La-related protein 1 (LARP1) represses terminal oligopyrimidine (TOP) mRNA translation downstream of mTOR complex 1 (mTORC1)

Journal of Biological Chemistry

Volumn 290, Issue 26, 2015, Pages 15996-16020

  Fonseca, Bruno D ^a   Zakaria, Chadi ^b   Jia, Jian Jun ^a   Graber, Tyson E ^a,b   Svitkin, Yuri ^b   Tahmasebi, Soroush ^b   Healy, Danielle ^a   Hoang, Huy Dung ^a   Jensen, Jacob M ^c   Diao, Ilo T ^c   Lussier, Alexandre ^b   Dajadian, Christopher ^b   Padmanabhan, Niranjan ^b   Wang, Walter ^b   Matta Camacho, Edna ^b   Hearnden, Jaclyn ^b   Smith, Ewan M ^d   Tsukumo, Yoshinori ^b   Yanagiya, Akiko ^b   Morita, Masahiro ^b   Petroulakis, Emmanuel ^b,e   González, Jose L ^f   Hernández, Greco ^f   Alain, Tommy ^a   Damgaard, Christian K ^c   more..

^a CHILDREN S HOSPITAL OF EASTERN ONTARIO   (Canada)

^b MCGILL UNIVERSITY   (Canada)

^c AARHUS UNIVERSITY   (Denmark)

^d MRC TOXICOLOGY UNIT   (United Kingdom)

^e PFIZER INC   (United States)

^f INSTITUTO NACIONAL DE CANCEROLOGÍA   (Mexico)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTICS; BIOSYNTHESIS; DRUG THERAPY; MAMMALS; PROTEINS;

DRUG RESISTANCE; EUKARYOTIC INITIATION FACTOR; INHIBITORY EFFECT; MAMMALIAN TARGET; OLIGOPYRIMIDINE; PROTEIN SYNTHESIS; RIBOSOMAL PROTEINS; RNA INTERFERENCE;

NUCLEIC ACIDS;

INITIATION FACTOR 4G; LA RELATED PROTEIN 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MEMBRANE PROTEIN; REGULATORY ASSOCIATED PROTEIN MAMMALIAN TARGET OF RAPAMYCIN; SCAFFOLD PROTEIN; TERMINAL OLIGOPYRIMIDINE; UNCLASSIFIED DRUG; AUTOANTIGEN; INITIATION FACTOR 4E; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1; MESSENGER RNA; MULTIPROTEIN COMPLEX; PROTEIN BINDING; RIBONUCLEOPROTEIN; RPTOR PROTEIN, HUMAN; SIGNAL TRANSDUCING ADAPTOR PROTEIN; SS-B ANTIGEN; TARGET OF RAPAMYCIN KINASE; TOP PROTEIN, HUMAN;

ARTICLE; BINDING AFFINITY; CONTROLLED STUDY; ENZYME REPRESSION; EUKARYOTIC CELL; HUMAN; HUMAN CELL; MOLECULAR CLONING; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN FUNCTION; PROTEIN MOTIF; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; REGULATORY MECHANISM; RNA TRANSLATION; SIGNAL TRANSDUCTION; SITE DIRECTED MUTAGENESIS; CHEMISTRY; DOWN REGULATION; GENETICS; METABOLISM; PROTEIN SYNTHESIS;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; AUTOANTIGENS; DOWN-REGULATION; EUKARYOTIC INITIATION FACTOR-4E; HUMANS; MEMBRANE GLYCOPROTEINS; MULTIPROTEIN COMPLEXES; PROTEIN BINDING; PROTEIN BIOSYNTHESIS; RIBONUCLEOPROTEINS; RNA, MESSENGER; TOR SERINE-THREONINE KINASES;

EID: 84941313390     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M114.621730     Document Type: Article

References (100)

