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TOR pp 245–257Cite as

Novel Regulatory Mechanisms of mTOR Signaling

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 279))

Abstract

As a master regulator of cellular processes ranging from cell growth and proliferation to differentiation, the mammalian target of rapamycin (mTOR) is critically involved in a complex signaling network. mTOR appears to govern an amino acid sensing pathway that integrates with a phosphatidylinositol 3-kinase-dependent mitogenic pathway to activate the downstream effectors. Recent findings have revealed some unexpected regulatory mechanisms of mTOR signaling. A direct link between mTOR and mitogenic signals is found to be mediated by the lipid second messenger phosphatidic acid. In addition, cytoplasmic-nuclear shuttling of mTOR appears to be required for the cytoplasmic functions of this protein. A new picture of the rapamycin-sensitive signaling network is emerging, with implications in putative upstream regulators and additional downstream targets for mTOR.

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References

  • Alessi, DR, Kozlowski, MT, Weng, QP, Morrice, N, and Avruch, J (1998) 3-Phospho-inositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro. Curr Biol 8:69–81

    Article  PubMed  CAS  Google Scholar 

  • Brenneisen, P, Wenk, J, Wlaschek, M, Krieg, T, and Scharffetter-Kochanek, K (2000) Activation of p70 ribosomal protein S6 kinase is an essential step in the DNA damage-dependent signaling pathway responsible for the ultraviolet B-mediated increase in interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3) protein levels in human dermal fibroblasts. J Biol Chem 275:4336–4344

    Article  PubMed  CAS  Google Scholar 

  • Brown, EJ, Beal, PA, Keith, CT, Chen, J, Shin, TB, and Schreiber, SL (1995) Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature 377:441–446

    Article  PubMed  CAS  Google Scholar 

  • Brown, EJ, Albers, MW, Shin, TB, Ichikawa, K, Keith, CT, Lane, WS, and Schreiber, SL (1994) A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369:756–758

    Article  PubMed  CAS  Google Scholar 

  • Brunn, GJ, Hudson, CC, Sekulic, A, Williams, JM, Hosoi, H, Houghton, PJ, Lawrence, JC, Jr., and Abraham, RT (1997) Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277:99–101

    Article  PubMed  CAS  Google Scholar 

  • Buckland, AG and Wilton, DC (2000) Anionic phospholipids, interfacial binding and the regulation of cell functions. Biochim Biophys Acta 1483:199–216

    Article  PubMed  CAS  Google Scholar 

  • Castedo, M, Ferri, KF, Blanco, J, Roumier, T, Larochette, N, Barretina, J, Amendola, A, Nardacci, R, Metivier, D, Este, JA, Piacentini, M, and Kroemer, G (2001) Human immunodeficiency virus 1 envelope glycoprotein complex-induced apoptosis involves mammalian target of rapamycin/FKBP12-rapamycin-associated protein-mediated p53 phosphorylation. J Exp Med 194:1097–1110

    Article  PubMed  CAS  Google Scholar 

  • Chen, J, Zheng, XF, Brown, EJ, and Schreiber, SL (1995) Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-as-sociated protein and characterization of a critical serine residue. Proc Natl Acad Sci US A 92:4947–4951

    Article  CAS  Google Scholar 

  • Chiu, MI, Katz, H, and Berlin, V (1994) RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci USA 91:12574–12578

    Article  PubMed  CAS  Google Scholar 

  • Choi, J, Chen, J, Schreiber, SL, and Clardy, J (1996) Structure of the FKBP12-ra-pamycin complex interacting with the binding domain of human FRAP. Science 273:239–242

    Article  PubMed  CAS  Google Scholar 

  • Chou, MM and Blenis, J (1996) The 70 kDa S6 kinase complexes with and is activated by the Rho family G proteins Cdc42 and Racl. Cell 85:573–583

    Article  PubMed  CAS  Google Scholar 

  • Du, G, Altshuller, YM, Kim, Y, Han, JM, Ryu, SH, Morris, AJ, and Frohman, MA (2000) Dual requirement for rho and protein kinase C in direct activation of phospholipase DI through G protein-coupled receptor signaling. Mol Biol Cell 11:4359–4368

    PubMed  CAS  Google Scholar 

  • English, D, Cui, Y, and Siddiqui, RA (1996) Messenger functions of phosphatidic acid. Chem Phys Lipids 80:117–132

    Article  PubMed  CAS  Google Scholar 

  • Exton, JH (1999) Regulation of phospholipase D. Biochim Biophys Acta 1439:121–133

    Article  PubMed  CAS  Google Scholar 

  • Fang, Y, Vilella-Bach, M, Bachmann, R, Flanigan, A, and Chen, J (2001) Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 294:1942–1945

