Erratum: mTOR Signaling in Growth, Metabolism, and Disease (Cell (2017) 168(6) (960–976) (S0092867417301824) (10.1016/j.cell.2017.02.004));mTOR Signaling in Growth, Metabolism, and Disease

Cell

Volumn 168, Issue 6, 2017, Pages 960-976

  Saxton, Robert A ^a,b,c   Sabatini, David M ^a,b,c  

^a WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH   (United States)

^b MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^c KOCH INSTITUTE FOR INTEGRATIVE CANCER RESEARCH   (United States)

Author keywords

aging; cancer; cell growth; diabetes; metabolism; mTOR; mTORC1; mTORC2; nutrients; signaling

Indexed keywords

AMINO ACID; DNA; GLUCOSE; GROWTH FACTOR; LIPID; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; OXYGEN; TARGET OF RAPAMYCIN KINASE;

ADIPOGENESIS; AGING; BRAIN FUNCTION; CELL GROWTH; CELL METABOLISM; DNA DAMAGE; ENERGY; EUKARYOTIC CELL; GLUCOSE HOMEOSTASIS; GLUCOSE METABOLISM; HUMAN; IMMUNITY; LIPID HOMEOSTASIS; LIPID METABOLISM; MALIGNANT NEOPLASM; MUSCLE FUNCTION; MUSCLE MASS; NONHUMAN; NUCLEOTIDE METABOLISM; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN METABOLISM; PROTEIN SYNTHESIS; REVIEW; ANIMAL; DIABETES MELLITUS; METABOLISM; MUSCLE; NEOPLASM; SIGNAL TRANSDUCTION;

AGING; ANIMALS; DIABETES MELLITUS; GLUCOSE; HUMANS; MUSCLES; NEOPLASMS; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 85014844261     PISSN: 00928674     EISSN: 10974172     Source Type: Journal    
DOI: 10.1016/j.cell.2017.03.035     Document Type: Erratum

References (183)

1. Alain, T., Morita, M., Fonseca, B.D., Yanagiya, A., Siddiqui, N., Bhat, M., Zammit, D., Marcus, V., Metrakos, P., Voyer, L.A., et al. eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies. Cancer Res. 72 (2012), 6468–6476.
2. Anthony, J.C., Yoshizawa, F., Anthony, T.G., Vary, T.C., Jefferson, L.S., Kimball, S.R., Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. J. Nutr. 130 (2000), 2413–2419.
3. Araki, K., Turner, A.P., Shaffer, V.O., Gangappa, S., Keller, S.A., Bachmann, M.F., Larsen, C.P., Ahmed, R., mTOR regulates memory CD8 T-cell differentiation. Nature 460 (2009), 108–112.
4. Arriola Apelo, S.I., Neuman, J.C., Baar, E.L., Syed, F.A., Cummings, N.E., Brar, H.K., Pumper, C.P., Kimple, M.E., Lamming, D.W., Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging Cell 15 (2016), 28–38.
5. Aylett, C.H., Sauer, E., Imseng, S., Boehringer, D., Hall, M.N., Ban, N., Maier, T., Architecture of human mTOR complex 1. Science 351 (2016), 48–52.
6. Baar, K., Esser, K., Phosphorylation of p70(S6k) correlates with increased skeletal muscle mass following resistance exercise. Am. J. Physiol. 276 (1999), C120–C127.
7. Bar-Peled, L., Schweitzer, L.D., Zoncu, R., Sabatini, D.M., Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 150 (2012), 1196–1208.
8. Bar-Peled, L., Chantranupong, L., Cherniack, A.D., Chen, W.W., Ottina, K.A., Grabiner, B.C., Spear, E.D., Carter, S.L., Meyerson, M., Sabatini, D.M., A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340 (2013), 1100–1106.
9. Baretić, D., Berndt, A., Ohashi, Y., Johnson, C.M., Williams, R.L., Tor forms a dimer through an N-terminal helical solenoid with a complex topology. Nat. Commun., 7, 2016, 11016.
10. Basel-Vanagaite, L., Hershkovitz, T., Heyman, E., Raspall-Chaure, M., Kakar, N., Smirin-Yosef, P., Vila-Pueyo, M., Kornreich, L., Thiele, H., Bode, H., et al. Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. Am. J. Hum. Genet. 93 (2013), 524–529.
11. Ben-Sahra, I., Howell, J.J., Asara, J.M., Manning, B.D., Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339 (2013), 1323–1328.
12. Ben-Sahra, I., Hoxhaj, G., Ricoult, S.J., Asara, J.M., Manning, B.D., mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 351 (2016), 728–733.
13. Bentzinger, C.F., Romanino, K., Cloëtta, D., Lin, S., Mascarenhas, J.B., Oliveri, F., Xia, J., Casanova, E., Costa, C.F., Brink, M., et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 8 (2008), 411–424.
14. Binda, M., Péli-Gulli, M.P., Bonfils, G., Panchaud, N., Urban, J., Sturgill, T.W., Loewith, R., De Virgilio, C., The Vam6 GEF controls TORC1 by activating the EGO complex. Mol. Cell 35 (2009), 563–573.
