Mechanisms of amino acid sensing in mTOR signaling pathway

Amino acids are fundamental nutrients for protein synthesis and cell growth (increase in cell size). Recently, many compelling evidences have shown that the level of amino acids is sensed by extra- or intra-cellular amino acids sensor(s) and regulates protein synthesis/degradation. Mammalian target of rapamycin complex 1 (mTORC1) is placed in a central position in cell growth regulation and dysregulation of mTOR signaling pathway has been implicated in many serious human diseases including cancer, diabetes, and tissue hypertrophy. Although amino acids are the most potent activator of mTORC1, how amino acids activate mTOR signaling pathway is still largely unknown. This is partly because of the diversity of amino acids themselves including structure and metabolism. In this review, current proposed amino acid sensing mechanisms to regulate mTORC1 and the evidences pro/against the proposed models are discussed.

• Publication year

  2009

• Venue

  Nutrition Research and Practice

• Publication date

  2009-03-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.4162/nrp.2009.3.1.64PMID 20016704PMCID 2788159
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• hVps 15 , but not Ca 2 + / CaM , is required for the activity and regulation of hVps 34 in mammalian cells

  2009cited by this paper
• Bidirectional transport of amino acids regulates mTOR and autophagy.

  2009cited by this paper
• RAG GTPases in nutrient-mediated TOR signaling pathway

  2009cited by this paper
• The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C

  2008cited by this paper
• The class III PI(3)K Vps34 promotes autophagy and endocytosis but not TOR signaling in Drosophila

  2008cited by this paper
• The regulation and function of Class III PI 3 Ks : novel roles for Vps 34

  2008influential reference
• The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1

  2008cited by this paper
• Regulation of TORC1 by Rag GTPases in nutrient response

  2008cited by this paper
• mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1).

  2008cited by this paper
• Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34.

  2008cited by this paper
• hVps15, but not Ca2+/CaM, is required for the activity and regulation of hVps34 in mammalian cells

  2008cited by this paper
• Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling

  2008cited by this paper
• The regulation and function of Class III PI3Ks: novel roles for Vps34.

  2008cited by this paper
• PRAS40 Regulates mTORC1 Kinase Activity by Functioning as a Direct Inhibitor of Substrate Binding*

  2007cited by this paper
• Defining the role of mTOR in cancer.

  2007cited by this paper
• Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase

  2007cited by this paper
• hvps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling.

  2007cited by this paper
• Expanding mTOR signaling

  2007cited by this paper
• Regulation of class III (Vps34) PI3Ks.

  2007cited by this paper
• Rheb Activates mTOR by Antagonizing Its Endogenous Inhibitor, FKBP38

  2007influential reference
• Rheb-TOR signaling promotes protein synthesis, but not glucose or amino acid import, in Drosophila

  2007cited by this paper
• PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase.

  2007cited by this paper
• Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40

  2007cited by this paper
• Identification of Protor as a novel Rictor-binding component of mTOR complex-2.

  2007cited by this paper
• Regulation of class III ( Vps 34 ) PI 3

  2007cited by this paper
• A MAP4 kinase related to Ste20 is a nutrient-sensitive regulator of mTOR signalling.

  2007cited by this paper
• The Proline-rich Akt Substrate of 40 kDa (PRAS40) Is a Physiological Substrate of Mammalian Target of Rapamycin Complex 1*

  2007influential reference
• mTOR pathway as a target in tissue hypertrophy.

  2007cited by this paper
• Regulation of class IA PI3Ks.

  2007cited by this paper
• Regulation of membrane traffic by phosphoinositide 3-kinases

  2006cited by this paper
• A conserved GTPase-containing complex is required for intracellular sorting of the general amino-acid permease in yeast

  2006cited by this paper
• Regulation of the small GTPase Rheb by amino acids

  2006cited by this paper
• 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.

  2006cited by this paper
• Rheb binds and regulates the mTOR kinase.

  2005cited by this paper
• The Tuberous Sclerosis Protein TSC2 Is Not Required for the Regulation of the Mammalian Target of Rapamycin by Amino Acids and Certain Cellular Stresses*

  2005cited by this paper
• Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase.

  2005influential reference
• hVps34 Is a Nutrient-regulated Lipid Kinase Required for Activation of p70 S6 Kinase*

  2005cited by this paper
• Rheb Binding to Mammalian Target of Rapamycin (mTOR) Is Regulated by Amino Acid Sufficiency*

  2005cited by this paper
• Signaling by Target of Rapamycin Proteins in Cell Growth Control

  2005cited by this paper
• The TOR and EGO protein complexes orchestrate microautophagy in yeast.

