BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Upstream signalling of mTORC1 and its hyperactivation in type 2 diabetes (T2D)

  • Ali, Muhammad (Department of Biochemistry, Government College University) ;
  • Bukhari, Shazia Anwer (Department of Biochemistry, Government College University) ;
  • Ali, Muhammad (Department of Zoology, Government College University) ;
  • Lee, Han-Woong (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University)
  • Received : 2017.10.26
  • Published : 2017.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

Mammalian target of rapamycin complex 1 (mTORC1) plays a major role in cell growth, proliferation, polarity, differentiation, development, and controls transitioning between anabolic and catabolic states of the cell. It collects almost all extracellular and intracellular signals from growth factors, nutrients, and maintains cellular homeostasis, and is involved in several pathological conditions including, neurodegeneration, Type 2 diabetes (T2D), obesity, and cancer. In this review, we summarize current knowledge of upstream signaling of mTORC1 to explain etiology of T2D and hypertriglyceridemia, in which state, the role of telomere attrition is explained. We discuss if chronic inhibition of mTORC1 can reverse adverse effects resulting from hyperactivation. In conclusion, we suggest the regulatory roles of telomerase (TERT) and hexokinase II (HKII) on mTORC1 as possible remedies to treat hyperactivation. The former inhibits mTORC1 under nutrientrich while the latter under starved condition. We provide an idea of TOS (TOR signaling) motifs that can be used for regulation of mTORC1.

Keywords

References

  1. Workman JJ, Chen HF and Laribee RN (2014) Environmental signaling through the mechanistic target of rapamycin complex 1 mTORC1 goes nuclear. Cell Cycle 13, 714-725 https://doi.org/10.4161/cc.28112
  2. Dalle Pezze P, Sonntag AG, Thien A et al (2012) A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Sci Signal 5, ra25
  3. Cybulski N and Hall MN (2009) TOR complex 2: a signaling pathway of its own. Trends in Biochemical Sciences 34, 620-627 https://doi.org/10.1016/j.tibs.2009.09.004
  4. Kim DH, Sarbassov DD, Ali SM et al (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163-175 https://doi.org/10.1016/S0092-8674(02)00808-5
  5. Linares JF, Duran A, Yajima T, Pasparakis M, Moscat J and Diaz-Meco MT (2013) K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells. Mol Cell 51, 283-296 https://doi.org/10.1016/j.molcel.2013.06.020
  6. Duran A, Amanchy R, Linares JF et al (2011) p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol Cell 44, 134-146 https://doi.org/10.1016/j.molcel.2011.06.038
  7. Laplante M and Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149, 274-293 https://doi.org/10.1016/j.cell.2012.03.017
  8. Laplante M and Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122, 3589-3594 https://doi.org/10.1242/jcs.051011
  9. Avila-Flores A, Santos T, Rincon E and Merida I (2005) Modulation of the mammalian target of rapamycin pathway by diacylglycerol kinase-produced phosphatidic acid. J Biol Chem 280, 10091-10099 https://doi.org/10.1074/jbc.M412296200
  10. Zoncu R, Efeyan A and Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12, 21-35 https://doi.org/10.1038/nrm3025
  11. Ali M, Devkota S, Roh JI, Lee J and Lee HW (2016) Telomerase reverse transcriptase induces basal and amino acid starvation-induced autophagy through mTORC1. Biochem Biophys Res Commun 478, 1198-1204 https://doi.org/10.1016/j.bbrc.2016.08.094
  12. Cheng H, Fan X, Lawson WE, Paueksakon P and Harris RC (2015) Telomerase deficiency delays renal recovery in mice after ischemia-reperfusion injury by impairing autophagy. Kidney Int 88, 85-94 https://doi.org/10.1038/ki.2015.69
  13. Um SH, D'Alessio D and Thomas G (2006) Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 3, 393-402 https://doi.org/10.1016/j.cmet.2006.05.003
