mTOR Signaling in Growth, Metabolism, and Disease

Alain, 2012, eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies, Cancer Res., 72, 6468, 10.1158/0008-5472.CAN-12-2395 Anthony, 2000, Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway, J. Nutr., 130, 2413, 10.1093/jn/130.10.2413 Araki, 2009, mTOR regulates memory CD8 T-cell differentiation, Nature, 460, 108, 10.1038/nature08155 Arriola Apelo, 2016, Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system, Aging Cell, 15, 28, 10.1111/acel.12405 Aylett, 2016, Architecture of human mTOR complex 1, Science, 351, 48, 10.1126/science.aaa3870 Baar, 1999, Phosphorylation of p70(S6k) correlates with increased skeletal muscle mass following resistance exercise, Am. J. Physiol., 276, C120, 10.1152/ajpcell.1999.276.1.C120 Bar-Peled, 2012, Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1, Cell, 150, 1196, 10.1016/j.cell.2012.07.032 Bar-Peled, 2013, A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1, Science, 340, 1100, 10.1126/science.1232044 Baretić, 2016, Tor forms a dimer through an N-terminal helical solenoid with a complex topology, Nat. Commun., 7, 11016, 10.1038/ncomms11016 Basel-Vanagaite, 2013, Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum, Am. J. Hum. Genet., 93, 524, 10.1016/j.ajhg.2013.07.005 Ben-Sahra, 2013, Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1, Science, 339, 1323, 10.1126/science.1228792 Ben-Sahra, 2016, mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle, Science, 351, 728, 10.1126/science.aad0489 Bentzinger, 2008, Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy, Cell Metab., 8, 411, 10.1016/j.cmet.2008.10.002 Binda, 2009, The Vam6 GEF controls TORC1 by activating the EGO complex, Mol. Cell, 35, 563, 10.1016/j.molcel.2009.06.033 Bjedov, 2010, Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster, Cell Metab., 11, 35, 10.1016/j.cmet.2009.11.010 Bodine, 2001, Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo, Nat. Cell Biol., 3, 1014, 10.1038/ncb1101-1014 Brown, 1994, A mammalian protein targeted by G1-arresting rapamycin-receptor complex, Nature, 369, 756, 10.1038/369756a0 Brugarolas, 2004, Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex, Genes Dev., 18, 2893, 10.1101/gad.1256804 Brunn, 1997, Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin, Science, 277, 99, 10.1126/science.277.5322.99 Cafferkey, 1993, Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity, Mol. Cell. Biol., 13, 6012 Castets, 2013, Sustained activation of mTORC1 in skeletal muscle inhibits constitutive and starvation-induced autophagy and causes a severe, late-onset myopathy, Cell Metab., 17, 731, 10.1016/j.cmet.2013.03.015 Chantranupong, 2014, The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1, Cell Rep., 9, 1, 10.1016/j.celrep.2014.09.014 Chantranupong, 2016, The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway, Cell, 165, 153, 10.1016/j.cell.2016.02.035 Chen, 2009, mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells, Sci. Signal., 2, ra75, 10.1126/scisignal.2000559 Choo, 2008, Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation, Proc. Natl. Acad. Sci. USA, 105, 17414, 10.1073/pnas.0809136105 Chung, 1992, Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases, Cell, 69, 1227, 10.1016/0092-8674(92)90643-Q Cunningham, 2007, mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex, Nature, 450, 736, 10.1038/nature06322 Dibble, 2012, TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1, Mol. Cell, 47, 535, 10.1016/j.molcel.2012.06.009 Dorrello, 2006, S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth, Science, 314, 467, 10.1126/science.1130276 Düvel, 2010, Activation of a metabolic gene regulatory network downstream of mTOR complex 1, Mol. Cell, 39, 171, 10.1016/j.molcel.2010.06.022 Efeyan, 2013, Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival, Nature, 493, 679, 10.1038/nature11745 Eng, 1984, Activity of rapamycin (AY-22,989) against transplanted tumors, J. Antibiot., 37, 1231, 10.7164/antibiotics.37.1231 Feldman, 2009, Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2, PLoS Biol., 7, e38, 10.1371/journal.pbio.1000038 Feng, 2007, The regulation of AMPK beta1, TSC2, and PTEN expression by p53: Stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways, Cancer Res., 67, 3043, 10.1158/0008-5472.CAN-06-4149 Frey, 2014, A role for Raptor phosphorylation in the mechanical activation of mTOR signaling, Cell. Signal., 26, 313, 10.1016/j.cellsig.2013.11.009 