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Mammalian Target of Rapamycin: A Signaling Kinase for Every Aspect of Cellular Life

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mTOR

Part of the book series: Methods in Molecular Biology ((MIMB,volume 821))

Abstract

The mammalian (or mechanistic) target of rapamycin (mTOR) is an evolutionarily conserved serine-threonine kinase that is known to sense the environmental and cellular nutrition and energy status. Diverse mitogens, growth factors, and nutrients stimulate the activation of the two mTOR complexes mTORC1 and mTORC2 to regulate diverse functions, such as cell growth, proliferation, development, memory, longevity, angiogenesis, autophagy, and innate as well as adaptive immune responses. Dysregulation of the mTOR pathway is frequently observed in various cancers and in genetic disorders, such as tuberous sclerosis complex or cystic kidney disease. In this review, I will give an overview of the current understanding of mTOR signaling and its role in diverse tissues and cells. Genetic deletion of specific mTOR pathway proteins in distinct tissues and cells broadened our understanding of the cell-specific roles of mTORC1 and mTORC2. Inhibition of mTOR is an established therapeutic principle in transplantation medicine and in cancers, such as renal cell carcinoma. Pharmacological targeting of both mTOR complexes by novel drugs potentially expand the clinical applicability and efficacy of mTOR inhibition in various disease settings.

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References

  1. Yang, Q., and Guan, K. L. (2007) Expanding mTOR signaling. Cell Res 17, 666–81.

    Article  PubMed  CAS  Google Scholar 

  2. Abraham, R. T., and Wiederrecht, G. J. (1996) Immunopharmacology of rapamycin. Annu Rev Immunol 14, 483–510.

    Article  PubMed  CAS  Google Scholar 

  3. Zoncu, R., Efeyan, A., and Sabatini, D. M. (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12, 21–35.

    Article  PubMed  CAS  Google Scholar 

  4. Avruch, J., Long, X., Ortiz-Vega, S., Rapley, J., Papageorgiou, A., and Dai, N. (2009) Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab 296, E592–602.

    Article  PubMed  CAS  Google Scholar 

  5. Donahue, A. C., and Fruman, D. A. (2007) Distinct signaling mechanisms activate the target of rapamycin in response to different B-cell stimuli. Eur J Immunol 37, 2923–36.

    Article  PubMed  CAS  Google Scholar 

  6. Cao, W., Manicassamy, S., Tang, H., Kasturi, S. P., Pirani, A., Murthy, N., et al. (2008) Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nat Immunol 9, 1157–64.

    Article  PubMed  CAS  Google Scholar 

  7. Schmitz, F., Heit, A., Dreher, S., Eisenacher, K., Mages, J., Haas, T., et al. (2008) Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells. Eur J Immunol 38, 2981–92.

    Article  PubMed  CAS  Google Scholar 

  8. Weichhart, T., Costantino, G., Poglitsch, M., Rosner, M., Zeyda, M., Stuhlmeier, K. M., et al. (2008) The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 29, 565–77.

    Article  PubMed  CAS  Google Scholar 

  9. Fruman, D. A. (2004) Towards an understanding of isoform specificity in phosphoinositide 3-kinase signalling in lymphocytes. Biochem Soc Trans 32, 315–9.

    Article  PubMed  CAS  Google Scholar 

  10. Guertin, D. A., and Sabatini, D. M. (2005) An expanding role for mTOR in cancer. Trends Mol Med 11, 353–61.

    Article  PubMed  CAS  Google Scholar 

  11. Brazil, D. P., Yang, Z. Z., and Hemmings, B. A. (2004) Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem Sci 29, 233–42.

    Article  PubMed  CAS  Google Scholar 

  12. Deane, J. A., and Fruman, D. A. (2004) Phosphoinositide 3-kinase: diverse roles in immune cell activation. Annu Rev Immunol 22, 563–98.

    Article  PubMed  CAS  Google Scholar 

  13. Paul, E., and Thiele, E. (2008) Efficacy of sirolimus in treating tuberous sclerosis and lymphangioleiomyomatosis. N Engl J Med 358, 190–2.

    Article  PubMed  CAS  Google Scholar 

  14. Stocker, H., Radimerski, T., Schindelholz, B., Wittwer, F., Belawat, P., Daram, P., et al. (2003) Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 5, 559–65.

    Article  PubMed  CAS  Google Scholar 

  15. Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P., and Guan, K. L. (2008) Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10, 935–45.

    Article  PubMed  CAS  Google Scholar 

  16. Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A. L., Nada, S., and Sabatini, D. M. (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290–303.

