Skip to main content
SpringerLink
Log in

Control of Translation by the Target of Rapamycin Proteins

  • Chapter
Signaling Pathways for Translation

Part of the book series: Progress in Molecular and Subcellular Biology ((PMSB,volume 27))

Abstract

Regulation of translation rates, the frequency with which a given mRNA is translated, plays an important role in the control of cell growth and differentiation. Translational control is exerted in most instances at the initiation phase, a rate-limiting step during which the ribosome is recruited to mRNA. Initiation is a complex process mediated by many translation initiation factors (at least 30 polypeptides), and the regulation of translation initiation factor activity involves modulation of gene expression, binding to other factors or repressors, proteolytic cleavage and changes in phosphorylation state. It has been known for some time that the phosphorylation state of various translation factors/inhibitors (and other proteins required for translation, such as ribosomal proteins) is modulated in response to hormonal/mitogenic signals and environmental or nutritional stresses, but the identity of the signaling pathways involved in translational regulation are only beginning to emerge. In this review, we describe a signaling module involved in translational control both in yeast and in mammalian cells, the TOR (or FRAP/mTOR) signaling pathway. In mammals, this pathway regulates the activity of several translation factors (eIF4B and eIF4GI), translation inhibitors (the 4E-BPs), and the ribosomal S6 kinases (S6K1 and 2). In yeast, inhibition of Tor activity leads to polysomal disaggregation and G 1 cell cycle arrest.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  • Abraham RT, Wiederrecht GJ (1996) Immunopharmacology of rapamycin. Annu Rev Immunol 14:483–510

    PubMed  CAS  Google Scholar 

  • Alarcon CM, Heitman J, Cardenas ME (1999) Protein kinase activity and identification of a toxic effector domain of the target of rapamycin TOR proteins in yeast. Mol Biol Cell 10:2531–2546

    PubMed  CAS  Google Scholar 

  • Albers MW, Williams RT, Brown EJ, Tanaka A, Hall FL, Schreiber SL (1993) FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D 1-Cdk association in early G 1 of an osteosarcoma cell line. J Biol Chem 268:22825–22829

    PubMed  CAS  Google Scholar 

  • Andrade MA, Bork P (1995) HEAT repeats in the Huntington’s disease protein [letter]. Nat Genet 11:115–116

    PubMed  CAS  Google Scholar 

  • Baker H, Sidorowicz A, Sehgal SN, Vezina C (1978) Rapamycin (AY-22,989), a new antifungal antibiotic. III. In vitro and in vivo evaluation. J Antibiot (Tokyo) 31:539–545

    CAS  Google Scholar 

  • Barbet NC, Schneider U, Helliwell SB, Stansfield I, Tuite MF, Hall MN (1996) TOR controls translation initiation and early G 1 progression in yeast. Mol Biol Cell 7:25–42

    PubMed  CAS  Google Scholar 

  • Beck T, Hall MN (1999a) The TOR signalling pathway controls nuclear localization of nutrientregulated transcription factors. Nature 402:689–692

    PubMed  CAS  Google Scholar 

  • Beck T, Schmidt A, Hall MN (1999b) Starvation induces vacuolar targeting and degradation of the tryptophan permease in yeast. J Cell Biol 146:1227–1238

    PubMed  CAS  Google Scholar 

  • Belsham GJ, Denton RM (1980) The effect of insulin and adrenaline on the phosphorylation of a 22 000-molecular weight protein within isolated fat cells; possible identification as the inhibitor-1 of the “general phosphatase”. Biochem Soc Trans 8:382–383

    PubMed  CAS  Google Scholar 

  • Belsham GJ, Brownsey RW, Denton RM (1982) Reversibility of the insulin-stimulated phosphorylation of ATP citrate lyase and a cytoplasmic protein of subunit Mr 22000 in adipose tissue. Biochem J 204:345–352

    PubMed  CAS  Google Scholar 

  • Beretta L, Gingras A-C, Svitkin YV, Hall MN, Sonenberg N (1996) Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J 15:658–664

    PubMed  CAS  Google Scholar 

  • Berset C, Trachsel H, Altmann M (1998) The TOR (target of rapamycin) signal transduction pathway regulates the stability of translation initiation factor eIF4G in the yeast Saccharomyces cerevisiae. Proc Natl Acad Sci USA 95:4264–4269

    PubMed  CAS  Google Scholar 

  • Bierer BE, Mattila PS, Standaert RF, Herzenberg LA, Burakoff SJ, Crabtree G, Schreiber SL (1990) Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc Natl Acad Sci USA 87:9231–9235

    PubMed  CAS  Google Scholar 

  • Bierer BE, Schreiber SL, Burakoff SJ (1991) The effect of the immunosuppressant FK 506 on alternate pathways of T cell activation. Eur J Immunol 21:439–445

    PubMed  CAS  Google Scholar 

  • Blackshear PJ, Nemenoff RA, Avruch J (1982) Preliminary characterization of a heat-stable protein from rat adipose tissue whose phosphorylation is stimulated by insulin. Biochem J 204:817–824