  2005influential reference
• Dysregulation of the TSC-mTOR pathway in human disease

  2004cited by this paper
• Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton.

  2004cited by this paper
• Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive

  2004cited by this paper
• Autophagy in Health and Disease: A Double-Edged Sword

  2004cited by this paper
• Upstream and downstream of mTOR.

  2004cited by this paper
• Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling.

  2003cited by this paper
• Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins

  2003cited by this paper
• GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR.

  2003influential reference
• TSC2 mediates cellular energy response to control cell growth and survival.

  2003cited by this paper
• Rheb promotes cell growth as a component of the insulin/TOR signalling network

  2003cited by this paper
• Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb.

  2003cited by this paper
• Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2.

  2003cited by this paper
• Amino acid transporters: roles in amino acid sensing and signalling in animal cells.

  2003cited by this paper
• Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E.

  2002cited by this paper
• Metabolic and autocrine regulation of the mammalian target of rapamycin by pancreatic beta-cells.

  2002cited by this paper
• mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery.

  2002cited by this paper
• Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action.

  2002cited by this paper
• Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control.

  2002cited by this paper
• Expression and disruption of the Arabidopsis TOR (target of rapamycin) gene

  2002cited by this paper
• Metabolic regulation by leucine of translation initiation through the mTOR-signaling pathway by pancreatic beta-cells.

  2001cited by this paper
• Amino acids and insulin are both required to regulate assembly of the eIF4E. eIF4G complex in rat skeletal muscle.

  2001cited by this paper
• Mammalian TOR: A Homeostatic ATP Sensor

  2001influential reference
• TOR, a central controller of cell growth.

  2000cited by this paper
• Regulation of amino acid–sensitive TOR signaling by leucine analogues in adipocytes

  2000influential reference
• 4E-BP1 and S6K1: translational integration sites for nutritional and hormonal information in muscle.

  2000cited by this paper
• Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin.

  2000cited by this paper
• Phosphoinositide signaling and the regulation of membrane trafficking in yeast.

  2000cited by this paper
• Amino acids regulate skeletal muscle PHAS-I and p70 S6-kinase phosphorylation independently of insulin.

  2000cited by this paper
• Rapamycin Antifungal Action Is Mediated via Conserved Complexes with FKBP12 and TOR Kinase Homologs inCryptococcus neoformans

  1999cited by this paper
• Amino acid-dependent control of p70(s6k). Involvement of tRNA aminoacylation in the regulation.

  1999cited by this paper
• Amino Acid Sufficiency and mTOR Regulate p70 S6 Kinase and eIF-4E BP1 through a Common Effector Mechanism*

  1998cited by this paper
• Regulation of translation elongation factor‐2 by insulin via a rapamycin‐sensitive signalling pathway.

  1996cited by this paper
• The role of cellular hydration in the regulation of cell function.

  1996cited by this paper
• Immunopharmacology of rapamycin.

  1996cited by this paper
• Phosphorylation of Ribosomal Protein S6 Is Inhibitory for Autophagy in Isolated Rat Hepatocytes (*)

  1995cited by this paper
• RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs.

  1994cited by this paper
• Inhibition of macroautophagy and proteolysis in the isolated rat hepatocyte by a nontransportable derivative of the multiple antigen peptide Leu8-Lys4-Lys2-Lys-beta Ala.

  1994cited by this paper
• RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex.

  1994cited by this paper
• A mammalian protein targeted by G1-arresting rapamycin–receptor complex

  1994cited by this paper
• Control of hepatic proteolysis by leucine and isovaleryl-L-carnitine through a common locus. Evidence for a possible mechanism of recognition at the plasma membrane.

  1992cited by this paper
• Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast

  1991cited by this paper
• Effects of branched-chain amino acids on protein turnover.

  1989cited by this paper
• Amino acid infusion increases the sensitivity of muscle protein synthesis in vivo to insulin. Effect of branched-chain amino acids.

  1988cited by this paper
• Regulation of insulin release by factors that also modify glutamate dehydrogenase.

  1988cited by this paper
• L-leucine and a nonmetabolized analogue activate pancreatic islet glutamate dehydrogenase

  1980cited by this paper

• Hydrolysate of a low-carbon microbe protein improved the performance and antioxidant capacity in Micropterus salmoides

  2026cites this paper
• Endophyte mediated delivery of methionine-functionalized hydroxyapatite nanoparticles for stress alleviation in Zea mays L.