  14. Taylor PM (2014) Role of amino acid transporters in amino acid sensing. Am J Clin Nutr 99, 223S-230S https://doi.org/10.3945/ajcn.113.070086
  15. Jewell JL, Russell RC and Guan K-L (2013) Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol 14, 133-139 https://doi.org/10.1038/nrm3522
  16. Jia GH, Aroor AR, Martinez-Lemus LA and Sowers JR (2014) Overnutrition, mTOR signaling, and cardiovascular diseases. Am J Physiol Regul Integr Comp Physiol 307, R1198-R1206 https://doi.org/10.1152/ajpregu.00262.2014
  17. Greider CW (2016) Regulating telomere length from the inside out: the replication fork model. Gene Dev 30, 1483-1491 https://doi.org/10.1101/gad.280578.116
  18. Sahin E, Colla S, Liesa M et al (2011) Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359 https://doi.org/10.1038/nature09787
  19. Kuhlow D, Florian S, von Figura G et al (2010) Telomerase deficiency impairs glucose metabolism and insulin secretion. Aging (Albany NY) 2, 650
  20. Lynch CJ (2001) Role of leucine in the regulation of mTOR by amino acids: Revelations from structure-activity studies. J Nutr 131, 861s-865s https://doi.org/10.1093/jn/131.3.861S
  21. Wolfson RL, Chantranupong L, Saxton RA et al (2016) Sestrin2 is a leucine sensor for the mTORC1 pathway. Science (New York, N.Y.) 351, 43-48 https://doi.org/10.1126/science.aab2674
  22. Jewell JL, Kim YC, Russell RC et al (2015) Differential regulation of mTORC1 by leucine and glutamine. Science 347, 194-198 https://doi.org/10.1126/science.1259472
  23. Sancak Y, Peterson TR, Shaul YD et al (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496-1501 https://doi.org/10.1126/science.1157535
  24. Kim E, Goraksha-Hicks P, Li L, Neufeld TP and Guan KL (2008) Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10, 935-945 https://doi.org/10.1038/ncb1753
  25. Chantranupong L, Wolfson RL, Orozco JM et al (2014) The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep 9, 1-8 https://doi.org/10.1016/j.celrep.2014.09.014
  26. Parmigiani A, Nourbakhsh A, Ding B et al (2014) Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep 9, 1281-1291 https://doi.org/10.1016/j.celrep.2014.10.019
  27. Wang S, Tsun Z-Y, Wolfson RL et al (2015) Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347, 188-194 https://doi.org/10.1126/science.1257132
  28. Floyd S, Favre C, Lasorsa FM et al (2007) The insulin-like growth Factor-I-mTOR signaling pathway induces the mitochondrial pyrimidine nucleotide carrier to promote cell growth. Mol Biol Cell 18, 3545-3555 https://doi.org/10.1091/mbc.e06-12-1109
  29. Hinault C, Mothe-Satney I, Gautier N, Lawrence JC Jr, and Van Obberghen E (2004) Amino acids and leucine allow insulin activation of the PKB/mTOR pathway in normal adipocytes treated with wortmannin and in adipocytes from db/db mice. FASEB J 18, 1894-1896 https://doi.org/10.1096/fj.03-1409fje
  30. Dibble CC and Manning BD (2013) Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol 15, 555-564 https://doi.org/10.1038/ncb2763
  31. Inoki K, Li Y, Zhu TQ, Wu J and Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4, 648-657 https://doi.org/10.1038/ncb839
  32. Inoki K, Li Y, Xu T and Guan KL (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Gene Dev 17, 1829-1834 https://doi.org/10.1101/gad.1110003
  33. Catania C, Binder E and Cota D (2011) mTORC1 signaling in energy balance and metabolic disease. Int J Obes (Lond.) 35, 751-761 https://doi.org/10.1038/ijo.2010.208
  34. Nakashima RA, Paggi MG and Pedersen PL (1984) Contributions of glycolysis and oxidative phosphorylation to adenosine 5'-triphosphate production in AS-30D hepatoma cells. Cancer Res 44, 5702-5706
  35. Vander Heiden MG, Cantley LC and Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029-1033 https://doi.org/10.1126/science.1160809
  36. Bartlett K and Eaton S (2004) Mitochondrial ${\beta}$-oxidation. Eur J Biochem 271, 462-469 https://doi.org/10.1046/j.1432-1033.2003.03947.x
