Abstract
The mammalian target of rapamycin (mTOR) is an evolutionally conserved kinase which exists in two distinct structural and functional complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Of the two complexes, mTORC1 couples nutrient abundance to cell growth and proliferation by sensing and integrating a variety of inputs arising from amino acids, cellular stresses, energy status, and growth factors. Defects in mTORC1 regulation are implicated in the development of many metabolic diseases, including cancer and diabetes. Over the past decade, significant advances have been made in deciphering the complexity of the signaling processes contributing to mTORC1 regulation and function, but the mechanistic details are still not fully understood. In particular, how amino acid availability is sensed by cells and signals to mTORC1 remains unclear. In this review, we discuss the current understanding of nutrient-dependent control of mTORC1 signaling and will focus on the key components involved in amino acid signaling to mTORC1.
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Ahearn, I.M., Haigis, K., Bar-Sagi, D., and Philips, M.R. (2012). Regulating the regulator: post-translational modification of RAS. Nat. Rev. Mol. Cell Biol. 13, 39–51.
Ashrafi, K., Farazi, T.A., and Gordon, J.I. (1998). A role for Saccharomyces cerevisiae fatty acid activation protein 4 in regulating protein N-myristoylation during entry into stationary phase. J. Biol. Chem. 273, 25864–25874.
Ballif, B.A., Roux, P.P., Gerber, S.A., MacKeigan, J.P., Blenis, J., and Gygi, S.P. (2005). Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors. Proc. Natl. Acad. Sci. USA 102, 667–672.
Bar-Peled, L., Schweitzer, L.D., Zoncu, R., and Sabatini, D.M. (2012). Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 150, 1196–1208.
Barbet, N.C., Schneider, U., Helliwell, S.B., Stansfield, I., Tuite, M.F., and Hall, M.N. (1996). TOR controls translation initiation and early G1 progression in yeast. Mol. Biol. Cell 7, 25–42.
Ben-Sahra, I., Howell, J.J., Asara, J.M., and Manning, B.D. (2013). Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339, 1323–1328.
Binda, M., Peli-Gulli, M.P., Bonfils, G., Panchaud, N., Urban, J., Sturgill, T.W., Loewith, R., and De Virgilio, C. (2009). The Vam6 GEF controls TORC1 by activating the EGO complex. Mol. Cell 35, 563–573.
Bonfils, G., Jaquenoud, M., Bontron, S., Ostrowicz, C., Ungermann, C., and De Virgilio, C. (2012). Leucyl-tRNA synthetase controls TORC1 via the EGO complex. Mol. Cell 46, 105–110.
Brugarolas, J., Lei, K., Hurley, R.L., Manning, B.D., Reiling, J.H., Hafen, E., Witters, L.A., Ellisen, L.W., and Kaelin, W.G., Jr. (2004). Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18, 2893–2904.
Buerger, C., DeVries, B., and Stambolic, V. (2006). Localization of Rheb to the endomembrane is critical for its signaling function. Biochem. Biophys. Res. Commun. 344, 869–880.
Choo, A.Y., Kim, S.G., Vander Heiden, M.G., Mahoney, S.J., Vu, H., Yoon, S.O., Cantley, L.C., and Blenis, J. (2010). Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. Mol. Cell 38, 487–499.
Cornu, M., Albert, V., and Hall, M.N. (2013). mTOR in aging, metabolism, and cancer. Curr. Opin. Genet. Dev. 23, 53–62.
DeBerardinis, R.J., Lum, J.J., Hatzivassiliou, G., and Thompson, C.B. (2008). The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7, 11–20.
Dennis, P.B., Jaeschke, A., Saitoh, M., Fowler, B., Kozma, S.C., and Thomas, G. (2001). Mammalian TOR: a homeostatic ATP sensor. Science 294, 1102–1105.
DeYoung, M.P., Horak, P., Sofer, A., Sgroi, D., and Ellisen, L.W. (2008). Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 22, 239–251.