  2026cites this paper
• Integrated analysis of proteomics and metabolomics reveals interactions of energy metabolism and reproduction in hypothalamus of chicken during sexual maturation

  2025cites this paper
• Research on Function of Ribosomal Protein S6 Kinases, 1α and β, Based on Molecular Cloning and siRNA-Based Interference in Juvenile Blunt Snout Bream (Megalobrama amblycephala)

  2024cites this paper
• Exploring the Integrated Role of miRNAs and lncRNAs in Regulating the Transcriptional Response to Amino Acids and Insulin-like Growth Factor 1 in Gilthead Sea Bream (Sparus aurata) Myoblasts

  2024cites this paper
• A comparative study of dietary amino acid patterns: unveiling growth, composition, and molecular signatures in juvenile Onychostoma macrolepis

  2024cites this paper
• Metabolic reprogramming in inflammaging and aging in T cells

  2023cites this paper
• Supplementing branched-chain volatile fatty acids in dual-flow cultures varying in dietary forage and corn oil concentrations. III: Protein metabolism and incorporation into bacterial protein.

  2023cites this paper
• Effects of Dietary Histidine Levels on Growth Performance, Feed Utilization, and Expression of Related Genes of Juvenile Hybrid Grouper Epinephelus fuscoguttatus ♀×Epinephelus lanceolatus♂

  2022cites this paper
• Amino Acids in Cancer and Cachexia: An Integrated View

  2022cites this paper
• Amino Acids and IGF1 Regulation of Fish Muscle Growth Revealed by Transcriptome and microRNAome Integrative Analyses of Pacu (Piaractus mesopotamicus) Myotubes

  2022cites this paper
• Integrative epigenomic and transcriptomic analyses reveal metabolic switching by intermittent fasting in brain

  2022cites this paper
• Dietary supplementation of kaempferol improved the growth, lipid metabolism and flesh quality of juvenile grass carp (Ctenopharyngodon idellus) based on metabolomics

  2022cites this paper
• Mycobacterium tuberculosis Rv1987 protein induces M2 polarization of macrophages through activating the PI3K/Akt1/mTOR signaling pathway

  2021cites this paper
• Immune and Metabolic Effects of Rumen-Protected Methionine During a Heat Stress Challenge in Lactating Holstein Cows.

  2021cites this paper
• Egg components reverse the atrophy induced by injury in skeletal muscles

  2021cites this paper
• Conceptus metabolomic profiling reveals stage-specific phenotypes leading up to pregnancy recognition in cattle†

  2021cites this paper
• Supplementing with L-Tryptophan Increases Medium Protein and Alters Expression of Genes and Proteins Involved in Milk Protein Synthesis and Energy Metabolism in Bovine Mammary Cells

  2021cites this paper
• Growth performance, amino acid retention and mRNA levels of mTORC1 signaling pathway genes in Nile tilapia fingerlings fed protein-bound and crystalline amino acids

  2021cites this paper
• Regulation of mTORC1 by amino acids in mammalian cells: A general picture of recent advances

  2021cites this paper
• Effects of β‐Conglycinin on intestinal structure and intestinal permeability in Rhynchocypris lagowski Dybowski

  2021cites this paper
• Key Molecular Mechanisms of Aging, Biomarkers, and Potential Interventions

  2020cites this paper
• Dietary valine levels affect growth, protein utilisation, immunity and antioxidant status in juvenile hybrid grouper (Epinephelus fuscoguttatus ♀ × Epinephelus lanceolatus ♂)

  2020cites this paper
• High levels of fatty acids inhibit β-casein synthesis through suppression of the JAK2/STAT5 and mTOR signaling pathways in mammary epithelial cells of cows with clinical ketosis.

  2020cites this paper
• Beef extract supplementation promotes myoblast proliferation and myotube growth in C2C12 cells

  2020cites this paper
• Integrative Epigenomic and Transcriptomic Analysis Reveals Robust Metabolic Switching in the Brain During Intermittent Fasting

  2020cites this paper
• Transcriptional Mutagenesis Prevents Ribosomal DNA Deterioration: The Role of Duplications and Deletions

  2019cites this paper
• Supplementing L-Isoleucine Increases Medium Protein and Alters the Expression of Genes and Proteins Involved in Milk Protein Synthesis and Energy Metabolism in Bovine Mammary Cells

  2019influential citation
• Dietary methionine restriction improves glucose metabolism in the skeletal muscle of obese mice.