  37. Sato R, Goldstein JL and Brown MS (1993) Replacement of serine-871 of hamster 3-hydroxy-3-methylglutaryl-coa reductase prevents phosphorylation by AMP-activated kinase and blocks inhibition of sterol synthesis induced by ATP depletion. Proc Natl Acad Sci U S A 90, 9261-9265 https://doi.org/10.1073/pnas.90.20.9261
  38. Inoki K, Zhu TQ and Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577-590 https://doi.org/10.1016/S0092-8674(03)00929-2
  39. Gwinn DM, Shackelford DB, Egan DF et al (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30, 214-226 https://doi.org/10.1016/j.molcel.2008.03.003
  40. Sengupta S, Peterson TR, Laplante M, Oh S and Sabatini DM (2010) mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468, 1100-1104 https://doi.org/10.1038/nature09584
  41. Zielinski DC, Jamshidi N, Corbett AJ, Bordbar A, Thomas A and Palsson BO (2017) Systems biology analysis of drivers underlying hallmarks of cancer cell metabolism. Sci Rep 7, 41241 https://doi.org/10.1038/srep41241
  42. Towler MC and Hardie DG (2007) AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 100, 328-341 https://doi.org/10.1161/01.RES.0000256090.42690.05
  43. Kim J, Kundu M, Viollet B and Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13, 132-141 https://doi.org/10.1038/ncb2152
  44. Hardwick JP, Eckman K, Lee YK et al (2013) Eicosanoids in metabolic syndrome. Adv Pharmacol (San Diego, Calif.) 66, 157-266
  45. Kerner J and Hoppel C (2000) Fatty acid import into mitochondria. Biochim Biophys Acta 1486, 1-17 https://doi.org/10.1016/S1388-1981(00)00044-5
  46. Nojima H, Tokunaga C, Eguchi S et al (2003) The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates, p70 S6 kinase and 4E-BP1, through their TOR signaling (TOS) motif. J Biol Chem 278, 15461-15464 https://doi.org/10.1074/jbc.C200665200
  47. Roberts DJ, Tan-Sah VP, Ding EY, Smith JM and Miyamoto S (2014) Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition. Mol Cell 53, 521-533 https://doi.org/10.1016/j.molcel.2013.12.019
  48. Feng Z, Zhang H, Levine AJ and Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A 102, 8204-8209 https://doi.org/10.1073/pnas.0502857102
  49. Bukhari SA, Javed S, Ali M, Shahzadi A and Rehman M (2015) Serum haematological and biochemical indices of oxidative stress and their relationship with DNA damage and homocysteine in Pakistani type II diabetic patients. Pak J Pharm Sci 28, 881-889
  50. Association AD (2010) Diagnosis and classification of diabetes mellitus. Diabetes care 33, S62-S69 https://doi.org/10.2337/dc10-S062
  51. Billington CJ, Epstein LH, Goodwin NJ et al (2000) Overweight, obesity, and health risk. Arch Intern Med 160, 898-904 https://doi.org/10.1001/archinte.160.7.898
  52. Volkers M, Doroudgar S, Nguyen N et al (2014) PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity. Embo Mol Med 6, 57-65 https://doi.org/10.1002/emmm.201303183
  53. Samuel VT and Shulman GI (2012) Mechanisms for insulin resistance: common threads and missing links. Cell 148, 852-871 https://doi.org/10.1016/j.cell.2012.02.017
  54. Han J, Li E, Chen L et al (2015) The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1. Nature 524, 243-246 https://doi.org/10.1038/nature14557
  55. Cornu M, Oppliger W, Albert V et al (2014) Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21. Proc Natl Acad Sci U S A 111, 11592-11599 https://doi.org/10.1073/pnas.1412047111
  56. Passtoors WM, Beekman M, Deelen J et al (2013) Gene expression analysis of mTOR pathway: association with human longevity. Aging Cell 12, 24-31 https://doi.org/10.1111/acel.12015
  57. Engelman JA, Luo J and Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7, 606-619
  58. Chalhoub N and Baker SJ (2009) PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 4, 127-150 https://doi.org/10.1146/annurev.pathol.4.110807.092311
  59. Um SH, Frigerio F, Watanabe M et al (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200-205 https://doi.org/10.1038/nature02866
  60. Thedieck K, Holzwarth B, Prentzell MT et al (2013) Inhibition of mTORC1 by astrin and stress granules prevents apoptosis in cancer cells. Cell 154, 859-874 https://doi.org/10.1016/j.cell.2013.07.031