15. Bjedov, I., Toivonen, J.M., Kerr, F., Slack, C., Jacobson, J., Foley, A., Partridge, L., Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11 (2010), 35–46.
16. Bodine, S.C., Stitt, T.N., Gonzalez, M., Kline, W.O., Stover, G.L., Bauerlein, R., Zlotchenko, E., Scrimgeour, A., Lawrence, J.C., Glass, D.J., Yancopoulos, G.D., Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat. Cell Biol. 3 (2001), 1014–1019.
17. Brown, E.J., Albers, M.W., Shin, T.B., Ichikawa, K., Keith, C.T., Lane, W.S., Schreiber, S.L., A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369 (1994), 756–758.
18. Brugarolas, J., Lei, K., Hurley, R.L., Manning, B.D., Reiling, J.H., Hafen, E., Witters, L.A., Ellisen, L.W., Kaelin, W.G. Jr., Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18 (2004), 2893–2904.
19. Brunn, G.J., Hudson, C.C., Sekulić, A., Williams, J.M., Hosoi, H., Houghton, P.J., Lawrence, J.C. Jr., Abraham, R.T., Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277 (1997), 99–101.
20. Cafferkey, R., Young, P.R., McLaughlin, M.M., Bergsma, D.J., Koltin, Y., Sathe, G.M., Faucette, L., Eng, W.K., Johnson, R.K., Livi, G.P., Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity. Mol. Cell. Biol. 13 (1993), 6012–6023.
21. Castets, P., Lin, S., Rion, N., Di Fulvio, S., Romanino, K., Guridi, M., Frank, S., Tintignac, L.A., Sinnreich, M., Rüegg, M.A., Sustained activation of mTORC1 in skeletal muscle inhibits constitutive and starvation-induced autophagy and causes a severe, late-onset myopathy. Cell Metab. 17 (2013), 731–744.
22. Chantranupong, L., Wolfson, R.L., Orozco, J.M., Saxton, R.A., Scaria, S.M., Bar-Peled, L., Spooner, E., Isasa, M., Gygi, S.P., Sabatini, D.M., The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep. 9 (2014), 1–8.
23. Chantranupong, L., Scaria, S.M., Saxton, R.A., Gygi, M.P., Shen, K., Wyant, G.A., Wang, T., Harper, J.W., Gygi, S.P., Sabatini, D.M., The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. Cell 165 (2016), 153–164.
24. Chen, C., Liu, Y., Liu, Y., Zheng, P., mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal., 2, 2009, ra75.
25. Choo, A.Y., Yoon, S.O., Kim, S.G., Roux, P.P., Blenis, J., Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc. Natl. Acad. Sci. USA 105 (2008), 17414–17419.
26. Chung, J., Kuo, C.J., Crabtree, G.R., Blenis, J., Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell 69 (1992), 1227–1236.
27. Cunningham, J.T., Rodgers, J.T., Arlow, D.H., Vazquez, F., Mootha, V.K., Puigserver, P., mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 450 (2007), 736–740.
28. Dibble, C.C., Elis, W., Menon, S., Qin, W., Klekota, J., Asara, J.M., Finan, P.M., Kwiatkowski, D.J., Murphy, L.O., Manning, B.D., TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol. Cell 47 (2012), 535–546.
29. Dorrello, N.V., Peschiaroli, A., Guardavaccaro, D., Colburn, N.H., Sherman, N.E., Pagano, M., S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 314 (2006), 467–471.
30. Düvel, K., Yecies, J.L., Menon, S., Raman, P., Lipovsky, A.I., Souza, A.L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39 (2010), 171–183.
31. Efeyan, A., Zoncu, R., Chang, S., Gumper, I., Snitkin, H., Wolfson, R.L., Kirak, O., Sabatini, D.D., Sabatini, D.M., Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature 493 (2013), 679–683.
32. Eng, C.P., Sehgal, S.N., Vézina, C., Activity of rapamycin (AY-22,989) against transplanted tumors. J. Antibiot. 37 (1984), 1231–1237.
33. Feldman, M.E., Apsel, B., Uotila, A., Loewith, R., Knight, Z.A., Ruggero, D., Shokat, K.M., Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol., 7, 2009, e38.
34. Feng, Z., Hu, W., de Stanchina, E., Teresky, A.K., Jin, S., Lowe, S., Levine, A.J., 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 (2007), 3043–3053.
35. Frey, J.W., Jacobs, B.L., Goodman, C.A., Hornberger, T.A., A role for Raptor phosphorylation in the mechanical activation of mTOR signaling. Cell. Signal. 26 (2014), 313–322.
36. Frias, M.A., Thoreen, C.C., Jaffe, J.D., Schroder, W., Sculley, T., Carr, S.A., Sabatini, D.M., mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr. Biol. 16 (2006), 1865–1870.
