The opposing actions of target of rapamycin and AMP-Activated protein kinase in cell growth control

Cold Spring Harbor Perspectives in Medicine

Volumn 5, Issue 8, 2015, Pages 1-21

  Hindupur, Sravanth K ^a   González, Asier ^a   Hall, Michael N ^a  

^a UNIVERSITY OF BASEL   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ADENYLATE KINASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; STRESS ACTIVATED PROTEIN KINASE 1; TARGET OF RAPAMYCIN KINASE; TRANSCRIPTION FACTOR; GROWTH FACTOR;

ARTICLE; CELL AGING; CELL GROWTH; CELL SURFACE; ENZYME ACTIVE SITE; GROWTH REGULATION; LIPID METABOLISM; LYSOSOME; NONHUMAN; PROTEIN FUNCTION; SACCHAROMYCES CEREVISIAE; SIGNAL TRANSDUCTION; YEAST; ANIMAL; CELL DIVISION; HUMAN; METABOLISM; PHYSIOLOGY; AGING; AUTOPHAGY; ENERGY; EUKARYOTE EVOLUTION; MAMMAL; METABOLIC REGULATION; NUTRIENT; REGULATORY MECHANISM;

EUKARYOTA;

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; CELL DIVISION; HUMANS; SACCHAROMYCES CEREVISIAE; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84940021561     PISSN: None     EISSN: 21571422     Source Type: Journal    
DOI: 10.1101/cshperspect.a019141     Document Type: Article

References (220)

1. An Z, Wang H, Song P, Zhang M, Geng X, Zou MH. 2007. Nicotine-induced activation of AMP-activated protein kinase inhibits fatty acid synthase in 3T3L1 adipocytes: A role for oxidant stress. J Biol Chem 282: 26793–26801.
2. Anisimov VN. 2010. Metformin for aging and cancer prevention. Aging 2: 760–774.
3. Apfeld J, O’Connor G, McDonagh T, DiStefano PS, Curtis R. 2004. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev 18: 3004–3009.
4. Ashrafi K, Lin SS, Manchester JK, Gordon JI. 2000. Sip2p and its partner snf1p kinase affect aging in S. cerevisiae. Genes Dev 14: 1872–1885.
5. Aspuria PJ, Sato T, Tamanoi F. 2007. The TSC/Rheb/TOR signaling pathway in fission yeast and mammalian cells: Temperature sensitive and constitutive active mutants of TOR. Cell Cycle 6: 1692–1695.
6. Baena-Gonzalez E, Sheen J. 2008. Convergent energy and stress signaling. Trends Plant Sci 13: 474–482.
7. Barnes K, Ingram JC, Porras OH, Barros LF, Hudson ER, Fryer LG, Foufelle F, Carling D, Hardie DG, Baldwin SA. 2002. Activation of GLUT1 by metabolic and osmotic stress: Potential involvement of AMP-activated protein kinase (AMPK). J Cell Sci 115: 2433–2442.
8. Bar-Peled L, Sabatini DM. 2012. SnapShot: mTORC1 signaling at the lysosomal surface. Cell 151: 1390–1390 e1391.
9. Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM. 2012. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 150: 1196–1208.
10. Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM. 2013. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340: 1100–1106.
11. Bateman A. 1997. The structure of a domain common to archaebacteria and the homocystinuria disease protein. Trends Biochem Sci 22: 12–13.
12. Beck T, Hall MN. 1999. The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. Nature 402: 689–692.
13. Beg ZH, Brewer HB Jr., 1982. Modulation of rat liver 3-hydroxy-3-methylglutaryl-CoA reductase activity by reversible phosphorylation. Fed Proc 41: 2634–2638.
14. Ben-Sahra I, Howell JJ, Asara JM, Manning BD. 2013. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339: 1323– 1328.
15. Berggreen C, Gormand A, Omar B, Degerman E, Goransson O. 2009. Protein kinase B activity is required for the effects of insulin on lipid metabolism in adipocytes. Am J Physiol Endocrinol Metab 296: E635–E646.
16. Bertram PG, Choi JH, Carvalho J, Chan TF, Ai W, Zheng XF. 2002. Convergence of TOR-nitrogen and Snf1-glucose signaling pathways onto Gln3. Mol Cell Biol 22: 1246– 1252.
17. Betz C, Hall MN. 2013. Where is mTOR and what is it doing there? J Cell Biol 203: 563–574.
18. Betz C, Stracka D, Prescianotto-Baschong C, Frieden M, Demaurex N, Hall MN. 2013. Feature article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology. Proc Natl Acad Sci 110: 12526– 12534.
