MTOR: A pharmacologic target for autophagy regulation

Journal of Clinical Investigation

Volumn 125, Issue 1, 2015, Pages 25-32

  Kim, Young Chul ^a   Guan, Kun Liang ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 [2 (2,6 DIMETHYLMORPHOLINO) 4 MORPHOLINOPYRIDO[2,3 D]PYRIMIDIN 7 YL] 2 METHOXYBENZENEMETHANOL; AZD 8055; BAFILOMYCIN A1; EVEROLIMUS; HYDROXYCHLOROQUINE; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; METFORMIN; RAPAMYCIN; RAPAMYCIN DERIVATIVE; TEMSIROLIMUS; TORIN 1; UNCLASSIFIED DRUG; WYE 354; MTOR PROTEIN, HUMAN; TARGET OF RAPAMYCIN KINASE;

ANTINEOPLASTIC ACTIVITY; AUTOPHAGY; CELL GROWTH; CELL METABOLISM; CELL PROLIFERATION; CLINICAL TRIAL (TOPIC); DRUG TARGETING; ENZYME REGULATION; HUMAN; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; PHYSIOLOGY;

ANIMALS; AUTOPHAGY; HUMANS; METFORMIN; SIROLIMUS; TOR SERINE-THREONINE KINASES;

EID: 84920504512     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI73939     Document Type: Review

References (121)

1. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-293.
2. Kim DH, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell. 2003;11(4):895-904.
3. Jacinto E, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6(11):1122-1128.
4. Peterson TR, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137(5):873-886.
5. Kaizuka T, et al. Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem. 2010;285(26):20109-20116.
6. Hara K, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110(2):177-189.
7. Kim DH, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110(2):163-175.
8. Sancak Y, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007;25(6):903-915.
9. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol. 2007;9(3):316-323.
10. Thedieck K, et al. PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS One. 2007;2(11):e1217.
11. Wang L, Harris TE, Roth RA, Lawrence JC Jr. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem. 2007;282(27):20036-20044.
12. Sarbassov DD, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14(14):1296-1302.
13. Jacinto E, et al. SIN1/MIP1 maintains ric-tor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006;127(1):125-137.
14. Frias MA, et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol. 2006;16(18):1865-1870.
15. Pearce LR, et al. Identification of Protor as a novel Rictor-binding component of mTOR com-plex-2. Biochem J. 2007;405(3):513-522.
16. Yang Q, Inoki K, Ikenoue T, Guan KL. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev. 2006;20(20):2820-2832.
17. Shimobayashi M, Hall MN. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol. 2014;15(3):155-162.
18. Laplante M, Sabatini DM. Regulation of mTORC1 and its impact on gene expression at a glance. J Cell Sci. 2013;126(pt 8):1713-1719.
19. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002;4(9):648-657.
20. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell. 2002;10(1):151-162.
21. Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol. 2002;4(9):658-665.
22. Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003;17(15):1829-1834.
23. Tee AR, Manning BD, Roux PP, Cantley LC, 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. 2003;13(15):1259-1268.
24. Menon S, et al. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell. 2014;156(4):771-785.
25. Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol. 2003;5(6):566-571.
26. Stocker H, et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol. 2003;5(6):559-565.
27. Roux PP, Ballif BA, Anjum R, Gygi SP, 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 U S A. 2004;101(37):13489-13494.
28. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell. 2005;121(2):179-193.
29. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115(5):577-590.
30. Gwinn DM, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30(2):214-226.
31. Brugarolas J, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 2004;18(23):2893-2904.
32. DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 2008;22(2):239-251.
33. Jewell JL, Russell RC, Guan KL. Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol. 2013;14(3):133-139.
34. Bar-Peled L, Sabatini DM. Regulation of mTORC1 by amino acids. Trends Cell Biol. 2014;24(7):400-406.
35. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol. 2008;10(8):935-945.
36. Sancak Y, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 2008;320(5882):1496-1501.
37. Sekiguchi T, Hirose E, Nakashima N, Ii M, Nish-imoto T. Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B. J Biol Chem. 2001;276(10):7246-7257.
38. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010;141(2):290-303.
39. Thedieck K, et al. Inhibition of mTORC1 by astrin and stress granules prevents apoptosis in cancer cells. Cell. 2013;154(4):859-874.
40. Zhang J, et al. A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nat Cell Biol. 2013;15(10):1186-1196.
41. Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell. 2012;150(6):1196-1208.
42. Bar-Peled L, et al. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013;340(6136):1100-1106.
43. Tsun ZY, et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell. 2013;52(4):495-505.
44. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science. 2011;334(6056):678-683.
45. Han JM, et al. Leucyl-tRNA synthetase is an intra-cellular leucine sensor for the mTORC1-signal-ing pathway. Cell. 2012;149(2):410-424.
46. Efeyan A, et al. RagA, but not RagB, is essential for embryonic development and adult mice. Dev Cell. 2014;29(3):321-329.
47. Kim YC, et al. Rag GTPases are cardioprotective by regulating lysosomal function. Nat Commun. 2014;5:4241.
48. Zinzalla V, Stracka D, Oppliger W, Hall MN. Activation of mTORC2 by association with the ribosome. Cell. 2011;144(5):757-768.
49. Cybulski N, Polak P, Auwerx J, Ruegg MA, Hall MN. mTOR complex 2 in adipose tissue negatively controls whole-body growth. Proc Natl Acad Sci U S A. 2009;106(24):9902-9907.
50. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098-1101.
51. Harrington LS, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol. 2004;166(2):213-223.
52. Um SH, et al. Absence of S6K1 protects against age-and diet-induced obesity while enhancing insulin sensitivity. Nature. 2004;431(7005):200-205.
53. Julien LA, Carriere A, Moreau J, Roux PP. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol. 2010;30(4):908-921.
54. Tzatsos A, Kandror KV. Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Mol Cell Biol. 2006;26(1):63-76.
55. Hsu PP, et al. The mTOR-regulated phosphop-roteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011;332(6035):1317-1322.
56. Yu Y, et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science. 2011;332(6035):1322-1326.
57. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147(4):728-741.
58. Clark SL Jr. Cellular differentiation in the kidneys of newborn mice studies with the electron microscope. J Biophys Biochem Cytol. 1957;3(3):349-362.
59. De Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol. 1966;28:435-492.
60. Mitchener JS, Shelburne JD, Bradford WD, Hawkins HK. Cellular autophagocytosis induced by deprivation of serum and amino acids in HeLa cells. Am J Pathol. 1976;83(3):485-492.
61. Mortimore GE, Schworer CM. Induction of autophagy by amino-acid deprivation in perfused rat liver. Nature. 1977;270(5633):174-176.
62. Noda T, Ohsumi Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem. 1998;273(7):3963-3966.
63. Scott RC, Schuldiner O, Neufeld TP. Role and regulation of starvation-induced autoph-agy in the Drosophila fat body. Dev Cell. 2004;7(2):167-178.
64. Jung CH, Ro SH, Cao J, Otto NM, Kim DH. mTOR regulation of autophagy. FEBS Lett. 2010;584(7):1287-1295.