1. Laplante, M., and Sabatini, D. M. (2009) mTOR signaling at a glance. J. Cell Sci. 122, 3589-3594
2. Kim, D. H., Sarbassov, D. D., Ali, S. M., King, J. E., Latek, R. R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D. M. (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163-175
3. Hara, K., Maruki, Y., Long, X., Yoshino, K., Oshiro, N., Hidayat, S., Tokunaga, C., Avruch, J., and Yonezawa, K. (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177-189
4. Loewith, R., Jacinto, E., Wullschleger, S., Lorberg, A., Crespo, J. L., Bonenfant, D., Oppliger, W., Jenoe, P., and Hall, M. N. (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457-468
5. Coffman, K., Yang, B., Lu, J., Tetlow, A. L., Pelliccio, E., Lu, S., Guo, D. C., Tang, C., Dong, M. Q., and Tamanoi, F. (2014) Characterization of the raptor/4E-BP1 interaction by chemical cross-linking coupled with mass spectrometry analysis. J. Biol. Chem. 289, 4723-4734
6. Kim, D. H., Sarbassov, D. D., Ali, S. M., Latek, R. R., Guntur, K. V., Erdjument-Bromage, H., Tempst, P., and Sabatini, D. M. (2003) GβL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell 11, 895-904
7. Vander Haar, E., Lee, S. I., Bandhakavi, S., Griffin, T. J., and Kim, D. H. (2007) Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol. 9, 316-323
8. Fonseca, B. D., Smith, E. M., Lee, V. H., MacKintosh, C., and Proud, C. G. (2007) PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex. J. Biol. Chem. 282, 24514-24524
9. Oshiro, N., Takahashi, R., Yoshino, K., Tanimura, K., Nakashima, A., Eguchi, S., Miyamoto, T., Hara, K., Takehana, K., Avruch, J., Kikkawa, U., and Yonezawa, K. (2007) The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J. Biol. Chem. 282, 20329-20339
10. Sancak, Y., Thoreen, C. C., Peterson, T. R., Lindquist, R. A., Kang, S. A., Spooner, E., Carr, S. A., and Sabatini, D. M. (2007) PRAS40 is an insulinregulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25, 903-915
11. Thedieck, K., Polak, P., Kim, M. L., Molle, K. D., Cohen, A., Jenö, P., Arrieumerlou, C., and Hall, M. N. (2007) PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS One 2, e1217
12. Wang, L., Harris, T. E., Roth, R. A., and Lawrence, J. C., Jr. (2007) PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J. Biol. Chem. 282, 20036-20044
13. Peterson, T. R., Laplante, M., Thoreen, C. C., Sancak, Y., Kang, S. A., Kuehl, W. M., Gray, N. S., and Sabatini, D. M. (2009) DEPTOR is an mTORinhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137, 873-886
14. Sarbassov, D. D., Ali, S. M., Kim, D. H., Guertin, D. A., Latek, R. R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D. M. (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296-1302
15. Frias, M. A., Thoreen, C. C., Jaffe, J. D., Schroder, W., Sculley, T., Carr, S. A., and Sabatini, D. M. (2006) mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr. Biol. 16, 1865-1870
16. Jacinto, E., Facchinetti, V., Liu, D., Soto, N., Wei, S., Jung, S. Y., Huang, Q., Qin, J., and Su, B. (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127, 125-137
17. Woo, S. Y., Kim, D. H., Jun, C. B., Kim, Y. M., Haar, E. V., Lee, S. I., Hegg, J. W., Bandhakavi, S., Griffin, T. J., and Kim, D. H. (2007) PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor β expression and signaling. J. Biol. Chem. 282, 25604-25612
18. Pearce, L. R., Huang, X., Boudeau, J., Pawłowski, R., Wullschleger, S., Deak, M., Ibrahim, A. F., Gourlay, R., Magnuson, M. A., and Alessi, D. R. (2007) Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem. J. 405, 513-522