19. Bhalerao RP, Salchert K, Bako L, Okresz L, Szabados L, Muranaka T, Machida Y, Schell J, Koncz C. 1999. Regulatory interaction of PRL1 WD protein with Arabidopsis SNF1-like protein kinases. Proc Natl Acad Sci 96: 5322– 5327.
20. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L. 2010. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 11: 35–46.
21. Blommaart EF, Luiken JJ, Blommaart PJ, van Woerkom GM, Meijer AJ. 1995. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem 270: 2320–2326.
22. Bolster DR, Crozier SJ, Kimball SR, Jefferson LS. 2002. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem 277: 23977–23980.
23. Bozaquel-Morais BL, Madeira JB, Maya-Monteiro CM, Masuda CA, Montero-Lomeli M. 2010. A new fluorescencebased method identifies protein phosphatases regulating lipid droplet metabolism. PLoS ONE 5: e13692.
24. Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL. 1994. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369: 756–758.
25. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG Jr. 2004. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18: 2893–2904.
26. Budanov AV. 2011. Stress-responsive sestrins link p53 with redox regulation and mammalian target of rapamycin signaling. Antioxid Redox Signal 15: 1679–1690.
27. Budanov AV, Karin M. 2008. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134: 451–460.
28. Calabrese MF, Rajamohan F, Harris MS, Caspers NL, Magyar R, Withka JM, Wang H, Borzilleri KA, Sahasrabudhe PV, Hoth LR, et al. 2014. Structural basis for AMPK activation: Natural and synthetic ligands regulate kinase activity from opposite poles by different molecular mechanisms. Structure 22: 1161–1172.
29. Chantranupong L, Wolfson RL, Orozco JM, Saxton RA, Scaria SM, Bar-Peled L, Spooner E, Isasa M, Gygi SP, Sabatini DM. 2014. The sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep 9: 1–8.
30. Chaveroux C, Eichner LJ, Dufour CR, Shatnawi A, Khoutorsky A, Bourque G, Sonenberg N, Giguere V. 2013. Molecular and genetic crosstalks between mTOR and ERRa are key determinants of rapamycin-induced nonalcoholic fatty liver. Cell Metab 17: 586–598.
31. Chiu MI, Katz H, Berlin V. 1994. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci 91: 12574–12578.
32. Clark H, Carling D, Saggerson D. 2004. Covalent activation of heart AMP-activated protein kinase in response to physiological concentrations of long-chain fatty acids. Eur J Biochem 271: 2215–2224.
33. Cuervo AM. 2008. Autophagy and aging: Keeping that old broom working. Trends Genet 24: 604–612.
34. Curtis R, O’Connor G, DiStefano PS. 2006. Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolism pathways. Aging Cell 5: 119–126.
35. Cybulski N, Hall MN. 2009. TOR complex 2: A signaling pathway of its own. Trends Biochem Sci 34: 620–627.
36. Dagon Y, Hur E, Zheng B, Wellenstein K, Cantley LC, Kahn BB. 2012. p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin’s effect on food intake. Cell Metab 16: 104–112.
37. Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, et al. 2002. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 277: 35364–35370.
38. 0 -AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C a and native bovine protein phosphatase-2AC. FEBS Lett 377: 421–425.
39. Demetriades C, Doumpas N, Teleman AA. 2014. Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell 156: 786–799.
40. DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW. 2008. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 22: 239–251.
41. Diaz-Troya S, Perez-Perez ME, Florencio FJ, Crespo JL. 2008. The role of TOR in autophagy regulation from yeast to plants and mammals. Autophagy 4: 851–865.
42. Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski DJ, Murphy LO, Manning BD. 2012. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell 47: 535–546.
43. Di Como CJ, Arndt KT. 1996. Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases. Genes Dev 10: 1904–1916.
44. Dunlop EA, Hunt DK, Acosta-Jaquez HA, Fingar DC, Tee AR. 2011. ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy 7: 737–747.
45. Duran RV, Hall MN. 2012. Regulation of TOR by small GTPases. EMBO Rep 13: 121–128.
46. Duran RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E, Hall MN. 2012. Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell 47: 349–358.
47. Duran RV, MacKenzie ED, Boulahbel H, Frezza C, Heiserich L, Tardito S, Bussolati O, Rocha S, Hall MN, Gottlieb E. 2013. HIF-independent role of prolyl hydroxylases in the cellular response to amino acids. Oncogene 32: 4549– 4556.
48. Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, et al. 2010. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39: 171–183.
49. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, et al. 2011. Phosphorylation of ULK1 (hATG1) by AMPactivated protein kinase connects energy sensing to mitophagy. Science 331: 456–461.