  61. Melnik BC, John SM, Carrera-Bastos P and Cordain L (2012) The impact of cow's milk-mediated mTORC1- signaling in the initiation and progression of prostate cancer. Nutr Metab 9, 74 https://doi.org/10.1186/1743-7075-9-74
  62. Chang L, Chiang S-H and Saltiel AR (2004) Insulin signaling and the regulation of glucose transport. Mol Med 10, 65-71
  63. Uno K, Yamada T, Ishigaki Y et al (2015) A hepatic amino acid/mTOR/S6K-dependent signalling pathway modulates systemic lipid metabolism via neuronal signals. Nat Commun 6, 7940 https://doi.org/10.1038/ncomms8940
  64. Tremblay F, Lavigne C, Jacques H and Marette A (2007) Role of dietary proteins and amino acids in the pathogenesis of insulin resistance. Annu Rev Nutr 27, 293-310 https://doi.org/10.1146/annurev.nutr.25.050304.092545
  65. Zoncu R, Efeyan A and Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12, 21-35 https://doi.org/10.1038/nrm3025
  66. Laplante M and Sabatini DM (2010) mTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis. Proc Natl Acad Sci U S A 107, 3281-3282 https://doi.org/10.1073/pnas.1000323107
  67. Yecies JL, Zhang HH, Menon S et al (2011) Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab 14, 21-32 https://doi.org/10.1016/j.cmet.2011.06.002
  68. Kumashiro N, Beddow SA, Vatner DF et al (2013) Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance. Diabetes 62, 2183-2194 https://doi.org/10.2337/db12-1311
  69. Song SM, Andrikopoulos S, Filippis C, Thorburn AW, Khan D and Proietto J (2001) Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin. Am J Physiol-Endoc M 281, E275-E282
  70. Ginsberg HN (2000) Insulin resistance and cardiovascular disease. J Clin Invest 106, 453-458 https://doi.org/10.1172/JCI10762
  71. Shimomura I, Matsuda M, Hammer RE, Bashmakov Y, Brown MS and Goldstein JL (2000) Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell 6, 77-86 https://doi.org/10.1016/S1097-2765(05)00010-9
  72. Jin ES, Szuszkiewicz-Garcia M, Browning JD, Baxter JD, Abate N and Malloy CR (2015) Influence of liver triglycerides on suppression of glucose production by insulin in men. J Clin Endocr Metab 100, 235-243 https://doi.org/10.1210/jc.2014-2404
  73. Seppala-Lindroos A, Vehkavaara S, Hakkinen AM et al (2002) Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocr Metab 87, 3023-3028 https://doi.org/10.1210/jcem.87.7.8638
  74. Munoz P, Blanco R, Flores JM and Blasco MA (2005) XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer. Nat Genet 37, 1063-1071 https://doi.org/10.1038/ng1633
  75. Steinert S, Shay JW and Wright WE (2004) Modification of subtelomeric DNA. Mol Cell Biol 24, 4571-4580 https://doi.org/10.1128/MCB.24.10.4571-4580.2004
  76. Nettleton JA, Diez-Roux A, Jenny NS, Fitzpatrick AL and Jacobs DR (2008) Dietary patterns, food groups, and telomere length in the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Clin Nutr 88, 1405-1412
  77. Mirabello L, Huang WY, Wong JY et al (2009) The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer. Aging Cell 8, 405-413 https://doi.org/10.1111/j.1474-9726.2009.00485.x
  78. Knoops KT, de Groot LC, Kromhout D et al (2004) Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA 292, 1433-1439 https://doi.org/10.1001/jama.292.12.1433
  79. Ornish D, Lin J, Daubenmier J et al (2008) Increased telomerase activity and comprehensive lifestyle changes: a pilot study. Lancet Oncol 9, 1048-1057 https://doi.org/10.1016/S1470-2045(08)70234-1
  80. von Zglinicki T (2002) Oxidative stress shortens telomeres. Trends Biochem Sci 27, 339-344 https://doi.org/10.1016/S0968-0004(02)02110-2
  81. Rode L, Nordestgaard BG, Weischer M and Bojesen SE (2014) Increased body mass index, elevated C-reactive protein, and short telomere length. J Clin Endocrinol Metab 99, E1671-E1675 https://doi.org/10.1210/jc.2014-1161
  82. Jeanclos E, Krolewski A, Skurnick J et al (1998) Shortened telomere length in white blood cells of patients with IDDM. Diabetes 47, 482-486 https://doi.org/10.2337/diabetes.47.3.482