Dibble, C.C., Elis, W., Menon, S., Qin, W., Klekota, J., Asara, J.M., Finan, P.M., Kwiatkowski, D.J., Murphy, L.O., and Manning, B.D. (2012). TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol. Cell 47, 535–546.
Duran, A., Amanchy, R., Linares, J.F., Joshi, J., Abu-Baker, S., Porollo, A., Hansen, M., Moscat, J., and Diaz-Meco, M.T. (2011). p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol. Cell 44, 134–146.
Duran, R.V., Oppliger, W., Robitaille, A.M., Heiserich, L., Skendaj, R., Gottlieb, E., and Hall, M.N. (2012). Glutaminolysis activates Rag-mTORC1 signaling. Mol. Cell 47, 349–358.
Efeyan, A., Zoncu, R., and Sabatini, D.M. (2012). Amino acids and mTORC1: from lysosomes to disease. Trends Mol. Med. 18, 524–533.
Fang, J., Hsu, B.Y., MacMullen, C.M., Poncz, M., Smith, T.J., and Stanley, C.A. (2002). Expression, purification and characterization of human glutamate dehydrogenase (GDH) allosteric regulatory mutations. Biochem. J. 363, 81–87.
Forgac, M. (2007). Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat. Rev. Mol. Cell Biol. 8, 917–929.
Frias, M.A., Thoreen, C.C., Jaffe, J.D., Schroder, W., Sculley, T., Carr, S.A., and Sabatini, D.M. (2006). mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr. Biol. 16, 1865–1870.
Gao, M., and Kaiser, C.A. (2006). A conserved GTPase-containing complex is required for intracellular sorting of the general aminoacid permease in yeast. Nat. Cell Biol. 8, 657–667.
Gao, X., Zhang, Y., Arrazola, P., Hino, O., Kobayashi, T., Yeung, R.S., Ru, B., and Pan, D. (2002). Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat. Cell Biol. 4, 699–704.
Gong, R., Li, L., Liu, Y., Wang, P., Yang, H., Wang, L., Cheng, J., Guan, K.L., and Xu, Y. (2011). Crystal structure of the Gtr1p-Gtr2p complex reveals new insights into the amino acid-induced TORC1 activation. Genes Dev. 25, 1668–1673.
Guertin, D.A., Stevens, D.M., Thoreen, C.C., Burds, A.A., Kalaany, N.Y., Moffat, J., Brown, M., Fitzgerald, K.J., and Sabatini, D.M. (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.
Gulati, P., Gaspers, L.D., Dann, S.G., Joaquin, M., Nobukuni, T., Natt, F., Kozma, S.C., Thomas, A.P., and Thomas, G. (2008). Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab. 7, 456–465.
Gwinn, D.M., Shackelford, D.B., Egan, D.F., Mihaylova, M.M., Mery, A., Vasquez, D.S., Turk, B.E., and Shaw, R.J. (2008). AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226.
Han, J.M., Jeong, S.J., Park, M.C., Kim, G., Kwon, N.H., Kim, H.K., Ha, S.H., Ryu, S.H., and Kim, S. (2012). Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149, 410–424.
Hanker, A.B., Mitin, N., Wilder, R.S., Henske, E.P., Tamanoi, F., Cox, A.D., and Der, C.J. (2010). Differential requirement of CAAX-mediated posttranslational processing for Rheb localization and signaling. Oncogene 29, 380–391.
Hara, K., Yonezawa, K., Weng, Q.P., Kozlowski, M.T., Belham, C., and 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., Maruki, Y., Long, X., Yoshino, K., Oshiro, N., Hidayat, S., Tokunaga, C., Avruch, J., and Yonezawa, K. (2002). Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177–189.
Hardie, D.G., Ross, F.A., and Hawley, S.A. (2012). AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251–262.
