Abstract
The TOR (Target of Rapamycin) protein kinase pathway plays a central role in sensing and responding to nutrients, stress, and intracellular energy state. TOR complex 1 (TORC1) is comprised of TOR, Raptor, and Lst8 and its activity is sensitive to inhibition by the macrolide antibiotic rapamycin. TORC1 regulates protein synthesis, ribosome biogenesis, autophagy, and ultimately cell growth through the phosphorylation of S6 K, 4E-BP, and other substrates. As TORC1 activity is positively or negatively modulated in response to upstream regulators, cellular growth rate is, respectively, enhanced or suppressed. A separate multiprotein TOR complex, TORC2, is insensitive to direct inhibition by rapamycin and does not regulate growth patterns directly; TORC2 can, however, impact certain aspects of TORC1 signaling and cell survival. TOR signaling is an ancient pathway, conserved among the yeasts, Dictyostelium, C. elegans, Drosophila, mammals, and Arabidopsis. This review will focus on the regulation of TORC1 in mammalian cells in the context of amino acid sensing/regulation and intracellular ATP homeostasis, but will also include comparisons among other organisms.
Similar content being viewed by others
References
Arsham AM, Neufeld TP (2006) Thinking globally and acting locally with TOR. Curr Opin Cell Biol 18:589–597
Avruch J et al (2006) Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. Oncogene 25:6361–6372
Bai X et al (2007) Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 318:977–980
Beck T, Hall MN (1999) The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. Nature 402:689–692
Blinder D, Coschigano PW, Magasanik B (1996) Interaction of the GATA factor Gln3p with the nitrogen regulator Ure2p in Saccharomyces cerevisiae. J Bacteriol 178:4734–4736
Browne GJ, Proud CG (2004) A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin. Mol Cell Biol 24:2986–2997
Cardenas ME, Cutler NS, Lorenz MC, Di Como CJ, Heitman J (1999) The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev 13:3271–3279
Cooper TG (2002) Transmitting the signal of excess nitrogen in Saccharomyces cerevisiae from the Tor proteins to the GATA factors: connecting the dots. FEMS Microbiol Rev 26:223–238
Daugherty JR, Rai R, el Berry HM, Cooper TG (1993) Regulatory circuit for responses of nitrogen catabolic gene expression to the GLN3 and DAL80 proteins and nitrogen catabolite repression in Saccharomyces cerevisiae. J Bacteriol 175:64–73
Dong J, Pan D (2004) Tsc2 is not a critical target of Akt during normal Drosophila development. Genes Dev 18:2479–2484
Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M (2006) S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 314:467–471
Fingar DC, Salama S, Tsou C, Harlow E, Blenis J (2002) Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev 16:1472–1487
Gingras AC, Raught B, Sonenberg N (1999) eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68:913–963
Gingras AC et al (2001) Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 15:2852–2864
Guertin DA et al (2006) 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 11:859–871
Hahn-Windgassen A, Nogueira V, Chen CC, Skeen JE, Sonenberg N, Hay N (2005) Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem 280:32081–32089
Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J (1998) Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem 273:14484–14494
Hara K et al (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110:177–189
Hardwick JS, Kuruvilla FG, Tong JK, Shamji AF, Schreiber SL (1999) Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. Proc Natl Acad Sci USA 96:14866–14870
Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945
Heitman J, Movva NR, Hall MN (1991) Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253:905–909
Hietakangas V, Cohen SM (2007) Re-evaluating AKT regulation: role of TOR complex 2 in tissue growth. Genes Dev 21:632–637
Holz MK, Ballif BA, Gygi SP, Blenis J (2005) mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123:569–580
Hsu YC, Chern JJ, Cai Y, Liu M, Choi KW (2007) Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase. Nature 445:785–788
Inoki K, Li Y, Zhu T, Wu J, Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648–657
Inoki K, Li Y, Xu T, Guan KL (2003a) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17:1829–1834
Inoki K, Zhu T, Guan KL (2003b) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590
Inoki K et al (2006) TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126:955–968
Jacinto E et al (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127:125–137
Kim DH et al (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110:163–175
Kim DH et al (2003) GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 11:895–904
Kimmel AR, Firtel RA (2004) Breaking symmetries: regulation of Dictyostelium development through chemoattractant and morphogen signal-response. Curr Opin Genet Dev 14:540–549