Frias, 2006, mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s, Curr. Biol., 16, 1865, 10.1016/j.cub.2006.08.001 Gan, 2012, PRR5L degradation promotes mTORC2-mediated PKC-δ phosphorylation and cell migration downstream of Gα12, Nat. Cell Biol., 14, 686, 10.1038/ncb2507 García-Martínez, 2008, mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1), Biochem. J., 416, 375, 10.1042/BJ20081668 Gingras, 1999, Regulation of 4E-BP1 phosphorylation: A novel two-step mechanism, Genes Dev., 13, 1422, 10.1101/gad.13.11.1422 Grabiner, 2014, A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity, Cancer Discov., 4, 554, 10.1158/2159-8290.CD-13-0929 Guertin, 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, 10.1016/j.devcel.2006.10.007 Guertin, 2009, mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice, Cancer Cell, 15, 148, 10.1016/j.ccr.2008.12.017 Gwinn, 2008, AMPK phosphorylation of raptor mediates a metabolic checkpoint, Mol. Cell, 30, 214, 10.1016/j.molcel.2008.03.003 Hagiwara, 2012, Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c, Cell Metab., 15, 725, 10.1016/j.cmet.2012.03.015 Hansen, 2007, Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans, Aging Cell, 6, 95, 10.1111/j.1474-9726.2006.00267.x Hara, 2002, Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action, Cell, 110, 177, 10.1016/S0092-8674(02)00833-4 Harrington, 2004, The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins, J. Cell Biol., 166, 213, 10.1083/jcb.200403069 Harrison, 2009, Rapamycin fed late in life extends lifespan in genetically heterogeneous mice, Nature, 460, 392, 10.1038/nature08221 Haxhinasto, 2008, The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells, J. Exp. Med., 205, 565, 10.1084/jem.20071477 Heitman, 1991, Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast, Science, 253, 905, 10.1126/science.1715094 Hietakangas, 2008, TOR complex 2 is needed for cell cycle progression and anchorage-independent growth of MCF7 and PC3 tumor cells, BMC Cancer, 8, 282, 10.1186/1471-2407-8-282 Holz, 2005, mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events, Cell, 123, 569, 10.1016/j.cell.2005.10.024 Hsieh, 2010, Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E, Cancer Cell, 17, 249, 10.1016/j.ccr.2010.01.021 Hsieh, 2012, The translational landscape of mTOR signalling steers cancer initiation and metastasis, Nature, 485, 55, 10.1038/nature10912 Hsu, 2011, The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling, Science, 332, 1317, 10.1126/science.1199498 Inoki, 2002, TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling, Nat Cell Biol., 4, 648, 10.1038/ncb839 Inoki, 2003, Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling, Genes Dev., 17, 1829, 10.1101/gad.1110003 Inoki, 2003, TSC2 mediates cellular energy response to control cell growth and survival, Cell, 115, 577, 10.1016/S0092-8674(03)00929-2 Inoki, 2006, TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth, Cell, 126, 955, 10.1016/j.cell.2006.06.055 Iyer, 2012, Genome sequencing identifies a basis for everolimus sensitivity, Science, 338, 221, 10.1126/science.1226344 Jacinto, 2004, Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive, Nat. Cell Biol., 6, 1122, 10.1038/ncb1183 Jacinto, 2006, SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity, Cell, 127, 125, 10.1016/j.cell.2006.08.033 Jewell, 2015, Metabolism. Differential regulation of mTORC1 by leucine and glutamine, Science, 347, 194, 10.1126/science.1259472 Jia, 2004, The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span, Development, 131, 3897, 10.1242/dev.01255 Jung, 2015, Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9, Mol. Cell. Biol., 35, 2479, 10.1128/MCB.00125-15 Kaeberlein, 2005, Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients, Science, 310, 1193, 10.1126/science.1115535 Kalender, 2010, Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner, Cell Metab., 11, 390, 10.1016/j.cmet.2010.03.014 Kang, 2013, mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin, Science, 341, 1236566, 10.1126/science.1236566 Kapahi, 2004, Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway, Curr. Biol., 14, 885, 10.1016/j.cub.2004.03.059 Khamzina, 2005, Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: Possible involvement in obesity-linked insulin resistance, Endocrinology, 146, 1473, 10.1210/en.2004-0921 Kim, 2002, mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery, Cell, 110, 163, 10.1016/S0092-8674(02)00808-5 