37. Gan, X., Wang, J., Wang, C., Sommer, E., Kozasa, T., Srinivasula, S., Alessi, D., Offermanns, S., Simon, M.I., Wu, D., PRR5L degradation promotes mTORC2-mediated PKC-δ phosphorylation and cell migration downstream of Gα12. Nat. Cell Biol. 14 (2012), 686–696.
38. García-Martínez, J.M., Alessi, D.R., mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem. J. 416 (2008), 375–385.
39. Gingras, A.C., Gygi, S.P., Raught, B., Polakiewicz, R.D., Abraham, R.T., Hoekstra, M.F., Aebersold, R., Sonenberg, N., Regulation of 4E-BP1 phosphorylation: A novel two-step mechanism. Genes Dev. 13 (1999), 1422–1437.
40. Grabiner, B.C., Nardi, V., Birsoy, K., Possemato, R., Shen, K., Sinha, S., Jordan, A., Beck, A.H., Sabatini, D.M., A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 4 (2014), 554–563.
41. Guertin, D.A., Stevens, D.M., Thoreen, C.C., Burds, A.A., Kalaany, N.Y., Moffat, J., Brown, M., Fitzgerald, K.J., Sabatini, D.M., 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 (2006), 859–871.
42. Guertin, D.A., Stevens, D.M., Saitoh, M., Kinkel, S., Crosby, K., Sheen, J.H., Mullholland, D.J., Magnuson, M.A., Wu, H., Sabatini, D.M., mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 15 (2009), 148–159.
43. Gwinn, D.M., Shackelford, D.B., Egan, D.F., Mihaylova, M.M., Mery, A., Vasquez, D.S., Turk, B.E., Shaw, R.J., AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30 (2008), 214–226.
44. Hagiwara, A., Cornu, M., Cybulski, N., Polak, P., Betz, C., Trapani, F., Terracciano, L., Heim, M.H., Rüegg, M.A., Hall, M.N., Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab. 15 (2012), 725–738.
45. Hansen, M., Taubert, S., Crawford, D., Libina, N., Lee, S.J., Kenyon, C., Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6 (2007), 95–110.
46. 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. Cell 110 (2002), 177–189.
47. Harrington, L.S., Findlay, G.M., Gray, A., Tolkacheva, T., Wigfield, S., Rebholz, H., Barnett, J., Leslie, N.R., Cheng, S., Shepherd, P.R., et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J. Cell Biol. 166 (2004), 213–223.
48. Harrison, D.E., Strong, R., Sharp, Z.D., Nelson, J.F., Astle, C.M., Flurkey, K., Nadon, N.L., Wilkinson, J.E., Frenkel, K., Carter, C.S., et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460 (2009), 392–395.
49. Haxhinasto, S., Mathis, D., Benoist, C., The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J. Exp. Med. 205 (2008), 565–574.
50. Heitman, J., Movva, N.R., Hall, M.N., Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253 (1991), 905–909.
51. Hietakangas, V., Cohen, S.M., TOR complex 2 is needed for cell cycle progression and anchorage-independent growth of MCF7 and PC3 tumor cells. BMC Cancer, 8, 2008, 282.
52. Holz, M.K., Ballif, B.A., Gygi, S.P., Blenis, J., mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123 (2005), 569–580.
53. Hsieh, A.C., Costa, M., Zollo, O., Davis, C., Feldman, M.E., Testa, J.R., Meyuhas, O., Shokat, K.M., Ruggero, D., Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell 17 (2010), 249–261.
54. Hsieh, A.C., Liu, Y., Edlind, M.P., Ingolia, N.T., Janes, M.R., Sher, A., Shi, E.Y., Stumpf, C.R., Christensen, C., Bonham, M.J., et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485 (2012), 55–61.
55. Hsu, P.P., Kang, S.A., Rameseder, J., Zhang, Y., Ottina, K.A., Lim, D., Peterson, T.R., Choi, Y., Gray, N.S., Yaffe, M.B., et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332 (2011), 1317–1322.
56. Inoki, K., Li, Y., Zhu, T., Guan, K.L., TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 4 (2002), 648–657.
57. Inoki, K., Li, Y., Xu, T., Guan, K.L., Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17 (2003), 1829–1834.
58. Inoki, K., Zhu, T., Guan, K.L., TSC2 mediates cellular energy response to control cell growth and survival. Cell 115 (2003), 577–590.
59. Inoki, K., Ouyang, H., Zhu, T., Lindvall, C., Wang, Y., Zhang, X., Yang, Q., Bennett, C., Harada, Y., Stankunas, K., et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126 (2006), 955–968.
60. Iyer, G., Hanrahan, A.J., Milowsky, M.I., Al-Ahmadie, H., Scott, S.N., Janakiraman, M., Pirun, M., Sander, C., Socci, N.D., Ostrovnaya, I., et al. Genome sequencing identifies a basis for everolimus sensitivity. Science, 338, 2012, 221.
61. Jacinto, E., Loewith, R., Schmidt, A., Lin, S., Rüegg, M.A., Hall, A., Hall, M.N., Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6 (2004), 1122–1128.