50. Estruch F, Treitel MA, Yang X, Carlson M. 1992. N-terminal mutations modulate yeast SNF1 protein kinase function. Genetics 132: 639–650.
51. Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, Dupuy F, Chambers C, Fuerth BJ, Viollet B, et al. 2013. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17: 113– 124.
52. Feng Z. 2010. p53 regulation of the IGF-1/AKT/mTOR pathways and the endosomal compartment. Cold Spring Harb Perspect Biol 2: a001057.
53. Foretz M, Guichard C, Ferre P, Foufelle F. 1999. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc Natl Acad Sci 96: 12737–12742.
54. 0 adenosine monophosphate-activated protein kinase in the heart results in activation of acetyl coenzyme A carboxylase and inhibition of fatty acid oxidation. Metabolism 46: 1270–1274.
55. Gao X, Pan D. 2001. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev 15: 1383–1392.
56. Gao X, Zhang Y, Arrazola P, Hino O, Kobayashi T, Yeung RS, Ru B, Pan D. 2002. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 4: 699–704.
57. Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G. 2003. Insulin activation of Rheb, a mediator of mTOR/ S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 11: 1457–1466.
58. Ghillebert R, Swinnen E, Wen J, Vandesteene L, Ramon M, Norga K, Rolland F, Winderickx J. 2011. The AMPK/ SNF1/SnRK1 fuel gauge and energy regulator: Structure, function and regulation. FEBS J 278: 3978–3990.
59. Goodfellow SJ, White RJ. 2007. Regulation of RNA polymerase III transcription during mammalian cell growth. Cell Cycle 6: 2323–2326.
60. Gowans GJ, Hawley SA, Ross FA, Hardie DG. 2013. AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab 18: 556–566.
61. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ. 2008. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30: 214–226.
62. Ha J, Daniel S, Broyles SS, Kim KH. 1994. Critical phosphorylation sites for acetyl-CoA carboxylase activity. J Biol Chem 269: 22162–22168.
63. Hahn-Windgassen A, Nogueira V, Chen CC, Skeen JE, Sonenberg N, Hay N. 2005. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem 280: 32081–32089.
64. Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C. 2008. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet 4: e24.
65. Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J. 1998. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem 273: 14484–14494.
66. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, et al. 2006. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441: 885–889.
67. Hardie DG. 2011. Cell biology. Why starving cells eat themselves. Science 331: 410–411.
68. Hardie DG. 2014. AMPK—Sensing energy while talking to other signaling pathways. Cell Metab 20: 1–14.
69. Hardie DG. 2015. AMPK: Positive and negative regulation, and its role in whole-body energy homeostasis. Curr Opin Cell Biol 33: 1–7.
70. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, et al. 2009. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460: 392–395.
71. Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG. 1996. Characterization of the AMPactivated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem 271: 27879–27887.
72. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, Hardie DG. 2005. Calmodulin-dependent protein kinase kinase-b is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2: 9–19.
73. Hawley SA, Ross FA, Gowans GJ, Tibarewal P, Leslie NR, Hardie DG. 2014. Phosphorylation by Akt within the ST loop of AMPK-a1 down-regulates its activation in tumour cells. Biochem J 459: 275–287.
74. He G, Zhang YW, Lee JH, Zeng SX, Wang YV, Luo Z, Dong XC, Viollet B, Wahl GM, Lu H. 2014. AMP-activated protein kinase Induces p53 by phosphorylating MDMX and inhibiting its activity. Mol Cell Biol 34: 148–157.
75. Hedbacker K, Carlson M. 2008. SNF1/AMPK pathways in yeast. Front Biosci 13: 2408–2420.
76. Heitman J, Movva NR, Hall MN. 1991. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253: 905–909.
77. 0 -AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle. J Appl Physiol 87: 1990–1995.
78. Hong SP, Carlson M. 2007. Regulation of snf1 protein kinase in response to environmental stress. J Biol Chem 282: 16838–16845.
79. Horman S, Vertommen D, Heath R, Neumann D, Mouton V, Woods A, Schlattner U, Wallimann T, Carling D, Hue L, et al. 2006. Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase a-subunits in heart via hierarchical phosphorylation of Ser485/491. J Biol Chem 281: 5335–5340.
80. Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S, Natsume T, Takehana K, Yamada N, et al. 2009. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20: 1981–1991.
81. Hrabak EM, Chan CW, Gribskov M, Harper JF, Choi JH, Halford N, Kudla J, Luan S, Nimmo HG, Sussman MR, et al. 2003. The Arabidopsis CDPK-SnRK superfamily of protein kinases. Plant Physiol 132: 666–680.