Kim, 2003, GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR, Mol. Cell, 11, 895, 10.1016/S1097-2765(03)00114-X Kim, 2008, Regulation of TORC1 by Rag GTPases in nutrient response, Nat. Cell Biol., 10, 935, 10.1038/ncb1753 Kim, 2011, AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1, Nat. Cell Biol., 13, 132, 10.1038/ncb2152 Kuma, 2004, The role of autophagy during the early neonatal starvation period, Nature, 432, 1032, 10.1038/nature03029 Kumar, 2008, Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances Basal glycogen synthase activity, Mol. Cell. Biol., 28, 61, 10.1128/MCB.01405-07 Kumar, 2010, Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism, Diabetes, 59, 1397, 10.2337/db09-1061 Kunz, 1993, Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression, Cell, 73, 585, 10.1016/0092-8674(93)90144-F Lamming, 2013, A central role for mTOR in lipid homeostasis, Cell Metab., 18, 465, 10.1016/j.cmet.2013.08.002 Lamming, 2012, Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity, Science, 335, 1638, 10.1126/science.1215135 Lee, 2007, IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway, Cell, 130, 440, 10.1016/j.cell.2007.05.058 Lee, 2016, Raptor/mTORC1 loss in adipocytes causes progressive lipodystrophy and fatty liver disease, Mol. Metab., 5, 422, 10.1016/j.molmet.2016.04.001 Li, 2014, mTORC2 phosphorylates protein kinase Cζ to regulate its stability and activity, EMBO Rep., 15, 191, 10.1002/embr.201338119 Li, 2010, mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists, Science, 329, 959, 10.1126/science.1190287 Lipton, 2014, The neurology of mTOR, Neuron, 84, 275, 10.1016/j.neuron.2014.09.034 Liu, 2015, PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex, Cancer Discov., 5, 1194, 10.1158/2159-8290.CD-15-0460 Loewith, 2011, Target of rapamycin (TOR) in nutrient signaling and growth control, Genetics, 189, 1177, 10.1534/genetics.111.133363 Long, 2005, Rheb binds and regulates the mTOR kinase, Curr. Biol., 15, 702, 10.1016/j.cub.2005.02.053 Ma, 2005, Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis, Cell, 121, 179, 10.1016/j.cell.2005.02.031 Ma, 2008, SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs, Cell, 133, 303, 10.1016/j.cell.2008.02.031 Mannick, 2014, mTOR inhibition improves immune function in the elderly, Sci. Transl. Med., 6, 268ra179, 10.1126/scitranslmed.3009892 Manning, 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, 10.1016/S1097-2765(02)00568-3 Martel, 1977, Inhibition of the immune response by rapamycin, a new antifungal antibiotic, Can. J. Physiol. Pharmacol., 55, 48, 10.1139/y77-007 Martina, 2012, MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB, Autophagy, 8, 903, 10.4161/auto.19653 Matsumoto, 2017, mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide, Nature, 541, 228, 10.1038/nature21034 Menon, 2014, Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome, Cell, 156, 771, 10.1016/j.cell.2013.11.049 Mori, 2009, Critical roles for the TSC-mTOR pathway in β-cell function, Am. J. Physiol. Endocrinol. Metab., 297, E1013, 10.1152/ajpendo.00262.2009 Nickerson, 2002, Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome, Cancer Cell, 2, 157, 10.1016/S1535-6108(02)00104-6 Nojima, 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, 10.1074/jbc.C200665200 Okosun, 2016, Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma, Nat. Genet., 48, 183, 10.1038/ng.3473 Palm, 2015, The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1, Cell, 162, 259, 10.1016/j.cell.2015.06.017 Panchaud, 2013, Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1, Sci. Signal., 6, ra42, 10.1126/scisignal.2004112 Parmigiani, 2014, Sestrins inhibit mTORC1 kinase activation through the GATOR complex, Cell Rep., 9, 1281, 10.1016/j.celrep.2014.10.019 Pearce, 2007, Identification of Protor as a novel Rictor-binding component of mTOR complex-2, Biochem. J., 405, 513, 10.1042/BJ20070540 Peng, 2014, Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling, Cell, 159, 122, 10.1016/j.cell.2014.08.038 Peng, 2017, SZT2 dictates GATOR control of mTORC1 signalling, Nature, 10.1038/nature21378 Peterson, 2009, DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival, Cell, 137, 873, 10.1016/j.cell.2009.03.046 Peterson, 2011, mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway, Cell, 146, 408, 10.1016/j.cell.2011.06.034 Petit, 2013, Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases, J. Cell Biol., 202, 1107, 