Hirose, E., Nakashima, N., Sekiguchi, T., and Nishimoto, T. (1998). RagA is a functional homologue of S. cerevisiae Gtr1p involved in the Ran/Gsp1-GTPase pathway. J. Cell Sci. 111(Pt 1), 11–21.
Horejsi, Z., Takai, H., Adelman, C.A., Collis, S.J., Flynn, H., Maslen, S., Skehel, J.M., de Lange, T., and Boulton, S.J. (2010). CK2 phospho-dependent binding of R2TP complex to TEL2 is essential for mTOR and SMG1 stability. Mol. Cell 39, 839–850.
Howell, J.J., and Manning, B.D. (2011). mTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Trends in Endocrinol. Metab. TEM 22, 94–102.
Hurov, K.E., Cotta-Ramusino, C., and Elledge, S.J. (2010). A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability. Genes Dev. 24, 1939–1950.
Inoki, K., Li, Y., Zhu, T., Wu, J., and Guan, K.L. (2002). TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4, 648–657.
Inoki, K., Li, Y., Xu, T., and Guan, K.L. (2003a). Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17, 1829–1834.
Inoki, K., Zhu, T., and Guan, K.L. (2003b). TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590.
Inoki, K., Kim, J., and Guan, K.L. (2012). AMPK and mTOR in cellular energy homeostasis and drug targets. Annu. Rev. Pharmacol. Toxicol. 52, 381–400.
Izumi, N., Yamashita, A., Iwamatsu, A., Kurata, R., Nakamura, H., Saari, B., Hirano, H., Anderson, P., and Ohno, S. (2010). AAA+ proteins RUVBL1 and RUVBL2 coordinate PIKK activity and function in nonsense-mediated mRNA decay. Sci. Signal. 3, ra27.
Jacinto, E., Loewith, R., Schmidt, A., Lin, S., Ruegg, M.A., Hall, A., and Hall, M.N. (2004). Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6, 1122–1128.
Jacinto, E., Facchinetti, V., Liu, D., Soto, N., Wei, S., Jung, S.Y., Huang, Q., Qin, J., and Su, B. (2006). SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127, 125–137.
Jeong, J.H., Lee, K.H., Kim, Y.M., Kim, D.H., Oh, B.H., and Kim, Y.G. (2012). Crystal structure of the Gtr1p(GTP)-Gtr2p(GDP) protein complex reveals large structural rearrangements triggered by GTP-to-GDP conversion. J. Biol. Chem. 287, 29648–29653.
Jewell, J.L., and Guan, K.L. (2013). Nutrient signaling to mTOR and cell growth. Trends Biochem. Sci. 38, 233–242.
Kalender, A., Selvaraj, A., Kim, S.Y., Gulati, P., Brule, S., Viollet, B., Kemp, B.E., Bardeesy, N., Dennis, P., Schlager, J.J. et al. (2010). Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 11, 390–401.
Kim, J., and Guan, K.L. (2011). Amino acid signaling in TOR activation. Annu. Rev. Biochem. 80, 1001–1032.
Kim, D.H., Sarbassov, D.D., Ali, S.M., King, J.E., Latek, R.R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D.M. (2002). mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175.
Kim, D.H., Sarbassov, D.D., Ali, S.M., Latek, R.R., Guntur, K.V., Erdjument-Bromage, H., Tempst, P., and Sabatini, D.M. (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.
Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T.P., and Guan, K.L. (2008). Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10, 935–945.
Kim, Y.M., Stone, M., Hwang, T.H., Kim, Y.G., Dunlevy, J.R., Griffin, T.J., and Kim, D.H. (2012). SH3BP4 is a negative regulator of amino acid-Rag GTPase-mTORC1 signaling. Mol. Cell 46, 833–846.
Kim, S.G., Hoffman, G.R., Poulogiannis, G., Buel, G.R., Jang, Y.J., Lee, K.W., Kim, B.Y., Erikson, R.L., Cantley, L.C., Choo, A.Y., et al. (2013). Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex. Mol. Cell 49, 172–185.