    Article  PubMed  CAS  Google Scholar 

  17. Sancak, Y., Peterson, T. R., Shaul, Y. D., Lindquist, R. A., Thoreen, C. C., Bar-Peled, L., et al. (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–501.

    Article  PubMed  CAS  Google Scholar 

  18. Hay, N., and Sonenberg, N. (2004) Upstream and downstream of mTOR. Genes Dev 18, 1926–45.

    Article  PubMed  CAS  Google Scholar 

  19. Kim, D. H., and Sabatini, D. M. (2004) Raptor and mTOR: subunits of a nutrient-sensitive complex. Curr Top Microbiol Immunol 279, 259–70.

    Article  PubMed  CAS  Google Scholar 

  20. Oshiro, N., Yoshino, K., Hidayat, S., Tokunaga, C., Hara, K., Eguchi, S., et al. (2004) Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function. Genes Cells 9, 359–66.

    Article  PubMed  CAS  Google Scholar 

  21. Jacinto, E., Loewith, R., Schmidt, A., Lin, S., Ruegg, M. A., Hall, A., et al. (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6, 1122–8.

    Article  PubMed  CAS  Google Scholar 

  22. Zinzalla, V., Stracka, D., Oppliger, W., and Hall, M. N. (2011) Activation of mTORC2 by Association with the Ribosome. Cell 144, 757–68.

    Article  PubMed  CAS  Google Scholar 

  23. Oh, W. J., Wu, C. C., Kim, S. J., Facchinetti, V., Julien, L. A., Finlan, M., et al. (2010) mTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide. EMBO J 29, 3939–51.

    Article  PubMed  CAS  Google Scholar 

  24. Sarbassov, D. D., Guertin, D. A., Ali, S. M., and Sabatini, D. M. (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–101.

    Article  PubMed  CAS  Google Scholar 

  25. Huang, J., Dibble, C. C., Matsuzaki, M., and Manning, B. D. (2008) The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 28, 4104–15.

    Google Scholar 

  26. Sarbassov dos, D., Ali, S. M., Sengupta, S., Sheen, J. H., Hsu, P. P., Bagley, A. F., et al. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22, 159–68.

    Article  PubMed  CAS  Google Scholar 

  27. Rosner, M., Hanneder, M., Siegel, N., Valli, A., and Hengstschlager, M. (2008) The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners. Mutat Res 658, 234–46.

    Article  PubMed  CAS  Google Scholar 

  28. Rosner, M., and Hengstschlager, M. (2008) Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalisation of the mTORC2 components rictor and sin1. Hum Mol Genet 17, 2934–48.

    Google Scholar 

  29. Dowling, R. J., Topisirovic, I., Alain, T., Bidinosti, M., Fonseca, B. D., Petroulakis, E., et al. (2010) mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 328, 1172–6.

    Article  PubMed  CAS  Google Scholar 

  30. Morice, W. G., Brunn, G. J., Wiederrecht, G., Siekierka, J. J., and Abraham, R. T. (1993) Rapamycin-induced inhibition of p34cdc2 kinase activation is associated with G1/S-phase growth arrest in T lymphocytes. J Biol Chem 268, 3734–8.

    PubMed  CAS  Google Scholar 

  31. Nourse, J., Firpo, E., Flanagan, W. M., Coats, S., Polyak, K., Lee, M. H., et al. (1994) Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature 372, 570–3.

    Article  PubMed  CAS  Google Scholar 

  32. Hong, F., Larrea, M. D., Doughty, C., Kwiatkowski, D. J., Squillace, R., and Slingerland, J. M. (2008) mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. Mol Cell 30, 701–11.

    Article  PubMed  CAS  Google Scholar 

  33. Rosner, M., Freilinger, A., Hanneder, M., Fujita, N., Lubec, G., Tsuruo, T., et al. (2007) p27Kip1 localization depends on the tumor suppressor protein tuberin. Hum Mol Genet 16, 1541–56.

    Article  PubMed  CAS  Google Scholar 

  34. Noda, T., and Ohsumi, Y. (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273, 3963–6.

    Article  PubMed  CAS  Google Scholar 

  35. Jung, C. H., Jun, C. B., Ro, S. H., Kim, Y. M., Otto, N. M., Cao, J., et al. (2009) ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20, 1992–2003.

    Article  PubMed  CAS  Google Scholar 

  36. Gangloff, Y. G., Mueller, M., Dann, S. G., Svoboda, P., Sticker, M., Spetz, J. F., et al. (2004) Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol Cell Biol 24, 9508–16.