    Article  PubMed  CAS  Google Scholar 

  • Frohman, MA, Sung, TC, and Morris, AJ (1999) Mammalian phospholipase D structure and regulation. Biochim Biophys Acta 1439:175–186

    Article  PubMed  CAS  Google Scholar 

  • Fumagalli, S and Thomas, G, S6 phosphorylation and signal transduction, in Translational control of gene expression, N. Sonenberg, J.W.B. Hershey, and M.B. Mathews, Editors. 2000, Cold Spring Harbor Lab Press: Cold Spring Harbor, p. 695–718

    Google Scholar 

  • Geng, D, Chura, J, and Roberts, MF (1998) Activation of phospholipase D by phosphatidic acid. Enhanced vesicle binding, phosphatidic acid-Ca2+ interaction, or an allosteric effect? J Biol Chem 273:12195–12202

    Article  PubMed  CAS  Google Scholar 

  • Gingras, AC, Raught, B, and Sonenberg, N (1999) eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68:913–963

    Article  PubMed  CAS  Google Scholar 

  • Gingras, AC, Raught, B, and Sonenberg, N (2001) Regulation of translation initiation by FRAP/mTOR. Genes Dev 15:807–826

    Article  PubMed  CAS  Google Scholar 

  • Graves, LM, He, Y, Lambert, J, Hunter, D, Li, X, and Earp, HS (1997) An intracellular calcium signal activates p70 but not p90 ribosomal S6 kinase in liver epithelial cells. J Biol Chem 272:1920–1928

    Article  PubMed  CAS  Google Scholar 

  • Hara, K, Yonezawa, K, Weng, Q-P, Kozlowski, MT, Belham, C, and 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

    Article  PubMed  CAS  Google Scholar 

  • Houle, MG and Bourgoin, S (1999) Regulation of phospholipase D by phosphorylation-dependent mechanisms. Biochim Biophys Acta 1439:135–149

    Article  PubMed  CAS  Google Scholar 

  • Iiboshi, Y, Papst, PJ, Kawasome, H, Hosoi, H, Abraham, RT, Houghton, PJ, and Terada, N (1999) Amino acid-dependent control of p70(s6 k). Involvement of tRNA aminoacylation in the regulation. J Biol Chem 274:1092–1099

    Article  PubMed  CAS  Google Scholar 

  • Keith, CT and Schreiber, SL (1995) PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints. Science 270:50–51

    Article  PubMed  CAS  Google Scholar 

  • Kim, JE and Chen, J (2000) Cytoplasmic-nuclear shuttling of FKBP12-rapamycin-as-sociated protein is involved in rapamycin-sensitive signaling and translation initiation. Proc Natl Acad Sci U S A 97:14340–14345

    Article  PubMed  CAS  Google Scholar 

  • Kunz, J, Schneider, U, Howald, I, Schmidt, A, and Hall, MN (2000) HEAT repeats mediate plasma membrane localization of Tor2p in yeast. J Biol Chem 275:37011–37020

    Article  PubMed  CAS  Google Scholar 

  • Leung, DW (2001) The structure and functions of human lysophosphatidic acid acyl-transferases. Front Biosci 6: D944-953

    Article  PubMed  CAS  Google Scholar 

  • Nishi, K, Yoshida, M, Fujiwara, D, Nishikawa, M, Horinouchi, S, and Beppu, T (1994) Leptomycin B targets a regulatory cascade of crml, a fission yeast nuclear protein, involved in control of higher order chromosome structure and gene expression. J Biol Chem 269:6320–6324

    PubMed  CAS  Google Scholar 

  • Park, IH, Bachmann, R, Shirazi, H, and Chen, J (2002) Regulation of ribosomal S6 kinase 2 by mammalian target of rapamycin. J Biol Chem 277: 31423–31429

    Article  PubMed  CAS  Google Scholar 

  • Peterson, RT and Schreiber, SL (1998) Translation control: connecting mitogens and the ribosome. Curr Biol 8: R248-250

    Article  PubMed  CAS  Google Scholar 

  • Sabatini, DM, Erdjument-Bromage, H, Lui, M, Tempst, P, and Snyder, SH (1994) RAFT1: a mammalian protein that binds to FKBP 12 in a rapamycin- dependent fashion and is homologous to yeast TORs. Cell 78:35–43

    Article  PubMed  CAS  Google Scholar 

  • Sabatini, DM, Barrow, RK, Blackshaw, S, Burnett, PE, Lai, MM, Field, ME, Bahr, BA, Kirsch, J, Betz, H, and Snyder, SH (1999) Interaction of RAFT1 with gephyrin required for rapamycin-sensitive signaling. Science 284:1161–1164