Kogan, K., Spear, E.D., Kaiser, C.A., and Fass, D. (2010). Structural conservation of components in the amino acid sensing branch of the TOR pathway in yeast and mammals. J. Mol. Biol. 402, 388–398.
Kurzbauer, R., Teis, D., de Araujo, M.E., Maurer-Stroh, S., Eisenhaber, F., Bourenkov, G.P., Bartunik, H.D., Hekman, M., Rapp, U.R., Huber, L.A., et al. (2004). Crystal structure of the p14/MP1 scaffolding complex: how a twin couple attaches mitogenactivated protein kinase signaling to late endosomes. Proc. Natl. Acad. Sci. USA 101, 10984–10989.
Laplante, M., and Sabatini, D.M. (2012). mTOR signaling in growth control and disease. Cell 149, 274–293.
Lizcano, J.M., Goransson, O., Toth, R., Deak, M., Morrice, N.A., Boudeau, J., Hawley, S.A., Udd, L., Makela, T.P., Hardie, D.G., et al. (2004). LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 23, 833–843.
Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K., and Avruch, J. (2005a). Rheb binds and regulates the mTOR kinase. Curr. Biol. 15, 702–713.
Long, X., Ortiz-Vega, S., Lin, Y., and Avruch, J. (2005b). Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J. Biol. Chem. 280, 23433–23436.
Ma, X.M., and Blenis, J. (2009). Molecular mechanisms of mTORmediated translational control. Nat. Rev. Mol. Cell Biol. 10, 307–318.
Maehama, T., Tanaka, M., Nishina, H., Murakami, M., Kanaho, Y., and Hanada, K. (2008). RalA functions as an indispensable signal mediator for the nutrient-sensing system. J. Biol. Chem. 283, 35053–35059.
Manning, B.D., Tee, A.R., Logsdon, M.N., Blenis, J., and Cantley, L.C. (2002). Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10, 151–162.
Mendoza, M.C., Er, E.E., and Blenis, J. (2011). The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem. Sci. 36, 320–328.
Nakashima, N., Noguchi, E., and Nishimoto, T. (1999). Saccharomyces cerevisiae putative G protein, Gtr1p, which forms complexes with itself and a novel protein designated as Gtr2p, negatively regulates the Ran/Gsp1p G protein cycle through Gtr2p. Genetics 152, 853–867.
Nicklin, P., Bergman, P., Zhang, B., Triantafellow, E., Wang, H., Nyfeler, B., Yang, H., Hild, M., Kung, C., Wilson, C., et al. (2009). Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521–534.
Nobukuni, T., Joaquin, M., Roccio, M., Dann, S.G., Kim, S.Y., Gulati, P., Byfield, M.P., Backer, J.M., Natt, F., Bos, J.L., et al. (2005). Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc. Natl. Acad. Sci. USA 102, 14238–14243.
Oh, W.J., and Jacinto, E. (2011). mTOR complex 2 signaling and functions. Cell Cycle 10, 2305–2316.
Oldham, S., Montagne, J., Radimerski, T., Thomas, G., and Hafen, E. (2000). Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. Genes Dev. 14, 2689–2694.
Oshiro, N., Takahashi, R., Yoshino, K., Tanimura, K., Nakashima, A., Eguchi, S., Miyamoto, T., Hara, K., Takehana, K., Avruch, J., et al. (2007). The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J. Biol. Chem. 282, 20329–20339.
Pearce, L.R., Huang, X., Boudeau, J., Pawlowski, R., Wullschleger, S., Deak, M., Ibrahim, A.F., Gourlay, R., Magnuson, M.A., and Alessi, D.R. (2007). Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem. J. 405, 513–522.
Peterson, T.R., Laplante, M., Thoreen, C.C., Sancak, Y., Kang, S.A., Kuehl, W.M., Gray, N.S., and Sabatini, D.M. (2009). DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137, 873–886.
Reiling, J.H., and Hafen, E. (2004). The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev. 18, 2879–2892.