    Article  PubMed  CAS  Google Scholar 

  37. Shor, B., Cavender, D., and Harris, C. (2009) A kinase-dead knock-in mutation in mTOR leads to early embryonic lethality and is dispensable for the immune system in heterozygous mice. BMC Immunol 10, 28.

    Article  PubMed  Google Scholar 

  38. Goorden, S. M., Hoogeveen-Westerveld, M., Cheng, C., van Woerden, G. M., Mozaffari, M., Post, L., et al. (2011) Rheb is essential for murine development. Mol Cell Biol 31, 1672–8.

    Google Scholar 

  39. Zou, J., Zhou, L., Du, X. X., Ji, Y., Xu, J., Tian, J., et al. (2011) Rheb1 is required for mTORC1 and myelination in postnatal brain development. Dev Cell 20, 97–108.

    Article  PubMed  CAS  Google Scholar 

  40. Haidinger, M., Hecking, M., Weichhart, T., Poglitsch, M., Enkner, W., Vonbank, K., et al. (2010) Sirolimus in renal transplant recipients with tuberous sclerosis complex: clinical effectiveness and implications for innate immunity. Transpl Int 23, 777–85.

    Article  PubMed  CAS  Google Scholar 

  41. Nie, D., Di Nardo, A., Han, J. M., Baharanyi, H., Kramvis, I., Huynh, T., et al. (2010) Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nat Neurosci 13, 163–72.

    Article  PubMed  CAS  Google Scholar 

  42. Abe, N., Borson, S. H., Gambello, M. J., Wang, F., and Cavalli, V. (2010) Mammalian target of rapamycin (mTOR) activation increases axonal growth capacity of injured peripheral nerves. J Biol Chem 285, 28034–43.

    Article  PubMed  CAS  Google Scholar 

  43. Park, K. K., Liu, K., Hu, Y., Smith, P. D., Wang, C., Cai, B., et al. (2008) Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322, 963–6.

    Article  PubMed  CAS  Google Scholar 

  44. Li, D., Zhou, J., Wang, L., Shin, M. E., Su, P., Lei, X., et al. (2010) Integrated biochemical and mechanical signals regulate multifaceted human embryonic stem cell functions. J Cell Biol 191, 631–44.

    Article  PubMed  CAS  Google Scholar 

  45. Zhou, J., Su, P., Wang, L., Chen, J., Zimmermann, M., Genbacev, O., et al. (2009) mTOR supports long-term self-renewal and suppresses mesoderm and endoderm activities of human embryonic stem cells. Proc Natl Acad Sci USA 106, 7840–5.

    Article  PubMed  CAS  Google Scholar 

  46. Lee, K. W., Yook, J. Y., Son, M. Y., Kim, M. J., Koo, D. B., Han, Y. M., et al. (2010) Rapamycin promotes the osteoblastic differentiation of human embryonic stem cells by blocking the mTOR pathway and stimulating the BMP/Smad pathway. Stem Cells Dev 19, 557–68.

    Article  PubMed  CAS  Google Scholar 

  47. Siegel, N., Rosner, M., Unbekandt, M., Fuchs, C., Slabina, N., Dolznig, H., et al. (2010) Contribution of human amniotic fluid stem cells to renal tissue formation depends on mTOR. Hum Mol Genet 19, 3320–31.

    Article  PubMed  CAS  Google Scholar 

  48. Easley. C.A.t., Ben-Yehudah. A., Redinger. C.J., Oliver. S.L., Varum. S.T., Eisinger. V.M., et al., (2010). mTOR-mediated activation of p70 S6K induces differentiation of pluripotent human embryonic stem cells. Cell Reprogram. 12, 263–73.

    PubMed  CAS  Google Scholar 

  49. Yilmaz, O. H., Valdez, R., Theisen, B. K., Guo, W., Ferguson, D. O., Wu, H., et al. (2006) Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–82.

    Article  PubMed  CAS  Google Scholar 

  50. Hobbs, R. M., Seandel, M., Falciatori, I., Rafii, S., and Pandolfi, P. P. (2010) Plzf regulates germline progenitor self-renewal by opposing mTORC1. Cell 142, 468–79.

    Article  PubMed  CAS  Google Scholar 

  51. Leibowitz, G., Cerasi, E., and Ketzinel-Gilad, M. (2008) The role of mTOR in the adaptation and failure of beta-cells in type 2 diabetes. Diabetes Obes Metab 10 Suppl 4, 157–69.