82. Huang K, Fingar DC. 2014. Growing knowledge of the mTOR signaling network. Semin Cell Dev Biol 36: 79–90.
83. Huang J, Manning BD. 2008. The TSC1-TSC2 complex: A molecular switchboard controlling cell growth. Biochem J 412: 179–190.
84. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT. 2002. Regulation of hypoxia-inducible factor 1a expression and function by the mammalian target of rapamycin. Mol Cell Biol 22: 7004–7014.
85. Hughes Hallett JE, Luo X, Capaldi AP. 2014. State transitions in the TORC1 signaling pathway and information processing in Saccharomyces cerevisiae. Genetics 198: 773– 786.
86. 2þ/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem 280: 29060–29066.
87. Iadevaia V, Zhang Z, Jan E, Proud CG. 2012. mTOR signaling regulates the processing of pre-rRNA in human cells. Nucleic Acids Res 40: 2527–2539.
88. Inoki K, Li Y, Zhu T, Wu J, Guan KL. 2002. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4: 648–657.
89. Inoki K, Li Y, Xu T, Guan KL. 2003a. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17: 1829–1834.
90. Inoki K, Zhu T, Guan KL. 2003b. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115: 577–590.
91. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, et al. 2006. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126: 955–968.
92. Inoki K, Kim J, Guan KL. 2012. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol 52: 381–400.
93. Jacinto E, Guo B, Arndt KT, Schmelzle T, Hall MN. 2001. TIP41 interacts with TAP42 and negatively regulates the TOR signaling pathway. Mol Cell 8: 1017–1026.
94. Jewell JL, Russell RC, Guan KL. 2013. Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol 14: 133–139.
95. Jia K, Chen D, Riddle DL. 2004. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131: 3897–3906.
96. Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB. 2005. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18: 283–293.
97. Jung CH, Seo M, Otto NM, Kim DH. 2011. ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy 7: 1212–1221.
98. Kaeberlein M, Powers RW 3rd, Steffen KK, Westman EA, Hu D, Dang N, Kerr EO, Kirkland KT, Fields S, Kennedy BK. 2005. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310: 1193–1196.
99. Kamada Y, Yoshino K, Kondo C, Kawamata T, Oshiro N, Yonezawa K, Ohsumi Y. 2010. Tor directly controls the Atg1 kinase complex to regulate autophagy. Mol Cell Biol 30: 1049–1058.
100. Kantidakis T, Ramsbottom BA, Birch JL, Dowding SN, White RJ. 2010. mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1. Proc Natl Acad Sci 107: 11823–11828.
101. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. 2004. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 14: 885– 890.
102. Kijanska M, Dohnal I, Reiter W, Kaspar S, Stoffel I, Ammerer G, Kraft C, Peter M. 2010. Activation of Atg1 kinase in autophagy by regulated phosphorylation. Autophagy 6: 1168–1178.
103. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL. 2008. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10: 935–945.
104. Kim J, Kundu M, Viollet B, Guan KL. 2011. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13: 132–141.
105. Kimura N, Tokunaga C, Dalal S, Richardson C, Yoshino K, Hara K, Kemp BE, Witters LA, Mimura O, Yonezawa K. 2003. A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway. Genes Cells 8: 65–79.
106. Kohda TA, Tanaka K, Konomi M, Sato M, Osumi M, Yamamoto M. 2007. Fission yeast autophagy induced by nitrogen starvation generates a nitrogen source that drives adaptation processes. Genes Cells 12: 155–170.
107. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, et al. 2006. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441: 880–884.
108. Kong M, Fox CJ, Mu J, Solt L, Xu A, Cinalli RM, Birnbaum MJ, Lindsten T, Thompson CB. 2004. The PP2A-associated protein a4 is an essential inhibitor of apoptosis. Science 306: 695–698.
109. Korta DZ, Tuck S, Hubbard EJ. 2012. S6K links cell fate, cell cycle and nutrient response in C. elegans germline stem/ progenitor cells. Development 139: 859–870.
110. Kovacic S, Soltys CL, Barr AJ, Shiojima I, Walsh K, Dyck JR. 2003. Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem 278: 39422–39427.
111. Kraft C, Kijanska M, Kalie E, Siergiejuk E, Lee SS, Semplicio G, Stoffel I, Brezovich A, Verma M, Hansmann I, et al. 2012. Binding of the Atg1/ULK1 kinase to the ubiquitinlike protein Atg8 regulates autophagy. EMBO J 31: 3691– 3703.
112. 1 progression. Cell 73: 585–596.
113. 0 AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes 48: 1667–1671.
