mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin

Science

Volumn 341, Issue 6144, 2013, Pages

  Kang, Seong A ^a,b   Pacold, Michael E ^a,b,c   Cervantes, Christopher L ^a,b   Lim, Daniel ^b   Lou, Hua Jane ^d   Ottina, Kathleen ^a,b   Gray, Nathanael S ^c,e   Turk, Benjamin E ^d   Yaffe, Michael B ^b,f   Sabatini, David M ^a,b  

^a WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH   (United States)

^b MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^c DANA FARBER CANCER INSTITUTE   (United States)

^d YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e HARVARD MEDICAL SCHOOL   (United States)

^f BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GROWTH FACTOR; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; PROLINE; RAPAMYCIN; SERINE; SYNTHETIC PEPTIDE; THREONINE; 1 (4 (4 PROPIONYLPIPERAZIN 1 YL) 3 (TRIFLUOROMETHYL)PHENYL) 9 (QUINOLIN 3 YL)BENZO(H)(1,6)NAPHTHYRIDIN 2(1H) ONE; 1-(4-(4-PROPIONYLPIPERAZIN-1-YL)-3-(TRIFLUOROMETHYL)PHENYL)-9-(QUINOLIN-3-YL)BENZO(H)(1,6)NAPHTHYRIDIN-2(1H)-ONE; AMINO ACID; MTOR PROTEIN, HUMAN; MTOR PROTEIN, MOUSE; MTORC1 COMPLEX, HUMAN; MTORC1 COMPLEX, MOUSE; NAPHTHYRIDINE DERIVATIVE; PEPTIDE; PROTEIN; TARGET OF RAPAMYCIN KINASE;

DRUG; ENZYME ACTIVITY; PEPTIDE; PROTEIN; SIGNAL; STARVATION; SUBSTRATE;

ARTICLE; BINDING SITE; CANCER RESISTANCE; CELL GROWTH; CONTROLLED STUDY; DRUG SENSITIVITY; ENZYME ACTIVITY; GENE MUTATION; HUMAN; HUMAN CELL; HYPOTHESIS; IN VITRO STUDY; MOLECULAR RECOGNITION; NUTRIENT; PRIORITY JOURNAL; PROTEIN MOTIF; PROTEIN PHOSPHORYLATION; QUALITY CONTROL; REGULATORY MECHANISM; SIGNAL TRANSDUCTION; STARVATION; ANIMAL; CELL LINE; CHEMISTRY; CULTURE MEDIUM; DRUG ANTAGONISM; METABOLISM; MOUSE; PHOSPHORYLATION;

AMINO ACID MOTIFS; AMINO ACIDS; ANIMALS; CELL LINE; CULTURE MEDIA; HUMANS; MICE; NAPHTHYRIDINES; PEPTIDES; PHOSPHORYLATION; PROTEINS; SIROLIMUS; TOR SERINE-THREONINE KINASES;

EID: 84880709668     PISSN: 00368075     EISSN: 10959203     Source Type: Journal    
DOI: 10.1126/science.1236566     Document Type: Article

References (49)