    Article  PubMed  CAS  Google Scholar 

  52. Mori, H., Inoki, K., Opland, D., Muenzberg, H., Villanueva, E. C., Faouzi, M., et al. (2009) Critical roles for the TSC-mTOR pathway in {beta}-cell function. Am J Physiol Endocrinol Metab 297, 1013–22.

    Google Scholar 

  53. Janeway, C. A., Jr. (2001) How the immune system works to protect the host from infection: a personal view. Proc Natl Acad Sci USA 98, 7461–8.

    Article  PubMed  CAS  Google Scholar 

  54. Saemann, M. D., Haidinger, M., Hecking, M., Horl, W. H., and Weichhart, T. (2009) The multifunctional role of mTOR in innate immunity: implications for transplant immunity. Am J Transplant 9, 2655–61.

    Article  PubMed  CAS  Google Scholar 

  55. Weichhart, T., and Saemann, M. D. (2009) The multiple facets of mTOR in immunity. Trends Immunol 30, 218–26.

    Article  PubMed  CAS  Google Scholar 

  56. Yang, C. S., Song, C. H., Lee, J. S., Jung, S. B., Oh, J. H., Park, J., et al. (2006) Intracellular network of phosphatidylinositol 3-kinase, mammalian target of the rapamycin/70 kDa ribosomal S6 kinase 1, and mitogen-activated protein kinases pathways for regulating mycobacteria-induced IL-23 expression in human macrophages. Cell Microbiol 8, 1158–71.

    Article  PubMed  CAS  Google Scholar 

  57. Ohtani, M., Nagai, S., Kondo, S., Mizuno, S., Nakamura, K., Tanabe, M., et al. (2008) Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells. Blood 112, 635–43.

    Article  PubMed  CAS  Google Scholar 

  58. Brouard, S., Puig-Pey, I., Lozano, J. J., Pallier, A., Braud, C., Giral, M., et al. (2010) Comparative Transcriptional and Phenotypic Peripheral Blood Analysis of Kidney Recipients under Cyclosporin A or Sirolimus Monotherapy. Am J Transplant 10, 2604–14.

    Google Scholar 

  59. Haidinger, M., Poglitsch, M., Geyeregger, R., Kasturi, S., Zeyda, M., Zlabinger, G. J., et al. (2010) A versatile role of mammalian target of rapamycin in human dendritic cell function and differentiation. J Immunol 185, 3919–31.

    Article  PubMed  CAS  Google Scholar 

  60. Weichhart, T., Haidinger, M., Katholnig, M., Kopecky, C., Poglitsch, M., Lassnig, C., et al. (2011) Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells. Blood 117, 4273–83.

    Google Scholar 

  61. Yoshida, T., Mett, I., Bhunia, A. K., Bowman, J., Perez, M., Zhang, L., et al. (2010) Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke-induced pulmonary injury and emphysema. Nat Med 16, 767–73.

    Article  PubMed  CAS  Google Scholar 

  62. Jagannath, C., Lindsey, D. R., Dhandayuthapani, S., Xu, Y., Hunter, R. L., Jr., and Eissa, N. T. (2009) Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med 15, 267–76.

    Article  PubMed  CAS  Google Scholar 

  63. Colonna, M., Trinchieri, G., and Liu, Y. J. (2004) Plasmacytoid dendritic cells in immunity. Nat Immunol 5, 1219–26.

    Article  PubMed  CAS  Google Scholar 

  64. Kaur, S., Lal, L., Sassano, A., Majchrzak-Kita, B., Srikanth, M., Baker, D. P., et al. (2007) Regulatory effects of mammalian target of rapamycin-activated pathways in type I and II interferon signaling. J Biol Chem 282, 1757–68.

    Article  PubMed  CAS  Google Scholar 

  65. Colina, R., Costa-Mattioli, M., Dowling, R. J., Jaramillo, M., Tai, L. H., Breitbach, C. J., et al. (2008) Translational control of the innate immune response through IRF-7. Nature 452, 323–8.

    Article  PubMed  CAS  Google Scholar 

  66. Zhu, J., Yamane, H., and Paul, W. E. (2010) Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 28, 445–89.

    Article  PubMed  CAS  Google Scholar 

  67. Delgoffe, G. M., Kole, T. P., Zheng, Y., Zarek, P. E., Matthews, K. L., Xiao, B., et al. (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–44.

    Article  PubMed  CAS  Google Scholar 

  68. Battaglia, M., Stabilini, A., and Roncarolo, M. G. (2005) Rapamycin selectively expands CD4  +  CD25  +  FoxP3+ regulatory T cells. Blood 105, 4743–8.