Kulkarni AA, Abul-Hamd AT, Rai R, El Berry H, Cooper TG (2001) Gln3p nuclear localization and interaction with Ure2p in Saccharomyces cerevisiae. J Biol Chem 276:32136–32144
Lee S et al (2005) TOR complex 2 integrates cell movement during chemotaxis and signal relay in Dictyostelium. Mol Biol Cell 16:4572–4583
Loewith R et al (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10:457–468
Long X, Spycher C, Han ZS, Rose AM, Muller F, Avruch J (2002) TOR deficiency in C. elegans causes developmental arrest and intestinal atrophy by inhibition of mRNA translation. Curr Biol 12:1448–1461
Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (2005a) Rheb binds and regulates the mTOR kinase. Curr Biol 15:702–713
Long X, Ortiz-Vega S, Lin Y, Avruch J (2005b) Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J Biol Chem 280:23433–23436
Marcotrigiano J, Gingras AC, Sonenberg N, Burley SK (1999) Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. Mol Cell 3:707–716
Mitchell AP, Magasanik B (1984) Regulation of glutamine-repressible gene products by the GLN3 function in Saccharomyces cerevisiae. Mol Cell Biol 4:2758–2766
Montagne J, Stewart MJ, Stocker H, Hafen E, Kozma SC, Thomas G (1999) Drosophila S6 kinase: a regulator of cell size. Science 285:2126–2129
Nobukuni T, Kozma SC, Thomas G (2007) hvps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling. Curr Opin Cell Biol 19:135–141
Nojima H et al (2003) The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem 278:15461–15464
Oshiro N et al (2004) Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function. Genes Cells 9:359–366
Oshiro N et al (2007) The proline-Rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mTOR complex 1. J Biol Chem 282(28):20329–20339
Pause A et al (1994) Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function. Nature 371:762–767
Pende M et al (2004) S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 24:3112–3124
Phang JM, Donald SP, Pandhare J, Liu Y (2008) The metabolism of proline, a stress substrate, modulates carcinogenic pathways. Amino Acids (in press)
Potter CJ, Pedraza LG, Xu T (2002) Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 4:658–665
Roccio M, Bos JL, Zwartkruis FJ (2006) Regulation of the small GTPase Rheb by amino acids. Oncogene 25:657–664
Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH (1994) RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78:35–43
Sancak Y et al (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25:903–915
Sarbassov DD et al (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14:1296–1302
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101
Saxena D, Kannan KB, Brandriss MC (2003) Rapamycin treatment results in GATA factor-independent hyperphosphorylation of the proline utilization pathway activator in Saccharomyces cerevisiae. Eukaryot Cell 2:552–559
Schmelzle T, Hall MN (2000) TOR, a central controller of cell growth. Cell 103:253–262
Shah OJ, Wang Z, Hunter T (2004) Inappropriate activation of the TSC/Rheb/mTOR/S6 K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 14:1650–1656
Tee AR, Proud CG (2002) Caspase cleavage of initiation factor 4E-binding protein 1 yields a dominant inhibitor of cap-dependent translation and reveals a novel regulatory motif. Mol Cell Biol 22:1674–1683
Teleman AA, Chen YW, Cohen SM (2005) 4E-BP functions as a metabolic brake used under stress conditions but not during normal growth. Genes Dev 19:1844–1848
Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH (2007) Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 9:316–323
Vezina C, Kudelski A, Sehgal SN (1975) Rapamycin (AY-22, 989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 28:721–726
Wang X, Li W, Parra JL, Beugnet A, Proud CG (2003) The C terminus of initiation factor 4E-binding protein 1 contains multiple regulatory features that influence its function and phosphorylation. Mol Cell Biol 23:1546–1557
Wang L, Harris TE, Roth RA, Lawrence JC (2007) PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 282(27):20036–20044
Wilkinson MG et al (1999) Sin1: an evolutionarily conserved component of the eukaryotic SAPK pathway. Embo J 18:4210–4221
Wu G, Morris SM (1998) Arginine metabolism: nitric oxide and beyond. Biochem J 336:1–17
Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484
Yang Q, Inoki K, Ikenoue T, Guan KL (2006) Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 20:2820–2832
Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D (2003) Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 5:578–581
Acknowledgments
We are indebted to the many insightful discussions with Vanessa McMains, Taruna Khurana, Ramanath Bhandari, and Daniel Rosel. This research was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Liao, XH., Majithia, A., Huang, X. et al. Growth control via TOR kinase signaling, an intracellular sensor of amino acid and energy availability, with crosstalk potential to proline metabolism. Amino Acids 35, 761–770 (2008). https://doi.org/10.1007/s00726-008-0100-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-008-0100-3