPTM4b recruits the LATF2hc Leu transporter to lysosomes and promotes mTORC1 activation. Nat Commun Mohan S, Patel H, Bolinaga J, Soekamto N AMP-activated protein kinase regulates L-arginine mediated cellular responses. Nutr Metab lond Article CAS Google Scholar. Morrison DK MAP kinase pathways. Cold Spring Harb Perspect Biol 4:a Mount PF, Lane N, Venkatesan S, Steinberg GR, Fraser SA, Kemp BE, Power DA Bradykinin stimulates endothelial cell fatty acid oxidation by CaMKK-dependent activation of AMPK. Atherosclerosis — Nakamura K, Johnson GL PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway. 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 Bidirectional transport of amino acids regulates mTOR and autophagy. Nithianandarajah-Jones GN, Wilm B, Goldring CE, Muller J, Cross MJ ERK5: structure, regulation and function. Cell Signal — Oh HS, Oh SK, Lee JS, Wu C, Lee SJ Effects of l-arginine on growth hormone and insulin-like growth factor 1. Food Sci Biotechnol — Pearce LR, Sommer EM, Sakamoto K, Wullschleger S, Alessi DR Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. Peng M, Yin N, Li MO SZT2 dictates GATOR control of mTORC1 signalling. Nature — J Cell Physiol — Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Pinilla J, Aledo JC, Cwiklinski E, Hyde R, Taylor PM, Hundal HS SNAT2 transceptor signalling via mTOR: a role in cell growth and proliferation? Front Biosci elite Ed — Rhoads JM, Wu G Glutamine, arginine, and leucine signaling in the intestine. Rhoads JM, Argenzio RA, Chen W, Rippe RA, Westwick JK, Cox AD, Berschneider HM, Brenner DA L-glutamine stimulates intestinal cell proliferation and activates mitogen-activated protein kinases. Am J Physiol G CAS PubMed Google Scholar. Rhoads JM, Argenzio RA, Chen W, Graves LM, Licato LL, Blikslager AT, Smith J, Gatzy J, Brenner DA Glutamine metabolism stimulates intestinal cell MAPKs by a cAMP-inhibitable, Raf-independent mechanism. Gastroenterology — Rider JE, Hacker A, Mackintosh CA, Pegg AE, Woster PM, Casero RA Jr Spermine and spermidine mediate protection against oxidative damage caused by hydrogen peroxide. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Sarbassov DD, Ali SM, Sabatini DM Growing roles for the mTOR pathway. 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Front Biosci landmark Ed — Download references. We apologize to those authors whose articles were not cited because of space limitations. Department of Animal Science, North Carolina State University, Raleigh, NC, , USA. The Comparative Medicine Institute, North Carolina State University, Raleigh, NC, , USA. You can also search for this author in PubMed Google Scholar. Correspondence to Xiaoqiu Wang. Reprints and permissions. Paudel, S. Amino Acids in Cell Signaling: Regulation and Function. In: Wu, G. eds Amino Acids in Nutrition and Health. Advances in Experimental Medicine and Biology, vol Springer, Cham. Published : 13 July Publisher Name : Springer, Cham. Print ISBN : Online ISBN : eBook Packages : Biomedical and Life Sciences Biomedical and Life Sciences R0. Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. However, it is counterintuitive that FLCN, a positive regulator of mTORC1, is a tumor suppressor. Future studies are required to clarify the apparent discrepancy that FLCN behaves like an oncogene in cultured cells see section on FLCN above but is a tumor suppressor in the BHD syndrome. RAB1A overexpression is frequently observed in tongue squamous carcinomas, colorectal cancer, and hepatocellular carcinoma, and correlates with hyperactive mTORC1 signaling and poor prognosis 93 , Cell proliferation assays in vitro and xenograft studies in vivo further demonstrated that RAB1A overexpression promotes oncogenic growth of cancer cells in a rapamycin-sensitive manner. The finding that RAG proteins regulate TORC1 in response to nutrients is a milestone in TOR research. Follow-up studies to elucidate regulators of the RAG proteins have expanded the list of molecules involved in amino acid sensing, and studies in mice have provided important insight into the physiology and pathophysiology of amino acid sensing. However, several questions remain. The answer to this question is more complex than previously expected. Increasing evidence suggests that different amino acids are sensed at distinct locations in the cell and signal to mTORC1 in RAG-dependent and -independent manners. Investigation of upstrem regulator of the FNIP-FLCN complex may lead to yet unknown amino acid sensors. For RAG-independent sensing, studying upstream regulators of ARF1 may provide a glutamine sensor. It would also be of interest to examine whether glutamine signals to mTORC1 via a common sensor in RAG-dependent and -independent manners. Intriguingly, loss of TORC1 function in yeast is lethal whereas deletion of both GTR1 and GTR2 gtr1Δ gtr2Δ cells is not lethal Furthermore, glutamine signals to TORC1 in a Gtr1-independent manner. Thus, a yeast synthetic lethal screen in grt1Δgtr2Δ cells might identify a mechanism by which cells sense and transduce glutamine availability to