62. Jacinto, E., Facchinetti, V., Liu, D., Soto, N., Wei, S., Jung, S.Y., Huang, Q., Qin, J., Su, B., SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127 (2006), 125–137.
63. Jewell, J.L., Kim, Y.C., Russell, R.C., Yu, F.X., Park, H.W., Plouffe, S.W., Tagliabracci, V.S., Guan, K.L., Metabolism. Differential regulation of mTORC1 by leucine and glutamine. Science 347 (2015), 194–198.
64. Jia, K., Chen, D., Riddle, D.L., The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131 (2004), 3897–3906.
65. Jung, J., Genau, H.M., Behrends, C., Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9. Mol. Cell. Biol. 35 (2015), 2479–2494.
66. Kaeberlein, M., Powers, R.W. 3rd, Steffen, K.K., Westman, E.A., Hu, D., Dang, N., Kerr, E.O., Kirkland, K.T., Fields, S., Kennedy, B.K., Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310 (2005), 1193–1196.
67. Kalender, A., Selvaraj, A., Kim, S.Y., Gulati, P., Brûlé, S., Viollet, B., Kemp, B.E., Bardeesy, N., Dennis, P., Schlager, J.J., et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 11 (2010), 390–401.
68. Kang, S.A., Pacold, M.E., Cervantes, C.L., Lim, D., Lou, H.J., Ottina, K., Gray, N.S., Turk, B.E., Yaffe, M.B., Sabatini, D.M., mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science, 341, 2013, 1236566.
69. Kapahi, P., Zid, B.M., Harper, T., Koslover, D., Sapin, V., Benzer, S., Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14 (2004), 885–890.
70. Khamzina, L., Veilleux, A., Bergeron, S., Marette, A., 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 (2005), 1473–1481.
71. Kim, D.H., Sarbassov, D.D., Ali, S.M., King, J.E., Latek, R.R., Erdjument-Bromage, H., Tempst, P., Sabatini, D.M., mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110 (2002), 163–175.
72. Kim, D.H., Sarbassov, D.D., Ali, S.M., Latek, R.R., Guntur, K.V., Erdjument-Bromage, H., Tempst, P., Sabatini, D.M., GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell 11 (2003), 895–904.
73. Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T.P., Guan, K.L., Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10 (2008), 935–945.
74. Kim, J., Kundu, M., Viollet, B., Guan, K.L., AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13 (2011), 132–141.
75. Kuma, A., Hatano, M., Matsui, M., Yamamoto, A., Nakaya, H., Yoshimori, T., Ohsumi, Y., Tokuhisa, T., Mizushima, N., The role of autophagy during the early neonatal starvation period. Nature 432 (2004), 1032–1036.
76. Kumar, A., Harris, T.E., Keller, S.R., Choi, K.M., Magnuson, M.A., Lawrence, J.C. Jr., Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances Basal glycogen synthase activity. Mol. Cell. Biol. 28 (2008), 61–70.
77. Kumar, A., Lawrence, J.C. Jr., Jung, D.Y., Ko, H.J., Keller, S.R., Kim, J.K., Magnuson, M.A., Harris, T.E., Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 59 (2010), 1397–1406.
78. Kunz, J., Henriquez, R., Schneider, U., Deuter-Reinhard, M., Movva, N.R., Hall, M.N., Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73 (1993), 585–596.
79. Lamming, D.W., Sabatini, D.M., A central role for mTOR in lipid homeostasis. Cell Metab. 18 (2013), 465–469.
80. Lamming, D.W., Ye, L., Katajisto, P., Goncalves, M.D., Saitoh, M., Stevens, D.M., Davis, J.G., Salmon, A.B., Richardson, A., Ahima, R.S., et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335 (2012), 1638–1643.
81. Lee, D.F., Kuo, H.P., Chen, C.T., Hsu, J.M., Chou, C.K., Wei, Y., Sun, H.L., Li, L.Y., Ping, B., Huang, W.C., et al. IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130 (2007), 440–455.
82. Lee, P.L., Tang, Y., Li, H., Guertin, D.A., Raptor/mTORC1 loss in adipocytes causes progressive lipodystrophy and fatty liver disease. Mol. Metab. 5 (2016), 422–432.
83. Li, X., Gao, T., mTORC2 phosphorylates protein kinase Cζ to regulate its stability and activity. EMBO Rep. 15 (2014), 191–198.
84. Li, N., Lee, B., Liu, R.J., Banasr, M., Dwyer, J.M., Iwata, M., Li, X.Y., Aghajanian, G., Duman, R.S., mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329 (2010), 959–964.
85. Lipton, J.O., Sahin, M., The neurology of mTOR. Neuron 84 (2014), 275–291.
86. Liu, P., Gan, W., Chin, Y.R., Ogura, K., Guo, J., Zhang, J., Wang, B., Blenis, J., Cantley, L.C., Toker, A., et al. PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex. Cancer Discov. 5 (2015), 1194–1209.
87. Loewith, R., Hall, M.N., Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics 189 (2011), 1177–1201.
88. Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K., Avruch, J., Rheb binds and regulates the mTOR kinase. Curr. Biol. 15 (2005), 702–713.
89. Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P., Pandolfi, P.P., Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121 (2005), 179–193.
90. Ma, X.M., Yoon, S.O., Richardson, C.J., Jülich, K., Blenis, J., SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs. Cell 133 (2008), 303–313.
91. Mannick, J.B., Del Giudice, G., Lattanzi, M., Valiante, N.M., Praestgaard, J., Huang, B., Lonetto, M.A., Maecker, H.T., Kovarik, J., Carson, S., et al. mTOR inhibition improves immune function in the elderly. Sci. Transl. Med., 6, 2014, 268ra179.
92. Manning, B.D., Tee, A.R., Logsdon, M.N., Blenis, J., Cantley, L.C., 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 (2002), 151–162.
93. Martel, R.R., Klicius, J., Galet, S., Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can. J. Physiol. Pharmacol. 55 (1977), 48–51.
94. Martina, J.A., Chen, Y., Gucek, M., Puertollano, R., MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 8 (2012), 903–914.
95. Matsumoto, A., Pasut, A., Matsumoto, M., Yamashita, R., Fung, J., Monteleone, E., Saghatelian, A., Nakayama, K.I., Clohessy, J.G., Pandolfi, P.P., mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. Nature 541 (2017), 228–232.
96. Menon, S., Dibble, C.C., Talbott, G., Hoxhaj, G., Valvezan, A.J., Takahashi, H., Cantley, L.C., Manning, B.D., Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156 (2014), 771–785.
97. Mori, H., Inoki, K., Opland, D., Münzberg, H., Villanueva, E.C., Faouzi, M., Ikenoue, T., Kwiatkowski, D.J., Macdougald, O.A., Myers, M.G. Jr., Guan, K.L., Critical roles for the TSC-mTOR pathway in β-cell function. Am. J. Physiol. Endocrinol. Metab. 297 (2009), E1013–E1022.
98. Nickerson, M.L., Warren, M.B., Toro, J.R., Matrosova, V., Glenn, G., Turner, M.L., Duray, P., Merino, M., Choyke, P., Pavlovich, C.P., et al. 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 (2002), 157–164.
99. Nojima, H., Tokunaga, C., Eguchi, S., Oshiro, N., Hidayat, S., Yoshino, K., Hara, K., Tanaka, N., Avruch, J., Yonezawa, K., 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 (2003), 15461–15464.
100. Okosun, J., Wolfson, R.L., Wang, J., Araf, S., Wilkins, L., Castellano, B.M., Escudero-Ibarz, L., Al Seraihi, A.F., Richter, J., Bernhart, S.H., et al. Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma. Nat. Genet. 48 (2016), 183–188.
101. Palm, W., Park, Y., Wright, K., Pavlova, N.N., Tuveson, D.A., Thompson, C.B., The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1. Cell 162 (2015), 259–270.
102. Panchaud, N., Péli-Gulli, M.P., De Virgilio, C., Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci. Signal., 6, 2013, ra42.
103. Parmigiani, A., Nourbakhsh, A., Ding, B., Wang, W., Kim, Y.C., Akopiants, K., Guan, K.L., Karin, M., Budanov, A.V., Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep. 9 (2014), 1281–1291.
104. Pearce, L.R., Huang, X., Boudeau, J., Pawłowski, R., Wullschleger, S., Deak, M., Ibrahim, A.F., Gourlay, R., Magnuson, M.A., Alessi, D.R., Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem. J. 405 (2007), 513–522.
105. Peng, M., Yin, N., Li, M.O., Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling. Cell 159 (2014), 122–133.
106. Peng, M., Yin, N., Li, M.O., SZT2 dictates GATOR control of mTORC1 signalling. Nature, 2017, 10.1038/nature21378 Published online February 15, 2017.
107. Peterson, T.R., Laplante, M., Thoreen, C.C., Sancak, Y., Kang, S.A., Kuehl, W.M., Gray, N.S., Sabatini, D.M., DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137 (2009), 873–886.
108. Peterson, T.R., Sengupta, S.S., Harris, T.E., Carmack, A.E., Kang, S.A., Balderas, E., Guertin, D.A., Madden, K.L., Carpenter, A.E., Finck, B.N., Sabatini, D.M., mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146 (2011), 408–420.
109. Petit, C.S., Roczniak-Ferguson, A., Ferguson, S.M., Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. J. Cell Biol. 202 (2013), 1107–1122.
110. Polak, P., Cybulski, N., Feige, J.N., Auwerx, J., Rüegg, M.A., Hall, M.N., Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab. 8 (2008), 399–410.
111. Pollizzi, K.N., Sun, I.H., Patel, C.H., Lo, Y.C., Oh, M.H., Waickman, A.T., Tam, A.J., Blosser, R.L., Wen, J., Delgoffe, G.M., Powell, J.D., Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation. Nat. Immunol. 17 (2016), 704–711.
112. Porstmann, T., Santos, C.R., Griffiths, B., Cully, M., Wu, M., Leevers, S., Griffiths, J.R., Chung, Y.L., Schulze, A., SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8 (2008), 224–236.