19. Sarbassov, D. D., Ali, S. M., Sengupta, S., Sheen, J. H., Hsu, P. P., Bagley, A. F., Markhard, A. L., and Sabatini, D. M. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159-168
20. Choo, A. Y., Yoon, S. O., Kim, S. G., Roux, P. P., and Blenis, J. (2008) Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-typespecific repression of mRNA translation. Proc. Natl. Acad. Sci. U. S. A. 105, 17414-17419
21. Thoreen, C. C., Kang, S. A., Chang, J. W., Liu, Q., Zhang, J., Gao, Y., Reichling, L. J., Sim, T., Sabatini, D. M., and Gray, N. S. (2009) An ATPcompetitive mammalian target of rapamycin inhibitor reveals rapamycinresistant functions of mTORC1. J. Biol. Chem. 284, 8023-8032
22. Fonseca, B. D., Smith, E. M., Yelle, N., Alain, T., Bushell, M., and Pause, A. (2014) The ever-evolving role of mTOR in translation. Semin. Cell Dev. Biol. 36, 102-112
23. Aitken, C. E., and Lorsch, J. R. (2012) A mechanistic overview of translation initiation in eukaryotes. Nat. Struct. Mol. Biol. 19, 568-576
24. Gingras, A. C., Raught, B., Gygi, S. P., Niedzwiecka, A., Miron, M., Burley, S. K., Polakiewicz, R. D., Wyslouch-Cieszynska, A., Aebersold, R., and Sonenberg, N. (2001) Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev. 15, 2852-2864
25. Raught, B., Peiretti, F., Gingras, A. C., Livingstone, M., Shahbazian, D., Mayeur, G. L., Polakiewicz, R. D., Sonenberg, N., and Hershey, J. W. (2004) Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J. 23, 1761-1769
26. Holz, M. K., Ballif, B. A., Gygi, S. P., and Blenis, J. (2005) mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123, 569-580
27. Shahbazian, D., Roux, P. P., Mieulet, V., Cohen, M. S., Raught, B., Taunton, J., Hershey, J. W., Blenis, J., Pende, M., and Sonenberg, N. (2006) The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. EMBO J. 25, 2781-2791
28. Van Gorp, A. G., Van Der Vos, K. E., Brenkman, A. B., Bremer, A., Van Den Broek, N., Zwartkruis, F., Hershey, J. W., Burgering, B. M., Calkhoven, C. F., and Coffer, P. J. (2009) AGC kinases regulate phosphorylation and activation of eukaryotic translation initiation factor 4B. Oncogene 28, 95-106
29. Dennis, M. D., Jefferson, L. S., and Kimball, S. R. (2012) Role of p70S6K1-mediated phosphorylation of eIF4B and PDCD4 proteins in the regulation of protein synthesis. J. Biol. Chem. 287, 42890-42899
30. Wang, X., Li, W., Williams, M., Terada, N., Alessi, D. R., and Proud, C. G. (2001) Regulation of elongation factor 2 kinase by p90 (RSK1) and p70 S6 kinase. EMBO J. 20, 4370-4379
31. Redpath, N. T., Foulstone, E. J., and Proud, C. G. (1996) Regulation of translation elongation factor-2 by insulin via a rapamycin-sensitive signalling pathway. EMBO J. 15, 2291-2297
32. Soulard, A., Cremonesi, A., Moes, S., Schütz, F., Jenö, P., and Hall, M. N. (2010) The rapamycin-sensitive phosphoproteome reveals that TOR controls protein kinase A toward some but not all substrates. Mol. Biol. Cell 21, 3475-3486
33. Demirkan, G., Yu, K., Boylan, J. M., Salomon, A. R., and Gruppuso, P. A. (2011) Phosphoproteomic profiling of in vivo signaling in liver by the mammalian target of rapamycin complex 1 (mTORC1). PLoS One 6, e21729
34. Yu, Y., Yoon, S. O., Poulogiannis, G., Yang, Q., Ma, X. M., Villén, J., Kubica, N., Hoffman, G. R., Cantley, L. C., Gygi, S. P., and Blenis, J. (2011) Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332, 1322-1326