  2019cites this paper
• Nutrigenomics as a tool to study the impact of diet on aging and age-related diseases: the Drosophila approach

  2019influential citation
• Dietary leucine affects glucose metabolism and lipogenesis involved in TOR/PI3K/Akt signaling pathway for juvenile blunt snout bream Megalobrama amblycephala

  2019cites this paper
• Effects of dietary leucine levels on growth, feed utilization, neuro-endocrine growth axis and TOR-related signaling genes expression of juvenile hybrid grouper (Epinephelus fuscoguttatus ♀ × Epinephelus lanceolatus ♂)

  2019cites this paper
• A first-in-human study of the novel metabolism-based anti-cancer agent SM-88 in subjects with advanced metastatic cancer

  2019cites this paper
• l-Lactate Dehydrogenase B Chain Associated with Milk Protein Content in Dairy Cows

  2019cites this paper
• mTORC1 and Nutrient Homeostasis: The Central Role of the Lysosome

  2018cites this paper
• The role of acidosis sensing in the regulation of chronic inflammation by skeletal muscle

  2018influential citation
• CDK8 mediates the dietary effects on developmental transition in Drosophila.

  2018cites this paper
• Biochemical characterization of progesterone‐induced alterations in bovine uterine fluid amino acid and carbohydrate composition during the conceptus elongation window†

  2018cites this paper
• Regulation of pancreas development and enzymatic gene expression by duodenal infusion of leucine and phenylalanine in dairy goats

  2018cites this paper
• Leucine Promotes the Growth of Fetal Pigs by Increasing Protein Synthesis through the mTOR Signaling Pathway in Longissimus Dorsi Muscle at Late Gestation.

  2018cites this paper
• Myostatin inhibits eEF2K-eEF2 by regulating AMPK to suppress protein synthesis.

  2017cites this paper
• mTORC1 as the main gateway to autophagy

  2017cites this paper
• Short communication: Short-term intravenous amino acid infusions as a method to detect limiting amino acids in dairy cattle diets.

  2017cites this paper
• Combination of histidine, lysine, methionine, and leucine promotes β-casein synthesis via the mechanistic target of rapamycin signaling pathway in bovine mammary epithelial cells.

  2017cites this paper
• Methionine, leucine, isoleucine, or threonine effects on mammary cell signaling and pup growth in lactating mice.

  2017cites this paper
• Therapeutic Exploitation of Metabolic Checkpoints In Cancer Cells

  2017cites this paper
• The Role of Maternal Nutrition During the Periconceptional Period and Its Effect on Offspring Phenotype.

  2017cites this paper
• Periconception in Physiology and Medicine

  2017cites this paper
• Contrôle de l'expression de Bcl-2 dans les lymphomes anaplasiques à grandes cellules par la protéine HuR en réponse au crizotinib : impact sur l'apoptose et l'autophagie

  2017cites this paper
• The interaction between lysyl-lysine and arginine in the neonatal Yucatan miniature pig small intestine

  2017influential citation
• Understanding the Regulation of the Human Amino Acid Transporter ASCT2

  2017cites this paper
• Astragaloside II promotes intestinal epithelial repair by enhancing L-arginine uptake and activating the mTOR pathway

  2017cites this paper
• Paternal low protein diet programs preimplantation embryo gene expression, fetal growth and skeletal development in mice.

  2017cites this paper
• Rag GTPase in amino acid signaling

  2016influential citation
• Lysine and Leucine Deficiencies Affect Myocytes Development and IGF Signaling in Gilthead Sea Bream (Sparus aurata)

  2016cites this paper
• Dynamics of mTORC1 activation in response to amino acids

  2016cites this paper
• Dietary arginine affects growth performance, plasma amino acid contents and gene expressions of the TOR signaling pathway in juvenile blunt snout bream, Megalobrama amblycephala

  2016cites this paper
• Role of ATF4 in directing gene expression in the basal state and during the unfolded protein response in liver

  2016cites this paper
• DOHaD and the Periconceptional Period, a Critical Window in Time

  2016cites this paper
• Amino acids trigger down-regulation of superoxide via TORC pathway in the midgut of Rhodnius prolixus

  2016cites this paper
• Arginine starvation in colorectal carcinoma cells: Sensing, impact on translation control and cell cycle distribution.

  2016cites this paper
• Rôle et régulation de l'autophagie dans les lymphomes anaplasiques à grandes cellules ALK positifs

  2016cites this paper
• mTOR, Autophagy, Aminoacidopathies, and Human Genetic Disorders

  2016cites this paper
• Alanyl-glutamine supplementation regulates mTOR and ubiquitin proteasome proteolysis signaling pathways in piglets.