Robitaille, A.M., Christen, S., Shimobayashi, M., Cornu, M., Fava, L.L., Moes, S., Prescianotto-Baschong, C., Sauer, U., Jenoe, P., and Hall, M.N. (2013). Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339, 1320–1323.
Roccio, M., Bos, J.L., and Zwartkruis, F.J. (2006). Regulation of the small GTPase Rheb by amino acids. Oncogene 25, 657–664.
Roux, P.P., Ballif, B.A., Anjum, R., Gygi, S.P., and Blenis, J. (2004). Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl. Acad. Sci. USA 101, 13489–13494.
Saito, K., Araki, Y., Kontani, K., Nishina, H., and Katada, T. (2005). Novel role of the small GTPase Rheb: its implication in endocytic pathway independent of the activation of mammalian target of rapamycin. J. Biochem. 137, 423–430.
Sancak, Y., Thoreen, C.C., Peterson, T.R., Lindquist, R.A., Kang, S.A., Spooner, E., Carr, S.A., and Sabatini, D.M. (2007). PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25, 903–915.
Sancak, Y., Peterson, T.R., Shaul, Y.D., Lindquist, R.A., Thoreen, C.C., Bar-Peled, L., and Sabatini, D.M. (2008). The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501.
Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A.L., Nada, S., and Sabatini, D.M. (2010). Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290–303.
Sarbassov, D.D., Ali, S.M., Kim, D.H., Guertin, D.A., Latek, R.R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D.M. (2004). Rictor, a novel binding partner of mTOR, defines a rapamycininsensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302.
Sarbassov, D.D., Ali, S.M., Sengupta, S., Sheen, J.H., Hsu, P.P., Bagley, A.F., Markhard, A.L., and Sabatini, D.M. (2006). Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168.
Schurmann, A., Brauers, A., Massmann, S., Becker, W., and Joost, H.G. (1995). Cloning of a novel family of mammalian GTPbinding proteins (RagA, RagBs, RagB1) with remote similarity to the Ras-related GTPases. J. Biol. Chem. 270, 28982–28988.
Sekiguchi, T., Hirose, E., Nakashima, N., Ii, M., and Nishimoto, T. (2001). Novel G proteins, Rag C and Rag D, interact with GTPbinding proteins, Rag A and Rag B. J. Biol. Chem. 276, 7246–7257.
Sengupta, S., Peterson, T.R., and Sabatini, D.M. (2010). Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol. Cell 40, 310–322.
Shackelford, D.B., and Shaw, R.J. (2009). The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat. Rev. 9, 563–575.
Shaw, R.J., Kosmatka, M., Bardeesy, N., Hurley, R.L., Witters, L.A., DePinho, R.A., and Cantley, L.C. (2004). The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl. Acad. Sci. USA 101, 3329–3335.
Smith, E.M., Finn, S.G., Tee, A.R., Browne, G.J., and Proud, C.G. (2005). The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J. Biol. Chem. 280, 18717–18727.
Sofer, A., Lei, K., Johannessen, C.M., and Ellisen, L.W. (2005). Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol. Cell. Biol. 25, 5834–5845.
Takahashi, K., Nakagawa, M., Young, S.G., and Yamanaka, S. (2005). Differential membrane localization of ERas and Rheb, two Ras-related proteins involved in the phosphatidylinositol 3-kinase/mTOR pathway. J. Biol. Chem. 280, 32768–32774.
Tao, Z., Barker, J., Shi, S.D., Gehring, M., and Sun, S. (2010). Steady-state kinetic and inhibition studies of the mammalian target of rapamycin (mTOR) kinase domain and mTOR complexes. Biochemistry 49, 8488–8498.
Tee, A.R., Anjum, R., and Blenis, J. (2003a). Inactivation of the tuberous sclerosis complex-1 and -2 gene products occurs by phosphoinositide 3-kinase/Akt-dependent and -independent phosphorylation of tuberin. J. Biol. Chem. 278, 37288–37296.