113. Powell, J.D., Pollizzi, K.N., Heikamp, E.B., Horton, M.R., Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30 (2012), 39–68.
114. Powers, R.W. 3rd, Kaeberlein, M., Caldwell, S.D., Kennedy, B.K., Fields, S., Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 20 (2006), 174–184.
115. Powis, K., Zhang, T., Panchuad, N., Wang, R., De Virgilio, C., Ding, J., Crystal structure of the Ego1-Ego2-Ego3 complex and its role in promoting Rag GTPase-dependent TORC1 signaling. Cell Res. 25 (2015), 1043–1059.
116. Rangwala, R., Chang, Y.C., Hu, J., Algazy, K.M., Evans, T.L., Fecher, L.A., Schuchter, L.M., Torigian, D.A., Panosian, J.T., Troxel, A.B., et al. Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy 10 (2014), 1391–1402.
117. Rebsamen, M., Pochini, L., Stasyk, T., de Araújo, M.E., Galluccio, M., Kandasamy, R.K., Snijder, B., Fauster, A., Rudashevskaya, E.L., Bruckner, M., et al. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature 519 (2015), 477–481.
118. Ricos, M.G., Hodgson, B.L., Pippucci, T., Saidin, A., Ong, Y.S., Heron, S.E., Licchetta, L., Bisulli, F., Bayly, M.A., Hughes, J., et al., Epilepsy Electroclinical Study Group. Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann. Neurol. 79 (2016), 120–131.
119. Risson, V., Mazelin, L., Roceri, M., Sanchez, H., Moncollin, V., Corneloup, C., Richard-Bulteau, H., Vignaud, A., Baas, D., Defour, A., et al. Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy. J. Cell Biol. 187 (2009), 859–874.
120. Robida-Stubbs, S., Glover-Cutter, K., Lamming, D.W., Mizunuma, M., Narasimhan, S.D., Neumann-Haefelin, E., Sabatini, D.M., Blackwell, T.K., TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15 (2012), 713–724.
121. Robitaille, A.M., Christen, S., Shimobayashi, M., Cornu, M., Fava, L.L., Moes, S., Prescianotto-Baschong, C., Sauer, U., Jenoe, P., Hall, M.N., Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339 (2013), 1320–1323.
122. Roczniak-Ferguson, A., Petit, C.S., Froehlich, F., Qian, S., Ky, J., Angarola, B., Walther, T.C., Ferguson, S.M., The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal., 5, 2012, ra42.
123. Rodrik-Outmezguine, V.S., Chandarlapaty, S., Pagano, N.C., Poulikakos, P.I., Scaltriti, M., Moskatel, E., Baselga, J., Guichard, S., Rosen, N., mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov. 1 (2011), 248–259.
124. Rodrik-Outmezguine, V.S., Okaniwa, M., Yao, Z., Novotny, C.J., McWhirter, C., Banaji, A., Won, H., Wong, W., Berger, M., de Stanchina, E., et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature 534 (2016), 272–276.
125. Rommel, C., Bodine, S.C., Clarke, B.A., Rossman, R., Nunez, L., Stitt, T.N., Yancopoulos, G.D., Glass, D.J., 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 (2001), 1009–1013.
126. Rousseau, A., Bertolotti, A., An evolutionarily conserved pathway controls proteasome homeostasis. Nature 536 (2016), 184–189.
127. Roux, P.P., Ballif, B.A., Anjum, R., Gygi, S.P., Blenis, J., 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 (2004), 13489–13494.
128. Sabatini, D.M., Erdjument-Bromage, H., Lui, M., Tempst, P., Snyder, S.H., RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78 (1994), 35–43.
129. Sabers, C.J., Martin, M.M., Brunn, G.J., Williams, J.M., Dumont, F.J., Wiederrecht, G., Abraham, R.T., Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J. Biol. Chem. 270 (1995), 815–822.
130. Sancak, Y., Thoreen, C.C., Peterson, T.R., Lindquist, R.A., Kang, S.A., Spooner, E., Carr, S.A., Sabatini, D.M., PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25 (2007), 903–915.
131. Sancak, Y., Peterson, T.R., Shaul, Y.D., Lindquist, R.A., Thoreen, C.C., Bar-Peled, L., Sabatini, D.M., The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320 (2008), 1496–1501.
132. Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A.L., Nada, S., Sabatini, D.M., Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141 (2010), 290–303.
133. Sarbassov, D.D., Ali, S.M., Kim, D.H., Guertin, D.A., Latek, R.R., Erdjument-Bromage, H., Tempst, P., Sabatini, D.M., Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14 (2004), 1296–1302.
134. Sarbassov, D.D., Guertin, D.A., Ali, S.M., Sabatini, D.M., Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307 (2005), 1098–1101.
135. Sarbassov, D.D., Ali, S.M., Sengupta, S., Sheen, J.H., Hsu, P.P., Bagley, A.F., Markhard, A.L., Sabatini, D.M., Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22 (2006), 159–168.