  83. Ma D, Zhu W, Hu S, Yu X and Yang Y (2013) Association between oxidative stress and telomere length in Type 1 and Type 2 diabetic patients. J Endocrinol Invest 36, 1032-1037
  84. Geraldes P and King GL (2010) Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res 106, 1319-1331 https://doi.org/10.1161/CIRCRESAHA.110.217117
  85. Guo N, Parry EM, Li L-S et al (2011) Short telomeres compromise ${\beta}$-cell signaling and survival. PLoS One 6, e17858 https://doi.org/10.1371/journal.pone.0017858
  86. Minamino T, Orimo M, Shimizu I et al (2009) A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med 15, 1082-1087 https://doi.org/10.1038/nm.2014
  87. Berg CE, Lavan BE and Rondinone CM (2002) Rapamycin partially prevents insulin resistance induced by chronic insulin treatment. Biophy Res Commun 293, 1021-1027 https://doi.org/10.1016/S0006-291X(02)00333-9
  88. Stallone G, Infante B, Grandaliano G and Gesualdo L (2009) Management of side effects of sirolimus therapy. Transplantation 87, S23-26 https://doi.org/10.1097/TP.0b013e3181a05b7a
  89. Cruzado JM (2008) Nonimmunosuppressive effects of mammalian target of rapamycin inhibitors. Transplant Rev 22, 73-81 https://doi.org/10.1016/j.trre.2007.09.003
  90. Morrisett JD, Abdel-Fattah G, Hoogeveen R et al (2002) Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res 43, 1170-1180
  91. Houde VP, Brule S, Festuccia WT et al (2010) Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes 59, 1338-1348 https://doi.org/10.2337/db09-1324
  92. Fraenkel M, Ketzinel-Gilad M, Ariav Y et al (2008) mTOR inhibition by rapamycin prevents ${\beta}$-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 57, 945-957 https://doi.org/10.2337/db07-0922
  93. Sundin T, Peffley DM and Hentosh P (2013) Disruption of an hTERT-mTOR-RAPTOR protein complex by a phytochemical perillyl alcohol and rapamycin. Mol Cell Biochem 375, 97-104
  94. Kawauchi K, Ihjima K and Yamada O (2005) IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3'-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells. J Immunol 174, 5261-5269 https://doi.org/10.4049/jimmunol.174.9.5261
  95. Guertin DA, Stevens DM, Thoreen CC et al (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKC alpha but not S6K1. Dev Cell 11, 859-871 https://doi.org/10.1016/j.devcel.2006.10.007
  96. Schalm SS and Blenis J (2002) Identification of a conserved motif required for mTOR signaling. Curr Biol 12, 632-639 https://doi.org/10.1016/S0960-9822(02)00762-5
  97. Linares JF, Duran A, Yajima T, Pasparakis M, Moscat J and Diaz-Meco MT (2013) K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells. Mol Cell 51, 283-296 https://doi.org/10.1016/j.molcel.2013.06.020
  98. Rosner M, Siegel N, Valli A, Fuchs C and Hengstschlager M (2010) mTOR phosphorylated at S2448 binds to raptor and rictor. Amino Acids 38, 223-228 https://doi.org/10.1007/s00726-008-0230-7
  99. Wrighton KH (2013) Cell signalling: Where the mTOR action is. Nat Rev Mol Cell Biol 14, 191 https://doi.org/10.1038/nrm3549
  100. Shimobayashi M and Hall MN (2014) Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15, 155-162 https://doi.org/10.1038/nrm3757
  101. Peterson TR, Laplante M, Thoreen CC et al (2009) DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137, 873-886 https://doi.org/10.1016/j.cell.2009.03.046
  102. Sancak Y, Thoreen CC, Peterson TR et al (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25, 903-915 https://doi.org/10.1016/j.molcel.2007.03.003
  103. Long X, Lin Y, Ortiz-Vega S, Yonezawa K and Avruch J (2005) Rheb binds and regulates the mTOR kinase. Curr Biol 15, 702-713 https://doi.org/10.1016/j.cub.2005.02.053
  104. Ohji G, Hidayat S, Nakashima A et al (2006) Suppression of the mTOR-raptor signaling pathway by the inhibitor of heat shock protein 90 geldanamycin. J Biochem 139, 129-135 https://doi.org/10.1093/jb/mvj008

Cited by

  1. Novel Factors of Viral Origin Inhibit TOR Pathway Gene Expression vol.9, pp.1664-042X, 2018, https://doi.org/10.3389/fphys.2018.01678