65. Russell RC, Yuan HX, Guan KL. Autophagy regulation by nutrient signaling. Cell Res. 2014;24(1):42-57.
66. Ganley IG, Lam du H, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem. 2009;284(18):12297-12305.
67. Hosokawa N, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell. 2009;20(7):1981-1991.
68. Jung CH, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell. 2009;20(7):1992-2003.
69. Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M, Ohsumi Y. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol. 2000;150(6):1507-1513.
70. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phospho-rylation of Ulk1. Nat Cell Biol. 2011;13(2):132-141.
71. Nazio F, et al. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat Cell Biol. 2013;15(4):406-416.
72. Kim J, et al. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell. 2013;152(1-2):290-303.
73. Yuan HX, Russell RC, Guan KL. Regulation of PIK3C3/VPS34 complexes by MTOR in nutrient stress-induced autophagy. Autophagy. 2013;9(12):1983-1995.
74. Settembre C, Fraldi A, Medina DL, Ballabio A. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol. 2013;14(5):283-296.
75. Settembre C, et al. TFEB links autoph-agy to lysosomal biogenesis. Science. 2011;332(6036):1429-1433.
76. Settembre C, et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 2012;31(5):1095-1108.
77. Martina JA, Chen Y, Gucek M, Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy. 2012;8(6):903-914.
78. Martina JA, Puertollano R. Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes. J Cell Biol. 2013;200(4):475-491.
79. Yu L, et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature. 2010;465(7300):942-946.
80. Oh WJ, et al. mTORC2 can associate with ribo-somes to promote cotranslational phosphory-lation and stability of nascent Akt polypeptide. EMBO J. 2010;29(23):3939-3951.
81. Rubinsztein DC, Codogno P, Levine B. Autoph-agy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov. 2012;11(9):709-730.
82. Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med. 2013;368(7):651-662.
83. Wander SA, Hennessy BT, Slingerland JM. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J Clin Invest. 2011;121(4):1231-1241.
84. Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov. 2011;10(11):868-880.
85. Lamming DW, Ye L, Sabatini DM, Baur JA. Rap-alogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest. 2013;123(3):980-989.
86. Li J, Kim SG, Blenis J. Rapamycin: one drug, many effects. Cell Metab. 2014;19(3):373-379.
87. Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamy-cin in yeast. Science. 1991;253(5022):905-909.
88. Brown EJ, et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 1994;369(6483):756-758.
89. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-depen-dent fashion and is homologous to yeast TORs. Cell. 1994;78(1):35-43.
90. Chiu MI, Katz H, Berlin V. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci U S A. 1994;91(26):12574-12578.
91. Sabers CJ, et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem. 1995;270(2):815-822.
92. Sparks CA, Guertin DA. Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene. 2010;29(26):3733-3744.
93. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006;5(8):671-688.
94. Takeuchi H, et al. Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res. 2005;65(8):3336-3346.
95. Ravikumar B, Duden R, Rubinsztein DC. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autoph-agy. Hum Mol Genet. 2002;11(9):1107-1117.
96. Ravikumar B, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004;36(6):585-595.
97. Nam HY, Han MW, Chang HW, Kim SY, Kim SW. Prolonged autophagy by MTOR inhibitor leads radioresistant cancer cells into senescence. Autophagy. 2013;9(10):1631-1632.
98. Tanemura M, et al. Rapamycin causes upregu-lation of autophagy and impairs islets function both in vitro and in vivo. Am J Transplant. 2012;12(1):102-114.
99. Castillo K, et al. Measurement of autophagy flux in the nervous system in vivo. Cell Death Dis. 2013;4:e917.
100. Parkhitko A, et al. Tumorigenesis in tuberous sclerosis complex is autophagy and p62/seques-tosome 1 (SQSTM1)-dependent. Proc Natl Acad Sci U S A. 2011;108(30):12455-12460.
101. Pazdur R. FDA Approval for Everolimus. National Cancer Institute Web site. http://www.cancer.gov/cancertopics/druginfo/fda-everolimus. Updated July 3, 2013. Accessed September 26, 2014.
102. Guertin DA, et al. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell. 2009;15(2):148-159.
103. Choo AY, Yoon SO, Kim SG, Roux PP, Blenis J. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc Natl Acad Sci U S A. 2008;105(45):17414-17419.
104. Kang SA, et al. mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science. 2013;341(6144):1236566.
105. Guertin DA, Sabatini DM. The pharmacology of mTOR inhibition. Sci Signal. 2009;2(67):pe24.
106. Thoreen CC, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamy-cin-resistant functions of mTORC1. J Biol Chem. 2009;284(12):8023-8032.
107. Nyfeler B, et al. Relieving autophagy and 4EBP1 from rapamycin resistance. Mol Cell Biol. 2011;31(14):2867-2876.
108. Chresta CM, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 2010;70(1):288-298.
109. Huang S, Yang ZJ, Yu C, Sinicrope FA. Inhibition of mTOR kinase by AZD8055 can antagonize chemotherapy-induced cell death through autophagy induction and down-reg-ulation of p62/sequestosome 1. J Biol Chem. 2011;286(46):40002-40012.
110. Hardie DG. Role of AMP-activated protein kinase in the metabolic syndrome and in heart disease. FEBS Lett. 2008;582(1):81-89.
111. Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 2007;67(22):10804-10812.
112. Kalender A, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-depen-dent manner. Cell Metab. 2010;11(5):390-401.
113. Ben Sahra I, et al. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 2011;71(13):4366-4372.
114. Buzzai M, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 2007;67(14):6745-6752.
115. Shi WY, et al. Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death Dis. 2012;3:e275.
116. Tomic T, et al. Metformin inhibits melanoma development through autophagy and apoptosis mechanisms. Cell Death Dis. 2011;2:e199.
117. Xie Z, et al. Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes. 2011;60(6):1770-1778.
118. Feng Y, et al. Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell Death Dis. 2014;5:e1088.
119. White E. The role for autophagy in cancer. J Clin Invest. 2015;125(1):5564-5568.
120. Levine B, Packer M, Codogno P. Development of autophagy inducers in clinical medicine. J Clin Invest. 2015;125(1):5536-5546.
121. Vakifahmetoglu-Norberg H, Xia H, Yuan J. Phar-macologic agents targeting autophagy. J Clin Invest. 2015;125(1):5527-5535.