    Article  PubMed  CAS  Google Scholar 

  • Sabers, CJ, Martin, MM, Brunn, GJ, Williams, JM, Dumont, FJ, Wiederrecht, G, and Abraham, RT (1995) Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 270:815–822

    Article  PubMed  CAS  Google Scholar 

  • Schmelzle, T and Hall, MN (2000) TOR, a central controller of cell growth. Cell 103:253–262

    Article  PubMed  CAS  Google Scholar 

  • Segrest, JP, Jones, MK, De Loof, H, Brouillette, CG, Venkatachalapathi, YV, and Anantharamaiah, GM (1992) The amphipathic helix in the exchangeable apolipoproteins: a review of secondary structure and function. J. Lipid Res. 33:141–166

    PubMed  CAS  Google Scholar 

  • Sung, TC, Roper, RL, Zhang, Y, Rudge, SA, Temel, R, Hammond, SM, Morris, AJ, Moss, B, Engebrecht, J, and Frohman, MA (1997) Mutagenesis of phospholipase D defines a superfamily including a trans-Golgi viral protein required for poxvirus pathogenicity. Embo J 16:4519–4530

    Article  PubMed  CAS  Google Scholar 

  • van Blitterswijk, WJ and Houssa, B (2000) Properties and functions of diacylglycerol kinases. Cell Signal 12:595–605

    Article  PubMed  Google Scholar 

  • Vilella-Bach, M, Nuzzi, P, Fang, Y, and Chen, J (1999) The FKBP12-rapamycin-bind-ing domain is required for FKBP12-rapamycin- associated protein kinase activity and Gl progression. J Biol Chem 274:4266–4272

    Article  PubMed  CAS  Google Scholar 

  • Willard, FS, Berven, LA, and Crouch, MF (2001) Lysophosphatidic acid activates the 70-kDa S6 kinase via the lipoxygenase pathway. Biochem Biophys Res Commun 287:607–613

    Article  PubMed  CAS  Google Scholar 

  • Withers, DJ, Ouwens, DM, Nave, BT, van der Zon, GC, Alarcon, CM, Cardenas, ME, Heitman, J, Maassen, JA, and Shepherd, PR (1997) Expression, enzyme activity, and subcellular localization of mammalian target of rapamycin in insulin-responsive cells. Biochem Biophys Res Commun 241:704–709

    Article  PubMed  CAS  Google Scholar 

  • Xu, G, Kwon, G, Marshall, CA, Lin, TA, Lawrence, JC, Jr., and McDaniel, ML (1998) Branched-chain amino acids are essential in the regulation of PHAS-I and p70 S6 kinase by pancreatic beta-cells. A possible role in protein translation and mitogenic signaling. J Biol Chem 273:28178–28184

    Article  PubMed  CAS  Google Scholar 

  • Yang, SF, Freer, S, and Benson, AA (1967) Transphosphatidylation by phospholipase D. J Biol Chem 242:477–484

    PubMed  CAS  Google Scholar 

  • Zhang, Y, Altshuller, YM, Hammond, SM, Hayes, F, Morris, AJ, and Frohman, MA (1999) Loss of receptor regulation by a phospholipase DI mutant unresponsive to protein kinase C. Embo J 18:6339–6348

    Article  PubMed  CAS  Google Scholar 

  • Zhang, Y, Dong, Z, Nomura, M, Zhong, S, Chen, N, and Bode, AM (2001) Signal transduction pathways involved in phosphorylation and activation of p70S6 K following exposure to UVA irradiation. J Biol Chem 276:20913–20923

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, 601 S. Goodwin Ave. B107, Urbana, IL, 61801, USA

    J. Chen

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  1. J. Chen
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Editors and Affiliations

  1. Friedrich-Miescher-Institute, Maulbeerstrasse 66, 4058, Basel, Switzerland

    George Thomas

  2. Whitehead Institute, 9 Cambridge Center, Cambridge, MA, 02142, USA

    David M. Sabatini MD, PhD

  3. Biozentrum, University of Basel, Klingelbergstrasse 70, 4056, Basel, Switzerland

    Michael N. Hall

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© 2004 Springer-Verlag Berlin Heidelberg

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Chen, J. (2004). Novel Regulatory Mechanisms of mTOR Signaling. In: Thomas, G., Sabatini, D.M., Hall, M.N. (eds) TOR. Current Topics in Microbiology and Immunology, vol 279. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18930-2_14

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  • DOI: https://doi.org/10.1007/978-3-642-18930-2_14

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-62360-8

  • Online ISBN: 978-3-642-18930-2

  • eBook Packages: Springer Book Archive

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