136. Sato, T., Nakashima, A., Guo, L., Coffman, K., Tamanoi, F., Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer. Oncogene 29 (2010), 2746–2752.
137. Saxton, R.A., Knockenhauer, K.E., Wolfson, R.L., Chantranupong, L., Pacold, M.E., Wang, T., Schwartz, T.U., Sabatini, D.M., Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science 351 (2016), 53–58.
138. Saxton, R.A., Chantranupong, L., Knockenhauer, K.E., Schwartz, T.U., Sabatini, D.M., Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature 536 (2016), 229–233.
139. Schalm, S.S., Fingar, D.C., Sabatini, D.M., Blenis, J., TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr. Biol. 13 (2003), 797–806.
140. Selman, C., Tullet, J.M., Wieser, D., Irvine, E., Lingard, S.J., Choudhury, A.I., Claret, M., Al-Qassab, H., Carmignac, D., Ramadani, F., et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326 (2009), 140–144.
141. Sengupta, S., Peterson, T.R., Laplante, M., Oh, S., Sabatini, D.M., mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468 (2010), 1100–1104.
142. Settembre, C., Zoncu, R., Medina, D.L., Vetrini, F., Erdin, S., Erdin, S., Huynh, T., Ferron, M., Karsenty, G., Vellard, M.C., et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31 (2012), 1095–1108.
143. Shah, O.J., Wang, Z., Hunter, T., Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol. 14 (2004), 1650–1656.
144. Shaw, R.J., Bardeesy, N., Manning, B.D., Lopez, L., Kosmatka, M., DePinho, R.A., Cantley, L.C., The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6 (2004), 91–99.
145. She, Q.B., Halilovic, E., Ye, Q., Zhen, W., Shirasawa, S., Sasazuki, T., Solit, D.B., Rosen, N., 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 (2010), 39–51.
146. Shigeyama, Y., Kobayashi, T., Kido, Y., Hashimoto, N., Asahara, S., Matsuda, T., Takeda, A., Inoue, T., Shibutani, Y., Koyanagi, M., et al. Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice. Mol. Cell. Biol. 28 (2008), 2971–2979.
147. Spilman, P., Podlutskaya, N., Hart, M.J., Debnath, J., Gorostiza, O., Bredesen, D., Richardson, A., Strong, R., Galvan, V., Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS ONE, 5, 2010, e9979.
148. Tabernero, J., Rojo, F., Calvo, E., Burris, H., Judson, I., Hazell, K., Martinelli, E., Ramon y Cajal, S., Jones, S., Vidal, L., et al. 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 (2008), 1603–1610.
149. Tang, Y., Wallace, M., Sanchez-Gurmaches, J., Hsiao, W.Y., Li, H., Lee, P.L., Vernia, S., Metallo, C.M., Guertin, D.A., Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism. Nat. Commun., 7, 2016, 11365.
150. Tee, A.R., Manning, B.D., Roux, P.P., Cantley, L.C., Blenis, J., Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13 (2003), 1259–1268.
151. Thedieck, K., Polak, P., Kim, M.L., Molle, K.D., Cohen, A., Jenö, P., Arrieumerlou, C., Hall, M.N., PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS ONE, 2, 2007, e1217.
152. Thomanetz, V., Angliker, N., Cloëtta, D., Lustenberger, R.M., Schweighauser, M., Oliveri, F., Suzuki, N., Rüegg, M.A., Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology. J. Cell Biol. 201 (2013), 293–308.
153. Thoreen, C.C., Kang, S.A., Chang, J.W., Liu, Q., Zhang, J., Gao, Y., Reichling, L.J., Sim, T., Sabatini, D.M., Gray, N.S., An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284 (2009), 8023–8032.
154. Thoreen, C.C., Chantranupong, L., Keys, H.R., Wang, T., Gray, N.S., Sabatini, D.M., A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485 (2012), 109–113.
155. Tsun, Z.Y., Bar-Peled, L., Chantranupong, L., Zoncu, R., Wang, T., Kim, C., Spooner, E., Sabatini, D.M., The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol. Cell 52 (2013), 495–505.
156. Um, S.H., Frigerio, F., Watanabe, M., Picard, F., Joaquin, M., Sticker, M., Fumagalli, S., Allegrini, P.R., Kozma, S.C., Auwerx, J., Thomas, G., Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431 (2004), 200–205.
157. Vander Haar, E., Lee, S.I., Bandhakavi, S., Griffin, T.J., Kim, D.H., Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol. 9 (2007), 316–323.
158. Vellai, T., Takacs-Vellai, K., Zhang, Y., Kovacs, A.L., Orosz, L., Müller, F., Genetics: Influence of TOR kinase on lifespan in C. elegans. Nature, 426, 2003, 620.
159. Verbist, K.C., Guy, C.S., Milasta, S., Liedmann, S., Kamiński, M.M., Wang, R., Green, D.R., Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532 (2016), 389–393.