    Article  PubMed  CAS  Google Scholar 

  69. Lee, K., Gudapati, P., Dragovic, S., Spencer, C., Joyce, S., Killeen, N., et al. (2010) Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32, 743–53.

    Google Scholar 

  70. Weichhart, T., and Saemann, M. D. (2010) T helper cell differentiation: understanding the needs of hierarchy. Immunity 32, 727–9.

    Article  PubMed  CAS  Google Scholar 

  71. Sinclair, L. V., Finlay, D., Feijoo, C., Cornish, G. H., Gray, A., Ager, A., et al. (2008) Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat Immunol 9, 513–21.

    Article  PubMed  CAS  Google Scholar 

  72. Araki, K., Turner, A. P., Shaffer, V. O., Gangappa, S., Keller, S. A., Bachmann, M. F., et al. (2009) mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–12.

    Article  PubMed  CAS  Google Scholar 

  73. Pearce, E. L., Walsh, M. C., Cejas, P. J., Harms, G. M., Shen, H., Wang, L. S., et al. (2009) Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–7.

    Article  PubMed  CAS  Google Scholar 

  74. Hands, S. L., Proud, C. G., and Wyttenbach, A. (2009) mTOR’s role in ageing: protein synthesis or autophagy? Aging (Albany NY) 1, 586–97.

    CAS  Google Scholar 

  75. Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., et al. (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–5.

    PubMed  CAS  Google Scholar 

  76. Colman, R. J., Anderson, R. M., Johnson, S. C., Kastman, E. K., Kosmatka, K. J., Beasley, T. M., et al. (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–4.

    Article  PubMed  CAS  Google Scholar 

  77. Selman, C., Tullet, J. M., Wieser, D., Irvine, E., Lingard, S. J., Choudhury, A. I., et al. (2009) Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–4.

    Article  PubMed  CAS  Google Scholar 

  78. Miller, J. L. (1999) Sirolimus approved with renal transplant indication. Am J Health Syst Pharm 56, 2177–8.

    Google Scholar 

  79. Moses, J. W., Leon, M. B., Popma, J. J., Fitzgerald, P. J., Holmes, D. R., O’Shaughnessy, C., et al. (2003) Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 349, 1315–23.

    Article  PubMed  CAS  Google Scholar 

  80. Faivre, S., Kroemer, G., and Raymond, E. (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5, 671–88.

    Article  PubMed  CAS  Google Scholar 

  81. Bissler, J. J., McCormack, F. X., Young, L. R., Elwing, J. M., Chuck, G., Leonard, J. M., et al. (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 358, 140–51.

    Article  PubMed  CAS  Google Scholar 

  82. Thoreen, C. C., Kang, S. A., Chang, J. W., Liu, Q., Zhang, J., Gao, Y., et al. (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284, 8023–32.

    Article  PubMed  CAS  Google Scholar 

  83. Thoreen, C. C., and Sabatini, D. M. (2009) Rapamycin inhibits mTORC1, but not completely. Autophagy 5, 725–6.

    Article  PubMed  CAS  Google Scholar 

  84. Yu, K., Shi, C., Toral-Barza, L., Lucas, J., Shor, B., Kim, J. E., et al. (2010) Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res 70, 621–31.

    Article  PubMed  CAS  Google Scholar 

  85. Yu, K., Toral-Barza, L., Shi, C., Zhang, W. G., Lucas, J., Shor, B., et al. (2009) Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 69, 6232–40.

    Article  PubMed  CAS  Google Scholar 

  86. Chresta, C. M., Davies, B. R., Hickson, I., Harding, T., Cosulich, S., Critchlow, S. E., et al. (2010) 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, 288–98.

    Article  PubMed  CAS  Google Scholar 

  87. Janes, M. R., and Fruman, D. A. (2010) Targeting TOR dependence in cancer. Oncotarget 1, 69–76.

    PubMed  Google Scholar 

  88. Janes, M. R., Limon, J. J., So, L., Chen, J., Lim, R. J., Chavez, M. A., et al. (2010) Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 16, 205–13.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

TW is supported by the Else-Kröner Fresenius Stiftung. I apologize to those authors whose primary work I did not reference directly in the text.

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Weichhart, T. (2012). Mammalian Target of Rapamycin: A Signaling Kinase for Every Aspect of Cellular Life. In: Weichhart, T. (eds) mTOR. Methods in Molecular Biology, vol 821. Humana Press. https://doi.org/10.1007/978-1-61779-430-8_1

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