35. Hsu, P. P., Kang, S. A., Rameseder, J., Zhang, Y., Ottina, K. A., Lim, D., Peterson, T. R., Choi, Y., Gray, N. S., Yaffe, M. B., Marto, J. A., and Sabatini, D. M. (2011) The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332, 1317-1322
36. Huber, A., Bodenmiller, B., Uotila, A., Stahl, M., Wanka, S., Gerrits, B., Aebersold, R., and Loewith, R. (2009) Characterization of the rapamycinsensitive phosphoproteome reveals that Sch9 is a central coordinator of protein synthesis. Genes Dev. 23, 1929-1943
37. Schultze, F. C., Petrova, D. T., Oellerich, M., Armstrong, V. W., and Asif, A. R. (2010) Differential proteome and phosphoproteome signatures in human T-lymphoblast cells induced by sirolimus. Cell Prolif. 43, 396-404
38. Meyuhas, O., and Dreazen, A. (2009) Ribosomal protein S6 kinase from TOP mRNAs to cell size. Prog. Mol. Biol. Transl. Sci. 90, 109-153
39. Tang, H., Hornstein, E., Stolovich, M., Levy, G., Livingstone, M., Templeton, D., Avruch, J., and Meyuhas, O. (2001) Amino acid-induced translation of TOP mRNAs is fully dependent on phosphatidylinositol 3-kinasemediated signaling, is partially inhibited by rapamycin, and is independent of S6K1 and rpS6 phosphorylation. Mol. Cell. Biol. 21, 8671-8683
40. Stolovich, M., Tang, H., Hornstein, E., Levy, G., Cohen, R., Bae, S. S., Birnbaum, M. J., and Meyuhas, O. (2002) Transduction of growth or mitogenic signals into translational activation of TOP mRNAs is fully reliant on the phosphatidylinositol 3-kinase-mediated pathway but requires neither S6K1 nor rpS6 phosphorylation. Mol. Cell. Biol. 22, 8101-8113
41. Patursky-Polischuk, I., Stolovich-Rain, M., Hausner-Hanochi, M., Kasir, J., Cybulski, N., Avruch, J., Rüegg, M. A., Hall, M. N., and Meyuhas, O. (2009) The TSC-mTOR pathway mediates translational activation of TOP mRNAs by insulin largely in a raptor- or rictor-independent manner. Mol. Cell. Biol. 29, 640-649
42. Meyuhas, O., and Kahan, T. (2014) The race to decipher the top secrets of TOP mRNAs. Biochim. Biophys. Acta 10.1016/j.bbagrm.2014.08.015
43. Thoreen, C. C., Chantranupong, L., Keys, H. R., Wang, T., Gray, N. S., and Sabatini, D. M. (2012) A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109-113
44. Hsieh, A. C., Liu, Y., Edlind, M. P., Ingolia, N. T., Janes, M. R., Sher, A., Shi, E. Y., Stumpf, C. R., Christensen, C., Bonham, M. J., Wang, S., Ren, P., Martin, M., Jessen, K., Feldman, M. E., et al. (2012) The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55-61
45. Miloslavski, R., Cohen, E., Avraham, A., Iluz, Y., Hayouka, Z., Kasir, J., Mudhasani, R., Jones, S. N., Cybulski, N., Rüegg, M. A., Larsson, O., Gandin, V., Rajakumar, A., Topisirovic, I., and Meyuhas, O. (2014) Oxygen sufficiency controls TOP mRNA translation via the TSC-RhebmTOR pathway in a 4E-BP-independent manner. J. Mol. Cell Biol. 6, 255-266
46. Pellizzoni, L., Cardinali, B., Lin-Marq, N., Mercanti, D., and Pierandrei-Amaldi, P. (1996) A Xenopus laevis homologue of the La autoantigen binds the pyrimidine tract of the 5' UTR of ribosomal protein mRNAs in vitro: implication of a protein factor in complex formation. J Mol. Biol. 259, 904-915
47. Pellizzoni, L., Lotti, F., Maras, B., and Pierandrei-Amaldi, P. (1997) Cellular nucleic acid binding protein binds a conserved region of the 5' UTR of Xenopus laevis ribosomal protein mRNAs. J. Mol. Biol. 267, 264-275
48. Crosio, C., Boyl, P. P., Loreni, F., Pierandrei-Amaldi, P., and Amaldi, F. (2000) La protein has a positive effect on the translation of TOP mRNAs in vivo. Nucleic Acids Res. 28, 2927-2934