160. Vézina, C., Kudelski, A., Sehgal, S.N., Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. 28 (1975), 721–726.
161. Wagle, N., Grabiner, B.C., Van Allen, E.M., Hodis, E., Jacobus, S., Supko, J.G., Stewart, M., Choueiri, T.K., Gandhi, L., Cleary, J.M., et al. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. 4 (2014), 546–553.
162. Wagle, N., Grabiner, B.C., Van Allen, E.M., Amin-Mansour, A., Taylor-Weiner, A., Rosenberg, M., Gray, N., Barletta, J.A., Guo, Y., Swanson, S.J., et al. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N. Engl. J. Med. 371 (2014), 1426–1433.
163. Wang, L., Harris, T.E., Roth, R.A., Lawrence, J.C. Jr., PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J. Biol. Chem. 282 (2007), 20036–20044.
164. Wang, S., Tsun, Z.Y., Wolfson, R.L., Shen, K., Wyant, G.A., Plovanich, M.E., Yuan, E.D., Jones, T.D., Chantranupong, L., Comb, W., et al. Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347 (2015), 188–194.
165. Wolfson, R.L., Chantranupong, L., Saxton, R.A., Shen, K., Scaria, S.M., Cantor, J.R., Sabatini, D.M., Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351 (2016), 43–48.
166. Wolfson, R.L., Chantranupong, L., Wyant, G.A., Gu, X., Orozoco, J.M., Condon, K.J., Petri, S., Kedir, J., Scaria, S.M., Abu-Remaileh, M., et al. KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature, 2017, 10.1038/nature21423 Published online February 15, 2017.
167. Woo, S.Y., Kim, D.H., Jun, C.B., Kim, Y.M., Haar, E.V., Lee, S.I., Hegg, J.W., Bandhakavi, S., Griffin, T.J., Kim, D.H., PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J. Biol. Chem. 282 (2007), 25604–25612.
168. Wu, J.J., Liu, J., Chen, E.B., Wang, J.J., Cao, L., Narayan, N., Fergusson, M.M., Rovira, I.I., Allen, M., Springer, D.A., et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep. 4 (2013), 913–920.
169. Yang, Q., Inoki, K., Ikenoue, T., Guan, K.L., Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev. 20 (2006), 2820–2832.
170. Yang, H., Rudge, D.G., Koos, J.D., Vaidialingam, B., Yang, H.J., Pavletich, N.P., mTOR kinase structure, mechanism and regulation. Nature 497 (2013), 217–223.
171. Yang, G., Murashige, D.S., Humphrey, S.J., James, D.E., A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation. Cell Rep. 12 (2015), 937–943.
172. Ye, J., Palm, W., Peng, M., King, B., Lindsten, T., Li, M.O., Koumenis, C., Thompson, C.B., GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2. Genes Dev. 29 (2015), 2331–2336.
173. Yilmaz, O.H., Katajisto, P., Lamming, D.W., Gültekin, Y., Bauer-Rowe, K.E., Sengupta, S., Birsoy, K., Dursun, A., Yilmaz, V.O., Selig, M., et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486 (2012), 490–495.
174. Yip, C.K., Murata, K., Walz, T., Sabatini, D.M., Kang, S.A., Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol. Cell 38 (2010), 768–774.
175. Yu, Y., Yoon, S.O., Poulogiannis, G., Yang, Q., Ma, X.M., Villén, J., Kubica, N., Hoffman, G.R., Cantley, L.C., Gygi, S.P., Blenis, J., Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332 (2011), 1322–1326.
176. Yuan, M., Pino, E., Wu, L., Kacergis, M., Soukas, A.A., Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2. J. Biol. Chem. 287 (2012), 29579–29588.
177. Zeng, L.H., Xu, L., Gutmann, D.H., Wong, M., Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann. Neurol. 63 (2008), 444–453.
178. Zhang, T., Peli-Gulli, M.P., Yang, H., De Virgilio, C., Ding, J., Ego3 functions as a homodimer to mediate the interaction between Gtr1-Gtr2 and Ego1 in the ego complex to activate TORC1. Structure 20 (2012), 2151–2160.
179. Zhang, Y., Nicholatos, J., Dreier, J.R., Ricoult, S.J., Widenmaier, S.B., Hotamisligil, G.S., Kwiatkowski, D.J., Manning, B.D., Coordinated regulation of protein synthesis and degradation by mTORC1. Nature 513 (2014), 440–443.
180. Zhao, J., Zhai, B., Gygi, S.P., Goldberg, A.L., mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy. Proc. Natl. Acad. Sci. USA 112 (2015), 15790–15797.
181. Zheng, Y., Collins, S.L., Lutz, M.A., Allen, A.N., Kole, T.P., Zarek, P.E., Powell, J.D., A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J. Immunol. 178 (2007), 2163–2170.
182. Zinzalla, V., Stracka, D., Oppliger, W., Hall, M.N., Activation of mTORC2 by association with the ribosome. Cell 144 (2011), 757–768.
183. Zoncu, R., Bar-Peled, L., Efeyan, A., Wang, S., Sancak, Y., Sabatini, D.M., mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 334 (2011), 678–683.