10.1083/jcb.201307084 Polak, 2008, Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration, Cell Metab., 8, 399, 10.1016/j.cmet.2008.09.003 Pollizzi, 2016, Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation, Nat. Immunol., 17, 704, 10.1038/ni.3438 Porstmann, 2008, SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth, Cell Metab., 8, 224, 10.1016/j.cmet.2008.07.007 Powell, 2012, Regulation of immune responses by mTOR, Annu. Rev. Immunol., 30, 39, 10.1146/annurev-immunol-020711-075024 Powers, 2006, Extension of chronological life span in yeast by decreased TOR pathway signaling, Genes Dev., 20, 174, 10.1101/gad.1381406 Powis, 2015, Crystal structure of the Ego1-Ego2-Ego3 complex and its role in promoting Rag GTPase-dependent TORC1 signaling, Cell Res., 25, 1043, 10.1038/cr.2015.86 Rangwala, 2014, Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma, Autophagy, 10, 1391, 10.4161/auto.29119 Rebsamen, 2015, SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1, Nature, 519, 477, 10.1038/nature14107 Ricos, 2016, Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy, Ann. Neurol., 79, 120, 10.1002/ana.24547 Risson, 2009, Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy, J. Cell Biol., 187, 859, 10.1083/jcb.200903131 Robida-Stubbs, 2012, TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO, Cell Metab., 15, 713, 10.1016/j.cmet.2012.04.007 Robitaille, 2013, Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis, Science, 339, 1320, 10.1126/science.1228771 Roczniak-Ferguson, 2012, The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis, Sci. Signal., 5, ra42, 10.1126/scisignal.2002790 Rodrik-Outmezguine, 2011, mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling, Cancer Discov., 1, 248, 10.1158/2159-8290.CD-11-0085 Rodrik-Outmezguine, 2016, Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor, Nature, 534, 272, 10.1038/nature17963 Rommel, 2001, Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways, Nat. Cell Biol., 3, 1009, 10.1038/ncb1101-1009 Rousseau, 2016, An evolutionarily conserved pathway controls proteasome homeostasis, Nature, 536, 184, 10.1038/nature18943 Roux, 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, 10.1073/pnas.0405659101 Sabatini, 1994, RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs, Cell, 78, 35, 10.1016/0092-8674(94)90570-3 Sabers, 1995, Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells, J. Biol. Chem., 270, 815, 10.1074/jbc.270.2.815 Sancak, 2007, PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase, Mol. Cell, 25, 903, 10.1016/j.molcel.2007.03.003 Sancak, 2008, The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1, Science, 320, 1496, 10.1126/science.1157535 Sancak, 2010, Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids, Cell, 141, 290, 10.1016/j.cell.2010.02.024 Sarbassov, 2004, Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton, Curr. Biol., 14, 1296, 10.1016/j.cub.2004.06.054 Sarbassov, 2005, Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex, Science, 307, 1098, 10.1126/science.1106148 Sarbassov, 2006, Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB, Mol. Cell, 22, 159, 10.1016/j.molcel.2006.03.029 Sato, 2010, Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer, Oncogene, 29, 2746, 10.1038/onc.2010.28 Saxton, 2016, Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway, Science, 351, 53, 10.1126/science.aad2087 Saxton, 2016, Mechanism of arginine sensing by CASTOR1 upstream of mTORC1, Nature, 536, 229, 10.1038/nature19079 Schalm, 2003, TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function, Curr. Biol., 13, 797, 10.1016/S0960-9822(03)00329-4 Selman, 2009, Ribosomal protein S6 kinase 1 signaling regulates mammalian life span, Science, 326, 140, 10.1126/science.1177221 Sengupta, 2010, mTORC1 controls fasting-induced ketogenesis and its modulation by ageing, Nature, 468, 1100, 10.1038/nature09584 Settembre, 2012, A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB, EMBO J., 31, 1095, 10.1038/emboj.2012.32 Shah, 2004, Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies, Curr. Biol., 14, 1650, 10.1016/j.cub.2004.08.026 Shaw, 2004, The LKB1 tumor suppressor negatively regulates mTOR signaling, Cancer Cell, 6, 91, 10.1016/j.ccr.2004.06.007 She, 2010, 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors, Cancer Cell, 18, 39, 10.1016/j.ccr.2010.05.023 Shigeyama, 2008, Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice, Mol. Cell. Biol., 28, 2971, 10.1128/MCB.01695-07 