49. Cardinali, B., Carissimi, C., Gravina, P., and Pierandrei-Amaldi, P. (2003) La protein is associated with terminal oligopyrimidine mRNAs in actively translating polysomes. J. Biol. Chem. 278, 35145-35151
50. Intine, R. V., Tenenbaum, S. A., Sakulich, A. L., Keene, J. D., and Maraia, R. J. (2003) Differential phosphorylation and subcellular localization of La RNPs associated with precursor tRNAs and translation-related mRNAs. Mol. Cell 12, 1301-1307
51. Damgaard, C. K., and Lykke-Andersen, J. (2011) Translational coregulation of 5' TOP mRNAs by TIA-1 and TIAR. Genes Dev. 25, 2057-2068
52. Aoki, K., Adachi, S., Homoto, M., Kusano, H., Koike, K., and Natsume, T. (2013) LARP1 specifically recognizes the 3' terminus of poly (A) mRNA. FEBS Lett. 587, 2173-2178
53. Tcherkezian, J., Cargnello, M., Romeo, Y., Huttlin, E. L., Lavoie, G., Gygi, S. P., and Roux, P. P. (2014) Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5' TOP mRNA translation. Genes Dev. 28, 357-371
54. Deragon, J. M., and Bousquet-Antonelli, C. (2015) The role of LARP1 in translation and beyond. Wiley Interdiscip. Rev. RNA, 10.1002/wrna.1282
55. Mura, M., Hopkins, T. G., Michael, T., Abd-Latip, N., Weir, J., Aboagye, E., Mauri, F., Jameson, C., Sturge, J., Gabra, H., Bushell, M., Willis, A. E., Curry, E., and Blagden, S. P. (2014) LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression. Oncogene 10.1038/onc.2014.428
56. Kang, S. A., Pacold, M. E., Cervantes, C. L., Lim, D., Lou, H. J., Ottina, K., Gray, N. S., Turk, B. E., Yaffe, M. B., and Sabatini, D. M. (2013) mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science 341, 1236566
57. Rapley, J., Oshiro, N., Ortiz-Vega, S., and Avruch, J. (2011) The mechanism of insulin-stimulated 4E-BP protein binding to mammalian target of rapamycin (mTOR) complex 1 and its contribution tomTORcomplex 1 signaling. J. Biol. Chem. 286, 38043-38053
58. Blagden, S. P., Gatt, M. K., Archambault, V., Lada, K., Ichihara, K., Lilley, K. S., Inoue, Y. H., and Glover, D. M. (2009) Drosophila Larp associates with poly (A)-binding protein and is required for male fertility and syncytial embryo development. Dev. Biol. 334, 186-197
59. Burrows, C., Abd Latip, N., Lam, S. J., Carpenter, L., Sawicka, K., Tzolovsky, G., Gabra, H., Bushell, M., Glover, D. M., Willis, A. E., and Blagden, S. P. (2010) The RNA binding protein Larp1 regulates cell division, apoptosis and cell migration. Nucleic Acids Res. 38, 5542-5553
60. Buchan, J. R., and Parker, R. (2009) Eukaryotic stress granules: the ins and outs of translation. Mol. Cell 36, 932-941
61. Anderson, P., and Kedersha, N. (2009) Stress granules. Curr. Biol. 19, R397-R398
62. Anderson, P., and Kedersha, N. (2009) RNA granules: post-transcriptional and epigenetic modulators of gene expression. Nat. Rev. Mol. Cell Biol. 10, 430-436
63. Ginalski, K., Zhang, H., and Grishin, N. V. (2004) Raptor protein contains a caspase-like domain. Trends Biochem. Sci. 29, 522-524
64. Schalm, S. S., and Blenis, J. (2002) Identification of a conserved motif required for mTOR signaling. Curr. Biol. 12, 632-639
65. Schalm, S. S., Fingar, D. C., Sabatini, D. M., and Blenis, J. (2003) TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr. Biol. 13, 797-806
66. Nojima, H., Tokunaga, C., Eguchi, S., Oshiro, N., Hidayat, S., Yoshino, K., Hara, K., Tanaka, N., Avruch, J., and Yonezawa, K. (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
67. Lee, V. H., Healy, T., Fonseca, B. D., Hayashi, A., and Proud, C. G. (2008) Analysis of the regulatory motifs in eukaryotic initiation factor 4E-binding protein 1. FEBS J. 275, 2185-2199