114. Laplante M, Sabatini DM. 2012. mTOR signaling in growth control and disease. Cell 149: 274–293.
115. Lee S, Comer FI, Sasaki A, McLeod IX, Duong Y, Okumura K, Yates JR III, Parent CA, Firtel RA. 2005. TOR complex 2 integrates cell movement during chemotaxis and signal relay in Dictyostelium. Mol Biol Cell 16: 4572–4583.
116. Lee JH, Koh H, Kim M, Kim Y, Lee SY, Karess RE, Lee SH, Shong M, Kim JM, Kim J, et al. 2007. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 447: 1017–1020.
117. Lee JH, Budanov AV, Park EJ, Birse R, Kim TE, Perkins GA, Ocorr K, Ellisman MH, Bodmer R, Bier E, et al. 2010. Sestrin as a feedback inhibitor of TOR that prevents agerelated pathologies. Science 327: 1223–1228.
118. Levine B, Mizushima N, Virgin HW. 2011. Autophagy in immunity and inflammation. Nature 469: 323–335.
119. Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, et al. 2011. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 13: 376–388.
120. Lippai M, Csikos G, Maroy P, Lukacsovich T, Juhasz G, Sass M. 2008. SNF4Ag, the Drosophila AMPK g subunit is required for regulation of developmental and stress-induced autophagy. Autophagy 4: 476–486.
121. Liu Y, Bassham DC. 2010. TOR is a negative regulator of autophagy in Arabidopsis thaliana. PLoS ONE 5: e11883.
122. Ljubicic V, Hood DA. 2009. Diminished contraction-induced intracellular signaling towards mitochondrial biogenesis in aged skeletal muscle. Aging Cell 8: 394–404.
123. Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, Oppliger W, Jenoe P, Hall MN. 2002. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10: 457–468.
124. Loffler AS, Alers S, Dieterle AM, Keppeler H, Franz-Wachtel M, Kundu M, Campbell DG, Wesselborg S, Alessi DR, Stork B. 2011. Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop. Autophagy 7: 696–706.
125. Long X, Spycher C, Han ZS, Rose AM, Muller F, Avruch J. 2002. TOR deficiency in C. elegans causes developmental arrest and intestinal atrophy by inhibition of mRNA translation. Curr Biol 12: 1448–1461.
126. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. 2005. Rheb binds and regulates the mTOR kinase. Curr Biol 15: 702–713.
127. Lu JY, Lin YY, Sheu JC, Wu JT, Lee FJ, Chen Y, Lin MI, Chiang FT, Tai TY, Berger SL, et al. 2011. Acetylation of yeast AMPK controls intrinsic aging independently of caloric restriction. Cell 146: 969–979.
128. Ma XM, Blenis J. 2009. Molecular mechanisms of mTORmediated translational control. Nat Rev Mol Cell Biol 10: 307–318.
129. Mackintosh RW, Davies SP, Clarke PR, Weekes J, Gillespie JG, Gibb BJ, Hardie DG. 1992. Evidence for a protein kinase cascade in higher plants. 3-Hydroxy-3-methylglutaryl-CoA reductase kinase. Eur J Biochem 209: 923–931.
130. Mahfouz MM, Kim S, Delauney AJ, Verma DP. 2006. Arabidopsis TARGET OF RAPAMYCIN interacts with RAPTOR, which regulates the activity of S6 kinase in response to osmotic stress signals. Plant Cell 18: 477–490.
131. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. 2002. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 10: 151–162.
132. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, et al. 2013. Metformin improves healthspan and lifespan in mice. Nat Commun 4: 2192.
133. Mayer C, Grummt I. 2006. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene 25: 6384–6391.
134. Mayordomo I, Estruch F, Sanz P. 2002. Convergence of the target of rapamycin and the Snf1 protein kinase pathways in the regulation of the subcellular localization of Msn2, a transcriptional activator of STRE (stress response element)-regulated genes. J Biol Chem 277: 35650–35656.
135. Menon S, Dibble CC, Talbott G, Hoxhaj G, Valvezan AJ, Takahashi H, Cantley LC, Manning BD. 2014. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156: 771–785.
136. Miller BC, Zhao Z, Stephenson LM, Cadwell K, Pua HH, Lee HK, Mizushima NN, Iwasaki A, He YW, Swat W, et al. 2008. The autophagy gene ATG5 plays an essential role in B lymphocyte development. Autophagy 4: 309–314.
137. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, et al. 2011. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 66: 191–201.
138. Mitchelhill KI, Stapleton D, Gao G, House C, Michell B, Katsis F, Witters LA, Kemp BE. 1994. Mammalian AMP-activated protein kinase shares structural and functional homology with the catalytic domain of yeast Snf1 protein kinase. J Biol Chem 269: 2361–2364.
139. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. 2008. Autophagy fights disease through cellular self-digestion. Nature 451: 1069–1075.