  2016cites this paper
• Leucine and histidine independently regulate milk protein synthesis in bovine mammary epithelial cells via mTOR signaling pathway

  2015cites this paper
• Key mediators of intracellular amino acids signaling to mTORC1 activation

  2015cites this paper
• Maternal nutrition modifies trophoblast giant cell phenotype and fetal growth in mice

  2015cites this paper
• Cell signalling during blastocyst morphogenesis.

  2015cites this paper
• Do little embryos make big decisions? How maternal dietary protein restriction can permanently change an embryo's potential, affecting adult health.

  2015cites this paper
• Relationships between leucine and the pancreatic exocrine function for improving starch digestibility in ruminants.

  2015cites this paper
• Maternal nutrition modifies trophoblast giant cell phenotype and fetal 1 growth in mice 2 3

  2015cites this paper
• Renal Cancer – Epidemiology and Aetiology

  2015cites this paper
• Regulation of Translation by Essential Amino Acids and Glucose in Mammary Glands and Skeletal Muscle of Lactating Dairy Cows

  2015cites this paper
• Effects of individual branched-chain amino acids deprivation on insulin sensitivity and glucose metabolism in mice.

  2014cites this paper
• Dietary isoleucine requirement of juvenile blunt snout bream, Megalobrama amblycephala

  2014cites this paper
• The States of Pluripotency: Pluripotent Lineage Development in the Embryo and in the Dish

  2014cites this paper
• Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease

  2014cites this paper
• IGF-I and amino acids effects through TOR signaling on proliferation and differentiation of gilthead sea bream cultured myocytes.

  2014cites this paper
• Culture environment regulates amino acid turnover and glucose utilisation in human ES cells.

  2014influential citation
• Leucine markedly regulates pancreatic exocrine secretion in goats.

  2014cites this paper
• Analysis of Integrated Insulin-mTOR Signalling Network -Diabetes Perspective

  2013cites this paper
• Cellular signaling of amino acids towards mTORC1 activation in impaired human leucine catabolism.

  2013cites this paper
• Regulation of pancreatic exocrine secretion in goats: differential effects of short- and long-term duodenal phenylalanine treatment.

  2013cites this paper
• Characteristics and requirements of basal autophagy in HEK 293 cells

  2013cites this paper
• Mechanisms mediating the effects of alcohol and HIV anti-retroviral agents on mTORC1, mTORC2 and protein synthesis in myocytes.

  2012cites this paper
• Metabolic Induction and Early Responses of Mouse Blastocyst Developmental Programming following Maternal Low Protein Diet Affecting Life-Long Health

  2012influential citation
• Withdrawal of Essential Amino Acids Increases Autophagy by a Pathway Involving Ca 2 /Calmodulin-dependent Kinase

  2012cites this paper
• Withdrawal of Essential Amino Acids Increases Autophagy by a Pathway Involving Ca2+/Calmodulin-dependent Kinase Kinase-β (CaMKK-β)*

  2012cites this paper
• Lack of aminoacids in mouse hepatocytes in culture induces the selection of preneoplastic cells

  2012cites this paper
• Isoleucine and leucine independently regulate mTOR signaling and protein synthesis in MAC-T cells and bovine mammary tissue slices.

  2012cites this paper
• Role of the Yeast Ste20 Protein Kinase Ortholog Map4k4 in Adipose Tissue Function: A Dissertation

  2011cites this paper
• Régulation des la voie mTOR par la phospholipase D dans le muscle squelettique : implication dans le contrôle de la différenciation myogénique et de la taille des myocytes

  2011cites this paper
• Antitumorigenic Effect of a High Protein Diet in Mouse Skin

  2011influential citation
• Triennial Growth Symposium: leucine acts as a nutrient signal to stimulate protein synthesis in neonatal pigs.

  2011cites this paper
• Whole genome siRNA cell-based screen links mitochondria to Akt signaling network through uncoupling of electron transport chain

  2011cites this paper
• The Biochemical and Cellular Basis for Nutraceutical Strategies to Attenuate Neurodegeneration in Parkinson’s Disease

  2011cites this paper
• New insights into the signaling system and function of insulin in fish.

  2011cites this paper
• Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

  2011cites this paper
• The accumulation of mutant p53 in human cancer cells

  2011cites this paper
• Harnessing the cell death pathway for targeted cancer treatment.

  2011cites this paper