68. Xie, J., Kozlov, G., and Gehring, K. (2014) The "tale" of poly (A) binding protein: The MLLE domain and PAM2-containing proteins. Biochim. Biophys. Acta 1839, 1062-1068
69. Merret, R., Martino, L., Bousquet-Antonelli, C., Fneich, S., Descombin, J., Billey, E., Conte, M. R., and Deragon, J. M. (2013) The association of a La module with the PABP-interacting motif PAM2 is a recurrent evolutionary process that led to the neofunctionalization of La-related proteins. RNA 19, 36-50
70. Yang, R., Gaidamakov, S. A., Xie, J., Lee, J., Martino, L., Kozlov, G., Crawford, A. K., Russo, A. N., Conte, M. R., Gehring, K., and Maraia, R. J. (2011) La-related protein 4 binds poly (A), interacts with the poly (A) - binding protein MLLE domain via a variant PAM2w motif, and can promote mRNA stability. Mol. Cell. Biol. 31, 542-556
71. Chantranupong, L., Wolfson, R. L., and Sabatini, D. M. (2015) Nutrientsensing mechanisms across evolution. Cell 161, 67-83
72. Efeyan, A., Comb, W. C., and Sabatini, D. M. (2015) Nutrient-sensing mechanisms and pathways. Nature 517, 302-310
73. Nolan, R. D., and Arnstein, H. R. (1969) The dissociation of rabbit reticulocyte ribosomes with EDTA and the location of messenger ribonucleic acid. Eur. J. Biochem. 9, 445-450
74. Levy, S., Avni, D., Hariharan, N., Perry, R. P., and Meyuhas, O. (1991) Oligopyrimidine tract at the 5' end of mammalian ribosomal protein mRNAs is required for their translational control. Proc. Natl. Acad. Sci. U. S. A. 88, 3319-3323
75. Jefferies, H. B., Reinhard, C., Kozma, S. C., and Thomas, G. (1994) Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family. Proc. Natl. Acad. Sci. U. S. A. 91, 4441-4445
76. Terada, N., Patel, H. R., Takase, K., Kohno, K., Nairn, A. C., and Gelfand, E. W. (1994) Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins. Proc. Natl. Acad. Sci. U. S. A. 91, 11477-11481
77. Patursky-Polischuk, I., Kasir, J., Miloslavski, R., Hayouka, Z., Hausner-Hanochi, M., Stolovich-Rain, M., Tsukerman, P., Biton, M., Mudhasani, R., Jones, S. N., and Meyuhas, O. (2014) Reassessment of the role of TSC, mTORC1 and microRNAs in amino acids-meditated translational control of TOP mRNAs. PloS one 9, e109410
78. Schwartz, E. I., Intine, R. V., and Maraia, R. J. (2004) CK2 is responsible for phosphorylation of human La protein serine-366 and can modulate rpL37 5'-terminal oligopyrimidine mRNA metabolism. Mol. Cell. Biol. 24, 9580-9591
79. Kakegawa, T., Ohuchi, N., Hayakawa, A., Hirata, S., Matsuda, M., Kogure, K., Kobayashi, H., Inoue, A., and Kaspar, R. L. (2007) Identification of AUF1 as a rapamycin-responsive binding protein to the 5'-terminal oligopyrimidine element of mRNAs. Arch. Biochem. Biophys. 465, 274-281
80. Biberman, Y., and Meyuhas, O. (1997) Substitution of just five nucleotides at and around the transcription start site of rat β-actin promoter is sufficient to render the resulting transcript a subject for translational control. FEBS Lett. 405, 333-336
81. Biberman, Y., and Meyuhas, O. (1999) TOP mRNAs are translationally inhibited by a titratable repressor in both wheat germ extract and reticulocyte lysate. FEBS Lett. 456, 357-360
82. Topisirovic, I., Svitkin, Y. V., Sonenberg, N., and Shatkin, A. J. (2011) Cap and cap-binding proteins in the control of gene expression. Wiley Interdiscip. Rev. RNA 2, 277-298
83. Meyuhas, O. (2000) Synthesis of the translational apparatus is regulated at the translational level. Eur. J. Biochem. 267, 6321-6330