Tee, A.R., Manning, B.D., Roux, P.P., Cantley, L.C., and Blenis, J. (2003b). Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPaseactivating protein complex toward Rheb. Curr. Biol. 13, 1259–1268.
Vander Haar, E., Lee, S.I., Bandhakavi, S., Griffin, T.J., and Kim, D.H. (2007). Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol. 9, 316–323.
Venteicher, A.S., Meng, Z., Mason, P.J., Veenstra, T.D., and Artandi, S.E. (2008). Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly. Cell 132, 945–957.
Wang, L., Harris, T.E., and Lawrence, J.C., Jr. (2008). Regulation of proline-rich Akt substrate of 40 kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation. J. Biol. Chem. 283, 15619–15627.
Woo, S.Y., Kim, D.H., Jun, C.B., Kim, Y.M., Haar, E.V., Lee, S.I., Hegg, J.W., Bandhakavi, S., and Griffin, T.J. (2007). PRR5, a novel component of mTOR complex 2, regulates plateletderived growth factor receptor beta expression and signaling. J. Biol. Chem. 282, 25604–25612.
Woods, A., Johnstone, S.R., Dickerson, K., Leiper, F.C., Fryer, L.G., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M., and Carling, D. (2003). LKB1 is the upstream kinase in the AMPactivated protein kinase cascade. Curr. Biol. 13, 2004–2008.
Wullschleger, S., Loewith, R., and Hall, M.N. (2006). TOR signaling in growth and metabolism. Cell 124, 471–484.
Yan, L., Mieulet, V., Burgess, D., Findlay, G.M., Sully, K., Procter, J., Goris, J., Janssens, V., Morrice, N.A., and Lamb, R.F. (2010). PP2A T61 epsilon is an inhibitor of MAP4K3 in nutrient signaling to mTOR. Mol. Cell 37, 633–642.
Yang, Q., Inoki, K., Ikenoue, T., and Guan, K.L. (2006). Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev. 20, 2820–2832.
Yecies, J.L., and Manning, B.D. (2011). mTOR links oncogenic signaling to tumor cell metabolism. J. Mol. Med. (Berl.) 89, 221–228.
Yip, C.K., Murata, K., Walz, T., Sabatini, D.M., and Kang, S.A. (2010). Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol. Cell 38, 768–774.
Yoon, M.S., Du, G., Backer, J.M., Frohman, M.A., and Chen, J. (2011). Class III PI-3-kinase activates phospholipase D in an amino acid-sensing mTORC1 pathway. J. Cell Biol. 195, 435–447.
Zeng, Z., Sarbassov dos, D., Samudio, I.J., Yee, K.W., Munsell, M.F., Ellen Jackson, C., Giles, F.J., Sabatini, D.M., Andreeff, M., and Konopleva, M. (2007). Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109, 3509–3512.
Zhang, H., Stallock, J.P., Ng, J.C., Reinhard, C., and Neufeld, T.P. (2000). Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev. 14, 2712–2724.
Zhang, T., Peli-Gulli, M.P., Yang, H., De Virgilio, C., and Ding, J. (2012). Ego3 functions as a homodimer to mediate the interaction between Gtr1-Gtr2 and Ego1 in the ego complex to activate TORC1. Structure 20, 2151–2160.
Zoncu, R., Bar-Peled, L., Efeyan, A., Wang, S., Sancak, Y., and Sabatini, D.M. (2011a). mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 334, 678–683.
Zoncu, R., Efeyan, A., and Sabatini, D.M. (2011b). mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12, 21–35.
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Kim, S.G., Buel, G.R. & Blenis, J. Nutrient regulation of the mTOR Complex 1 signaling pathway. Mol Cells 35, 463–473 (2013). https://doi.org/10.1007/s10059-013-0138-2
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DOI: https://doi.org/10.1007/s10059-013-0138-2