140. Momcilovic M, Hong SP, Carlson M. 2006. Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J Biol Chem 281: 25336–25343.
141. Mortensen M, Soilleux EJ, Djordjevic G, Tripp R, Lutteropp M, Sadighi-Akha E, Stranks AJ, Glanville J, Knight S, Jacobsen SE, et al. 2011. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J Exp Med 208: 455–467.
142. Munday MR, Campbell DG, Carling D, Hardie DG. 1988. Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase. Eur J Biochem 175: 331–338.
143. Muoio DM, Seefeld K, Witters LA, Coleman RA. 1999. AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: Evidence that sn-glycerol-3-phosphate acyltransferase is a novel target. Biochem J 338: 783–791.
144. Ning J, Xi G, Clemmons DR. 2011. Suppression of AMPK activation via S485 phosphorylation by IGF-I during hyperglycemia is mediated by AKT activation in vascular smooth muscle cells. Endocrinology 152: 3143–3154.
145. Nomura W, Maeta K, Kita K, Izawa S, Inoue Y. 2010. Methylglyoxal activates Gcn2 to phosphorylate eIF2a independently of the TOR pathway in Saccharomyces cerevisiae. Appl Microbiol Biotechnol 86: 1887–1894.
146. Oakhill JS, Steel R, Chen ZP, Scott JW, Ling N, Tam S, Kemp BE. 2011. AMPK is a direct adenylate charge-regulated protein kinase. Science 332: 1433–1435.
147. Oh WJ, Jacinto E. 2011. mTOR complex 2 signaling and functions. Cell Cycle 10: 2305–2316.
148. Oldham S, Montagne J, Radimerski T, Thomas G, Hafen E. 2000. Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. Genes Dev 14: 2689–2694.
149. Orlova M, Kanter E, Krakovich D, Kuchin S. 2006. Nitrogen availability and TOR regulate the Snf1 protein kinase in Saccharomyces cerevisiae. Eukaryot Cell 5: 1831–1837.
150. Otto GP, Wu MY, Kazgan N, Anderson OR, Kessin RH. 2003. Macroautophagy is required for multicellular development of the social amoeba Dictyostelium discoideum. J Biol Chem 278: 17636–17645.
151. Pan DA, Hardie DG. 2002. A homologue of AMP-activated protein kinase in Drosophila melanogaster is sensitive to AMP and is activated by ATP depletion. Biochem J 367: 179–186.
152. Pan KZ, Palter JE, Rogers AN, Olsen A, Chen D, Lithgow GJ, Kapahi P. 2007. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell 6: 111–119.
153. Panchaud N, Peli-Gulli MP, De Virgilio C. 2013. Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci Signal 6: ra42.
154. Parmigiani A, Nourbakhsh A, Ding B, Wang W, Kim YC, Akopiants K, Guan K-L, Karin M, Budanov AV. 2014. Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep 9: 1281–1291.
155. Pattingre S, Levine B. 2006. Bcl-2 inhibition of autophagy: A new route to cancer? Cancer Res 66: 2885–2888.
156. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B. 2005. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122: 927–939.
157. Peng M, Yin N, Li MO. 2014. Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling. Cell 159: 122–133.
158. Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN, et al. 2011. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146: 408–420.
159. Petit CS, Roczniak-Ferguson A, Ferguson SM. 2013. Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. J Cell Biol 202: 1107–1122.
160. Polge C, Thomas M. 2007. SNF1/AMPK/SnRK1 kinases, global regulators at the heart of energy control? Trends Plant Sci 12: 20–28.
161. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A. 2008. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 8: 224–236.
162. Reinke A, Anderson S, McCaffery JM, Yates J 3rd, Aronova S, Chu S, Fairclough S, Iverson C, Wedaman KP, Powers T. 2004. TOR complex 1 includes a novel component, Tco89p (YPL180w), and cooperates with Ssd1p to maintain cellular integrity in Saccharomyces cerevisiae. J Biol Chem 279: 14752–14762.
163. Ricoult SJ, Manning BD. 2013. The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO Rep 14: 242–251.
164. Robitaille AM, Christen S, Shimobayashi M, Cornu M, Fava LL, Moes S, Prescianotto-Baschong C, Sauer U, Jenoe P, Hall MN. 2013. Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339: 1320–1323.
165. Rodriguez-Colman MJ, Sorolla MA, Vall-Llaura N, Tamarit J, Ros J, Cabiscol E. 2013. The FOX transcription factor Hcm1 regulates oxidative metabolism in response to early nutrient limitation in yeast. Role of Snf1 and Tor1/ Sch9 kinases. Biochim Biophys Acta 1833: 2004–2015.