84. Hornstein, E., Git, A., Braunstein, I., Avni, D., and Meyuhas, O. (1999) The expression of poly (A)-binding protein gene is translationally regulated in a growth-dependent fashion through a 5'-terminal oligopyrimidine tract motif. J. Biol. Chem. 274, 1708-1714
85. Hornstein, E., Harel, H., Levy, G., and Meyuhas, O. (1999) Overexpression of poly (A)-binding protein down-regulates the translation or the abundance of its own mRNA. FEBS Lett. 457, 209-213
86. Wedaman, K. P., Reinke, A., Anderson, S., Yates, J., 3rd, McCaffery, J. M., and Powers, T. (2003) Tor kinases are in distinct membrane-associated protein complexes in Saccharomyces cerevisiae. Mol. Biol. Cell 14, 1204-1220
87. Bertram, P. G., Zeng, C., Thorson, J., Shaw, A. S., and Zheng, X. F. (1998) The 14-3-3 proteins positively regulate rapamycin-sensitive signaling. Curr. Biol. 8, 1259-1267
88. Mori, H., Inoue, M., Yano, M., Wakabayashi, H., and Kido, H. (2000) 14-3-3 associates with a translational control factor FKBP12-rapamycinassociated protein in T-cells after stimulation by pervanadate. FEBS Lett. 467, 61-64
89. Fonseca, B. D., Lee, V. H., and Proud, C. G. (2008) The binding of PRAS40 to 14-3-3 proteins is not required for activation ofmTORC1signalling by phorbol esters/ERK. Biochem. J. 411, 141-149
90. Wang, L., Harris, T. E., and Lawrence, J. C., Jr. (2008) Regulation of proline-rich Akt substrate of 40 kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation. J. Biol. Chem. 283, 15619-15627
91. Ben-Sahra, I., Howell, J. J., Asara, J. M., and Manning, B. D. (2013) Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339, 1323-1328
92. Robitaille, A. M., Christen, S., Shimobayashi, M., Cornu, M., Fava, L. L., Moes, S., Prescianotto-Baschong, C., Sauer, U., Jenoe, P., and Hall, M. N. (2013) Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339, 1320-1323
93. Jung, C. H., Jun, C. B., Ro, S. H., Kim, Y. M., Otto, N. M., Cao, J., Kundu, M., and Kim, D. H. (2009) ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20, 1992-2003
94. Hosokawa, N., Hara, T., Kaizuka, T., Kishi, C., Takamura, A., Miura, Y., Iemura, S., Natsume, T., Takehana, K., Yamada, N., Guan, J. L., Oshiro, N., and Mizushima, N. (2009) Nutrient-dependentmTORC1association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981-1991
95. Ganley, I. G., Lam Du, H., Wang, J., Ding, X., Chen, S., and Jiang, X. (2009) ULK1. ATG13. FIP200 complex mediates mTOR signaling and is essential for autophagy. J. Biol. Chem. 284, 12297-12305
96. Chen, E. J., and Kaiser, C. A. (2003) LST8 negatively regulates amino acid biosynthesis as a component of the TOR pathway. J. Cell Biol. 161, 333-347
97. Kim, S. G., Hoffman, G. R., Poulogiannis, G., Buel, G. R., Jang, Y. J., Lee, K. W., Kim, B. Y., Erikson, R. L., Cantley, L. C., Choo, A. Y., and Blenis, J. (2013) Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex. Mol. Cell 49, 172-185
98. Gwinn, D. M., Shackelford, D. B., Egan, D. F., Mihaylova, M. M., Mery, A., Vasquez, D. S., Turk, B. E., and Shaw, R. J. (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214-226
99. Harthill, J. E., Pozuelo Rubio, M., Milne, F. C., and MacKintosh, C. (2002) Regulation of the 14-3-3-binding protein p39 by growth factors and nutrients in rat PC12 pheochromocytoma cells. Biochem. J. 368, 565-572
100. Nakashima, A., Kawanishi, I., Eguchi, S., Yu, E. H., Eguchi, S., Oshiro, N., Yoshino, K., Kikkawa, U., and Yonezawa, K. (2013) Association of CAD, a multifunctional protein involved in pyrimidine synthesis, with mLST8, a component of the mTOR complexes. J. Biomed. Sci. 20, 24