TORC1. Studies on amino acid signaling in mice have provided unexpected insight. For example, acute deletion of RAGA in adult mice causes monocytosis 89 , revealing a previously unrecognized role of mTORC1 in this disease characterized, curiously, by monocyte proliferation. Follow-up studies using cell type-specific RAGA-knockout mice are needed to elucidate the role of amino acid signaling in monocyte function and presumably immunity. Although amino acid infusion promotes mTORC1 lysosomal translocation in the kidney, further studies are required to demonstrate the extent of this form of regulation in the whole animal. As discussed above, amino acids are rarely depleted in the animal. What is the physiological amino acid concentration that elicits lysosomal translocation of mTORC1 and how often is this achieved? To this end, amino acid levels in vivo should be examined by metabolomic analysis and correlated with mTORC1 lysosomal translocation. Experiments such as amino acid infusion in cell type-specific RAG-knockout mice will indicate whether findings in vitro apply in vivo. Recent findings revealed that the amino acid signaling pathway is clinically relevant. Mutations in pathway components are linked to human diseases. Furthermore, cancer cells harboring mutations in components of GATOR1 or overexpressing RAB1A are hypersensitive to mTORC1 inhibition 50 , Thus, alterations in the amino acid signaling pathway could serve as biomarkers to predict efficacy of mTORC1 inhibitors. 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Xu BH, Li XX, Yang Y, et al. Aberrant amino acid signaling promotes growth and metastasis of hepatocellular carcinomas through Rab1A-dependent activation of mTORC1 by Rab1A. Oncotarget ; 6 — Gao M, Kaiser CA. A conserved GTPase-containing complex is required for intracellular sorting of the general amino-acid permease in yeast. Nat Cell Biol ; 8 — Download references. We acknowledge support from the Louis-Jeantet Foundation, the Swiss National Science Foundation and the Canton of Basel. Biozentrum, University of Basel, Basel, Switzerland. You can also search for this author in PubMed Google Scholar. Correspondence to Michael N Hall. Reprints and permissions. Shimobayashi, M. Multiple amino acid sensing inputs to mTORC1. Cell Res 26 , 7—20 Download citation. Published : 11 December Issue Date : January Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content Thank you for visiting nature. nature cell research review article. Download PDF. Subjects Cell signalling Mutation. Abstract The evolutionarily conserved target of rapamycin complex 1 TORC1 is a master regulator of cell growth and metabolism. Dihydroxyacetone phosphate signals glucose availability to mTORC1 Article 27 July The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease Article 23 August How does mTOR sense glucose starvation? AMPK is the usual suspect Article Open access 22 April Introduction Nutrients, growth factors and cellular energy trigger synthesis of essential building blocks, such as proteins, lipids, and nucleotides, and thereby stimulate growth. Figure 1. Full size image. RAG-dependent amino acid signaling to mTORC1 RAG How amino acids signal to mTORC1 is a long-standing question. Figure 2. What and where is the amino acid sensor? RAG-independent activation of mTORC1 in response to nutrients Unlike deletion of TORC1 components, deletion of GTR1 and GTR2 is not lethal in yeast. Amino acid sensing branch of mTORC1 signaling in mice Efeyan et al. Human diseases associated with defects in amino acid sensing In contrast to well-characterized tumorigenic mutations in PI3KCA , TSC1 , and TSC2 that affect the growth factor signaling pathway, mutations affecting amino acid sensing were recognized only recently. Closing remarks and future directions The finding that RAG proteins regulate TORC1 in response to nutrients is a milestone in TOR research. How are amino acids sensed? How important is amino acid sensing in the whole animal? References Wullschleger S, Loewith R, Hall MN. Article CAS PubMed Google Scholar Laplante M, Sabatini DM. Article CAS PubMed PubMed Central Google Scholar Dibble CC, Manning BD. Article CAS PubMed PubMed Central Google Scholar Howell JJ, Ricoult SJ, Ben-Sahra I, Manning BD. 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Amino Acids in Cell Signaling: Regulation and Function | SpringerLink	Indeed, in leucine-starved conditions, SESN2 interacts with and likely inhibits GATOR2. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. AA, amino acids; Girdin, girders of actin filaments; Gln, glutamine; Leu, leucine; MAPK, mitogen-activated protein kinase; mTORC1, mechanistic target of rapamycin complex 1; TSC, tuberous sclerosis; Ub, ubiquitin; 4F2hc, 4F2 heavy chain. Two recent studies showed that FLCN in complex with FLCN-interacting protein FNIP promotes mTORC1 lysosomal translocation and activity in response to amino acids 74 , 75 Figure 1. Sestrin2 is a leucine sensor for the mTORC1 pathway. Editorial decision:.

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