166. Rohde JR, Campbell S, Zurita-Martinez SA, Cutler NS, Ashe M, Cardenas ME. 2004. TOR controls transcriptional and translational programs via Sap-Sit4 protein phosphatase signaling effectors. Mol Cell Biol 24: 8332–8341.
167. Ruiz A, Xu X, Carlson M. 2011. Roles of two protein phosphatases, Reg1-Glc7 and Sit4, and glycogen synthesis in regulation of SNF1 protein kinase. Proc Natl Acad Sci 108: 6349–6354.
168. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. 1994. RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78: 35–43.
169. Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT. 1995. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 270: 815–822.
170. Saito K, Araki Y, Kontani K, Nishina H, Katada T. 2005. Novel role of the small GTPase Rheb: Its implication in endocytic pathway independent of the activation of mammalian target of rapamycin. J Biochem 137: 423– 430.
171. Sakamoto K, Zarrinpashneh E, Budas GR, Pouleur AC, Dutta A, Prescott AR, Vanoverschelde JL, Ashworth A, Jovanovic A, Alessi DR, et al. 2006. Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKa2 but not AMPKa1. Am J Physiol Endocrinol Metab 290: E780–E788.
172. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM. 2007. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25: 903–915.
173. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM. 2008. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320: 1496–1501.
174. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. 2010. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141: 290–303.
175. Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA. 2003. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 5: 566– 571.
176. Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M. 2007. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab 6: 280–293.
177. Scott RC, Schuldiner O, Neufeld TP. 2004. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev Cell 7: 167–178.
178. Scott RC, Juhasz G, Neufeld TP. 2007. Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death. Curr Biol 17: 1–11.
179. Scott JW, Ling N, Issa SM, Dite TA, O’Brien MT, Chen ZP, Galic S, Langendorf CG, Steinberg GR, Kemp BE, et al. 2014. Small molecule drug A-769662 and AMP synergistically activate naïve AMPK independent of upstream kinase signaling. Chem Biol 21: 619–627.
180. Serfontein J, Nisbet RE, Howe CJ, de Vries PJ. 2011. Conservation of structural and functional elements of TSC1 and TSC2: A bioinformatic comparison across animal models. Behav Genet 41: 349–356.
181. Shackelford DB, Vasquez DS, Corbeil J, Wu S, Leblanc M, Wu CL, Vera DR, Shaw RJ. 2009. mTOR and HIF-1amediated tumor metabolism in an LKB1 mouse model of Peutz–Jeghers syndrome. Proc Natl Acad Sci 106: 11137– 11142.
182. Shimano H, Yahagi N, Amemiya-Kudo M, Hasty AH, Osuga J, Tamura Y, Shionoiri F, Iizuka Y, Ohashi K, Harada K, et al. 1999. Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes. J Biol Chem 274: 35832–35839.
183. Shimobayashi M, Hall MN. 2014. Making new contacts: The mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15: 155–162.
184. Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL. 1999. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci 96: 13656– 13661.
185. Spasic MR, Callaerts P, Norga KK. 2008. Drosophila alicorn is a neuronal maintenance factor protecting against activity-induced retinal degeneration. J Neurosci 28: 6419– 6429.
186. Stocker H, Radimerski T, Schindelholz B, Wittwer F, Belawat P, Daram P, Breuer S, Thomas G, Hafen E. 2003. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 5: 559–565.
187. 0 -AMP. Plant J 19: 433–439.
188. Suttangkakul A, Li F, Chung T, Vierstra RD. 2011. The ATG1/ATG13 protein kinase complex is both a regulator and a target of autophagic recycling in Arabidopsis. Plant Cell 23: 3761–3779.
189. Takahara T, Maeda T. 2012. TORC1 of fission yeast is rapamycin-sensitive. Genes Cells 17: 698–708.
190. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. 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: 1259–1268.
191. Tekinay T, Wu MY, Otto GP, Anderson OR, Kessin RH. 2006. Function of the Dictyostelium discoideum Atg1 kinase during autophagy and development. Eukaryot Cell 5: 1797–1806.
192. Thelander M, Olsson T, Ronne H. 2004. Snf1-related protein kinase 1 is needed for growth in a normal day–night light cycle. EMBO J 23: 1900–1910.
193. Tschape JA, Hammerschmied C, Muhlig-Versen M, Athenstaedt K, Daum G, Kretzschmar D. 2002. The neurodegeneration mutant lochrig interferes with cholesterol homeostasis and Appl processing. EMBO J 21: 6367–6376.
194. Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, Spooner E, Sabatini DM. 2013. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell 52: 495–505.