Spilman, 2010, Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease, PLoS ONE, 5, e9979, 10.1371/journal.pone.0009979 Tabernero, 2008, Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: A phase I tumor pharmacodynamic study in patients with advanced solid tumors, J. Clin. Oncol., 26, 1603, 10.1200/JCO.2007.14.5482 Tang, 2016, Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism, Nat. Commun., 7, 11365, 10.1038/ncomms11365 Tee, 2003, Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb, Curr. Biol., 13, 1259, 10.1016/S0960-9822(03)00506-2 Thedieck, 2007, PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis, PLoS ONE, 2, e1217, 10.1371/journal.pone.0001217 Thomanetz, 2013, Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology, J. Cell Biol., 201, 293, 10.1083/jcb.201205030 Thoreen, 2009, An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1, J. Biol. Chem., 284, 8023, 10.1074/jbc.M900301200 Thoreen, 2012, A unifying model for mTORC1-mediated regulation of mRNA translation, Nature, 485, 109, 10.1038/nature11083 Tsun, 2013, The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1, Mol. Cell, 52, 495, 10.1016/j.molcel.2013.09.016 Um, 2004, Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity, Nature, 431, 200, 10.1038/nature02866 Vander Haar, 2007, Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40, Nat. Cell Biol., 9, 316, 10.1038/ncb1547 Vellai, 2003, Genetics: Influence of TOR kinase on lifespan in C. elegans, Nature, 426, 620, 10.1038/426620a Verbist, 2016, Metabolic maintenance of cell asymmetry following division in activated T lymphocytes, Nature, 532, 389, 10.1038/nature17442 Vézina, 1975, Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle, J. Antibiot., 28, 721, 10.7164/antibiotics.28.721 Wagle, 2014, Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib, Cancer Discov., 4, 546, 10.1158/2159-8290.CD-13-0353 Wagle, 2014, Response and acquired resistance to everolimus in anaplastic thyroid cancer, N. Engl. J. Med., 371, 1426, 10.1056/NEJMoa1403352 Wang, 2007, PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding, J. Biol. Chem., 282, 20036, 10.1074/jbc.M702376200 Wang, 2015, Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1, Science, 347, 188, 10.1126/science.1257132 Wolfson, 2016, Sestrin2 is a leucine sensor for the mTORC1 pathway, Science, 351, 43, 10.1126/science.aab2674 Wolfson, 2017, KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1, Nature, 10.1038/nature21423 Woo, 2007, PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling, J. Biol. Chem., 282, 25604, 10.1074/jbc.M704343200 Wu, 2013, Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression, Cell Rep., 4, 913, 10.1016/j.celrep.2013.07.030 Yang, 2006, Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity, Genes Dev., 20, 2820, 10.1101/gad.1461206 Yang, 2013, mTOR kinase structure, mechanism and regulation, Nature, 497, 217, 10.1038/nature12122 Yang, 2015, A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation, Cell Rep., 12, 937, 10.1016/j.celrep.2015.07.016 Ye, 2015, GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2, Genes Dev., 29, 2331, 10.1101/gad.269324.115 Yilmaz, 2012, mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake, Nature, 486, 490, 10.1038/nature11163 Yip, 2010, Structure of the human mTOR complex I and its implications for rapamycin inhibition, Mol. Cell, 38, 768, 10.1016/j.molcel.2010.05.017 Yu, 2011, Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling, Science, 332, 1322, 10.1126/science.1199484 Yuan, 2012, Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2, J. Biol. Chem., 287, 29579, 10.1074/jbc.M112.386854 Zeng, 2008, Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex, Ann. Neurol., 63, 444, 10.1002/ana.21331 Zhang, 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, 10.1016/j.str.2012.09.019 Zhang, 2014, Coordinated regulation of protein synthesis and degradation by mTORC1, Nature, 513, 440, 10.1038/nature13492 Zhao, 2015, mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy, Proc. Natl. Acad. Sci. USA, 112, 15790, 10.1073/pnas.1521919112 Zheng, 2007, A role for mammalian target of rapamycin in regulating T cell activation versus anergy, J. Immunol., 178, 2163, 10.4049/jimmunol.178.4.2163 Zinzalla, 2011, Activation of mTORC2 by association with the ribosome, Cell, 144, 757, 10.1016/j.cell.2011.02.014 Zoncu, 2011, mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase, Science, 334, 678, 10.1126/science.1207056