1. M. Laplante, D. M. Sabatini, mTOR signaling in growth control and disease. Cell 149, 274 (2012). doi: 10.1016/j.cell.2012.03.017; pmid: 22500797
2. D. A. Guertin, D. M. Sabatini, The pharmacology of mTOR inhibition. Sci. Signal. 2, pe24 (2009). doi: 10.1126/scisignal.267pe24; pmid: 19383975
3. D. Benjamin, M. Colombi, C. Moroni, M. N. Hall, Rapamycin passes the torch: A new generation of mTOR inhibitors. Nat. Rev. Drug Discov. 10, 868 (2011). doi: 10.1038/nrd3531; pmid: 22037041
4. E. J. Brown et al., A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756 (1994). doi: 10.1038/369756a0; pmid: 8008069
5. D. M. Sabatini, H. Erdjument-Bromage, M. Lui, P. Tempst, S. H. Snyder, RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35 (1994). doi: 10.1016/0092-8674(94) 90570-3; pmid: 7518356
6. C. J. Sabers et al., Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J. Biol. Chem. 270, 815 (1995). doi: 10.1074/jbc.270.2.815; pmid: 7822316
7. J. W. Choi, J. Chen, S. L. Schreiber, J. Clardy, Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 273, 239 (1996). doi: 10.1126/science.273.5272.239; pmid: 8662507
8. E. J. Brown et al., Control of p70 S6 kinase by kinase activity of FRAP in vivo. Nature 378, 644 (1995). doi: 10.1038/378644c0
9. G. J. Brunn et al., Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277, 99 (1997).
10. P. E. Burnett, R. K. Barrow, N. A. Cohen, S. H. Snyder, D. M. Sabatini, RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc. Natl. Acad. Sci. U.S.A. 95, 1432 (1998). doi: 10.1073/pnas.95.4.1432; pmid: 9465032
11. Z. H. Tao, J. Barker, S. D. H. Shi, M. Gehring, S. X. Sun, Steady-state kinetic and inhibition studies of the mammalian target of rapamycin (mTOR) kinase domain and mTOR complexes. Biochemistry 49, 8488 (2010). doi: 10.1021/bi100673c; pmid: 20804212
12. D. E. Harrison et al., Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392 (2009). pmid: 19587680
13. R. A. Miller et al., Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J. Gerontol. A Biol. Sci. Med. Sci. 66A, 191 (2011). doi: 10.1093/gerona/glq178; pmid: 20974732
14. I. Bjedov et al., Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35 (2010). doi: 10.1016/j.cmet.2009.11.010; pmid: 20074526
15. S. Robida-Stubbs et al., TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15, 713 (2012). doi: 10.1016/j.cmet.2012.04.007; pmid: 22560223
16. M. Kaeberlein et al., Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193 (2005). doi: 10.1126/science.1115535; pmid: 16293764
17. O. Medvedik, D. W. Lamming, K. D. Kim, D. A. Sinclair, MSN2 and MSN4 Link Calorie Restriction and TOR to Sirtuin-Mediated Lifespan Extension in Saccharomyces cerevisiae. PLoS Biol. 5, e261 (2007). doi: 10.1371/journal.pbio. 0050261
18. C. C. Thoreen et al., An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023 (2009). doi: 10.1074/jbc.M900301200; pmid: 19150980
19. M. E. Feldman et al., Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7, e38 (2009). doi: 10.1371/journal.pbio.1000038; pmid: 19209957
20. A. Y. Choo, S. O. Yoon, S. G. Kim, P. P. Roux, J. Blenis, Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc. Natl. Acad. Sci. U.S.A. 105, 17414 (2008). doi: 10.1073/pnas.0809136105; pmid: 18955708
21. S. A. Wander, B. T. Hennessy, J. M. Slingerland, Next-generation mTOR inhibitors in clinical oncology: How pathway complexity informs therapeutic strategy. J. Clin. Invest. 121, 1231 (2011). doi: 10.1172/JCI44145; pmid: 21490404
22. C. M. Chresta 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. 70, 288 (2010). doi: 10.1158/0008-5472.CAN-09-1751; pmid: 20028854
23. J. M. García-Martínez et al., Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem. J. 421, 29 (2009). doi: 10.1042/BJ20090489; pmid: 19402821
24. K. Yu et al., Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res. 69, 6232 (2009). doi: 10.1158/0008-5472.CAN-09-0299; pmid: 19584280
25. Q. S. Liu et al., Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3- (trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer. J. Med. Chem. 53, 7146 (2010). doi: 10.1021/jm101144f; pmid: 20860370