195. Urano J, Tabancay AP, Yang W, Tamanoi F. 2000. The Saccharomyces cerevisiae Rheb G-protein is involved in regulating canavanine resistance and arginine uptake. J Biol Chem 275: 11198–11206.
196. Usaite R, Jewett MC, Oliveira AP, Yates JR 3rd, Olsson L, Nielsen J. 2009. Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulator. Mol Syst Biol 5: 319.
197. Valbuena N, Moreno S. 2012. AMPK phosphorylation by Ssp1 is required for proper sexual differentiation in fission yeast. J Cell Sci 125: 2655–2664.
198. Valentine RJ, Coughlan KA, Ruderman NB, Saha AK. 2014. Insulin inhibits AMPK activity and phosphorylates AMPK Ser(485/491) through Akt in hepatocytes, myotubes and incubated rat skeletal muscle. Arch Biochem Biophys 562: 62–69.
199. van Dam TJ, Zwartkruis FJ, Bos JL, Snel B. 2011. Evolution of the TOR pathway. J Mol Evol 73: 209–220.
200. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F. 2003. Genetics: Influence of TOR kinase on lifespan in C. elegans. Nature 426: 620.
201. Vernoud V, Horton AC, Yang Z, Nielsen E. 2003. Analysis of the small GTPase gene superfamily of Arabidopsis. Plant Physiol 131: 1191–1208.
202. Wang GL, Semenza GL. 1993. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci 90: 4304–4308.
203. Wang Z, Wilson WA, Fujino MA, Roach PJ. 2001. Antagonistic controls of autophagy and glycogen accumulation by Snf1p, the yeast homolog of AMP-activated protein kinase, and the cyclin-dependent kinase Pho85p. Mol Cell Biol 21: 5742–5752.
204. Weidemann A, Johnson RS. 2008. Biology of HIF-1a. Cell Death Differ 15: 621–627.
205. 0 AMP-activated protein kinase. J Biol Chem 267: 2864– 2867.
206. Woods A, Munday MR, Scott J, Yang X, Carlson M, Carling D. 1994. Yeast SNF1 is functionally related to mammalian AMP-activated protein kinase and regulates acetyl-CoA carboxylase in vivo. J Biol Chem 269: 19509– 19515.
207. 2þ/calmodulin-dependent protein kinase kinase-b acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab 2: 21–33.
208. Wullschleger S, Loewith R, Hall MN. 2006. TOR signaling in growth and metabolism. Cell 124: 471–484.
209. Xiao B, Sanders MJ, Carmena D, Bright NJ, Haire LF, Underwood E, Patel BR, Heath RB, Walker PA, Hallen S, et al. 2013. Structural basis of AMPK regulation by small molecule activators. Nat Commun 4: 3017.
210. Yeh LA, Lee KH, Kim KH. 1980. Regulation of rat liver acetyl-CoA carboxylase. Regulation of phosphorylation and inactivation of acetyl-CoA carboxylase by the adenylate energy charge. J Biol Chem 255: 2308– 2314.
211. Yeh YY, Wrasman K, Herman PK. 2010. Autophosphorylation within the Atg1 activation loop is required for both kinase activity and the induction of autophagy in Saccharomyces cerevisiae. Genetics 185: 871– 882.
212. Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL 3rd, Lee JJ, Tilghman SM, Gumbiner BM, Costantini F. 1997. The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell 90: 181–192.
213. Zhang C, Cuervo AM. 2008. Restoration of chaperonemediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med 14: 959– 965.
214. Zhang H, Stallock JP, Ng JC, Reinhard C, Neufeld TP. 2000. Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev 14: 2712–2724.
215. Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D. 2003. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 5: 578–581.
216. Zhang J, Vaga S, Chumnanpuen P, Kumar R, Vemuri GN, Aebersold R, Nielsen J. 2011. Mapping the interaction of Snf1 with TORC1 in Saccharomyces cerevisiae. Mol Syst Biol 7: 545.
217. Zhang YL, Guo H, Zhang CS, Lin SY, Yin Z, Peng Y, Luo H, Shi Y, Lian G, Zhang C, et al. 2013. AMP as a low-energy charge signal autonomously initiates assembly of AXINAMPK-LKB1 complex for AMPK activation. Cell Metab 18: 546–555.
218. Zhang CS, Jiang B, Li M, Zhu M, Peng Y, Zhang YL, Wu YQ, Li TY, Liang Y, Lu Z, et al. 2014. The lysosomal v-ATPaseragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab 20: 526–540.
219. Zinzalla V, Stracka D, Oppliger W, Hall MN. 2011. Activation of mTORC2 by association with the ribosome. Cell 144: 757–768.
220. þ-ATPase. Science 334: 678–683.