26. P. P. Hsu et al., The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332, 1317 (2011).
27. Y. H. Yu et al., Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332, 1322 (2011). doi: 10.1126/science.1199484; pmid: 21659605
28. D. H. Kim et al., mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163 (2002). doi: 10.1016/S0092-8674(02)00808-5; pmid: 12150925
29. C. K. Yip, K. Murata, T. Walz, D. M. Sabatini, S. A. Kang, Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol. Cell 38, 768 (2010). doi: 10.1016/j.molcel.2010.05.017; pmid: 20542007
30. K. Hara et al., Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177 (2002). doi: 10.1016/S0092-8674(02)00833-4; pmid: 12150926
31. T. R. Peterson et al., mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146, 408 (2011). doi: 10.1016/j.cell.2011.06. 034; pmid: 21816276
32. M. Pende et al., S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol. Cell. Biol. 24, 3112 (2004). doi: 10.1128/MCB.24.8.3112-3124.2004; pmid: 15060135
33. P. Jenö, L. M. Ballou, I. Novak-Hofer, G. Thomas, Identification and characterization of a mitogen-activated S6 kinase. Proc. Natl. Acad. Sci. U.S.A. 85, 406 (1988). doi: 10.1073/pnas.85.2.406; pmid: 3257566
34. D. J. Price, R. A. Nemenoff, J. Avruch, Purification of a hepatic S6 kinase from cycloheximide-treated Rats. J. Biol. Chem. 264, 13825 (1989).pmid: 2760046
35. J. Chung, C. J. Kuo, G. R. Crabtree, J. Blenis, Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell 69, 1227 (1992). doi: 10.1016/0092-8674(92)90643-Q; pmid: 1377606
36. D. J. Price, J. R. Grove, V. Calvo, J. Avruch, B. E. Bierer, Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science 257, 973 (1992). doi: 10.1126/science.1380182; pmid: 1380182
37. C. C. Dibble, J. M. Asara, B. D. Manning, Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol. Cell. Biol. 29, 5657 (2009). doi: 10.1128/MCB.00735-09; pmid: 19720745
38. D. Boulbes et al., Rictor phosphorylation on the Thr-1135 site does not require mammalian target of rapamycin complex 2. Mol. Cancer Res. 8, 896 (2010). doi: 10.1158/1541-7786. MCR-09-0409; pmid: 20501647
39. J. Kim, M. Kundu, B. Viollet, K. L. Guan, AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132 (2011). doi: 10.1038/ncb2152; pmid: 21258367
40. C. H. Jung et al., ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20, 1992 (2009). doi: 10.1091/mbc.E08-12-1249; pmid: 19225151
41. N. Hosokawa et al., Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981 (2009). doi: 10.1091/mbc.E08-12-1248; pmid: 19211835
42. D. F. Egan et al., Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456 (2011). doi: 10.1126/science.1196371; pmid: 21205641
43. H. Cheong, T. Lindsten, J. M. Wu, C. Lu, C. B. Thompson, Ammonia-induced autophagy is independent of ULK1/ULK2 kinases. Proc. Natl. Acad. Sci. U.S.A. 108, 11121 (2011). doi: 10.1073/pnas.1107969108; pmid: 21690395
44. N. Mizushima, B. Levine, A. M. Cuervo, D. J. Klionsky, Autophagy fights disease through cellular self-digestion. Nature 451, 1069 (2008). doi: 10.1038/nature06639; pmid: 18305538
45. S. M. Ali, D. M. Sabatini, Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site. J. Biol. Chem. 280, 19445 (2005). doi: 10.1074/jbc.C500125200; pmid: 15809305
46. M. P. Stokes et al., Profiling of UV-induced ATM/ATR signaling pathways. Proc. Natl. Acad. Sci. U.S.A. 104, 19855 (2007). doi: 10.1073/pnas.0707579104; pmid: 18077418
47. J. Mok et al., Deciphering protein kinase specificity through large-scale analysis of yeast phosphorylation site motifs. Sci. Signal. 3, ra12 (2010).
48. J. E. Hutti et al., A rapid method for determining protein kinase phosphorylation specificity. Nat. Methods 1, 27 (2004). doi: 10.1038/nmeth708; pmid: 15782149
49. J. C. Obenauer, L. C. Cantley, M. B. Yaffe, Scansite 2.0: Proteome-wide prediction of cell signaling interactions using short sequence motifs. Nucleic Acids Res. 31, 3635 (2003). doi: 10.1093/nar/gkg584; pmid: 12824383