    PubMed  CAS  Google Scholar 

  • Blackshear PJ, Nemenoff RA, Avruch J (1983) Insulin and growth factors stimulate the phosphorylation of a Mr-22000 protein in 3T3-L1 adipocytes. Biochem J 214:11–19

    PubMed  CAS  Google Scholar 

  • Bosotti R, Isacchi A, Sonnhammer EL (2000) FAT: a novel domain in PIK-related kinases. Trends Biochem Sci 25:225–227

    PubMed  CAS  Google Scholar 

  • Bradley D (1999) FDA approves new immunosuppressants. Pharmaceutical Sci Tech Today 2:472

    Google Scholar 

  • Brown EJ, Schreiber SL (1996) A signaling pathway to translational control. Cell 86:517–520

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Brunn GJ, Williams J, Sabers C, Wiederrecht G, Lawrence JC Jr, Abraham RT (1996) Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J 15:5256–5267

    PubMed  CAS  Google Scholar 

  • Brunn GJ, Fadden P, Haystead TAJ, Lawrence JC Jr (1997a) The mammalian target of rapamycin phosphorylates sites having a (Ser/Thr)-Pro motif and is activated by antibodies to a region near its COOH terminus. J Biol Chem 272:32547–32550

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM (1998) RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA 95:1432–1437

    PubMed  CAS  Google Scholar 

  • Cafferkey R, Young PR, McLaughlin MM, Bergsma DJ, Koltin Y, Sathe GM, Faucette L, Eng WK, Johnson RK, Livi GP (1993) Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity. Mol Cell Biol 13:6012–6023

    PubMed  CAS  Google Scholar 

  • Cafferkey R, McLaughlin MM, Young PR, Johnson RK, Livi GP (1994) Yeast TOR (DRR) proteins: amino-acid sequence alignment and identification of structural motifs. Gene 141:133–136

    PubMed  CAS  Google Scholar 

  • Campbell LE, Wang X, Proud CG (1999) Nutrients differentially regulate multiple translation factors and their control by insulin. Biochem J 344:433–441

    PubMed  CAS  Google Scholar 

  • Canman CE, Lim DS (1998) The role of ATM in DNA damage responses and cancer. Oncogene 17:3301–3308

    PubMed  Google Scholar 

  • Cardenas ME, Heitman J (1995) FKBP12-rapamycin target TOR2 is a vacuolar protein with an associated phosphatidylinositol-4 kinase activity. EMBO J 14:5892–5907

    PubMed  CAS  Google Scholar 

  • Cardenas ME, Cutler NS, Lorenz MC, Di Como CJ, Heitman J (1999) The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev 13:3271–3279

    PubMed  CAS  Google Scholar 

  • Chen Y, Chen H, Rhoad AE, Warner L, Caggiano TJ, Failli A, Zhang H, Hsiao CL, Nakanishi K, Molnar-Kimber KL (1994) A putative sirolimus (rapamycin) effector protein. Biochem Biophys Res Commun 203:1–7

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Chen J, Peterson RT, Schreiber SL (1998) Alpha 4 associates with protein phosphatases 2 A, 4, and 6. Biochem Biophys Res Commun 247:827–832

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Cosentino GP, Schmelzle T, Haghighat A, Helliwell SB, Hall MN, Sonenberg N (2000) Eaplp, a novel eukaryotic translation initiation factor 4E-associated protein in Saccharomyces cerevisiae. Mol Cell Biol 20:4604–4613

    PubMed  CAS  Google Scholar 

  • Critchlow SE, Jackson SP (1998) DNA end-joining: from yeast to man. Trends Biochem Sci 23:394–398

    PubMed  CAS  Google Scholar 

  • Danaie P, Altmann M, Hall MN, Trachsel H, Helliwell SB (1999) CLN3 expression is sufficient to restore Gl-to-S-phase progression in Saccharomyces cerevisiae mutants defective in translation initiation factor eIF4E. Biochem J 340 (Pt 1):135–141

    PubMed  CAS  Google Scholar 

  • De Moor CH, Jansen M, Bonte EJ, Thomas AA, Sussenbach JS, Van den Brande JL (1994) Influence of the four leader sequences of the human insulin-like-growth-factor-2 mRNAs on the expression of reporter genes. Eur J Biochem 226:1039–1047

    PubMed  Google Scholar 

  • De Moor CH, Jansen M, Bonte EJ, Thomas AA, Sussenbach JS, Van Den Brande JL (1995) Proteins binding to the leader of the 6.0 kb mRNA of human insulin-like growth factor 2 influence translation. Biochem J 307 (Pt 1):225–231

    PubMed  Google Scholar 

  • Di Como CJ, Arndt KT (1996) Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2 A phosphatases. Genes Dev 10:1904–1916

    PubMed  Google Scholar 

  • Dolinski K, Muir S, Cardenas M, Heitman J (1997) All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 94:13093–13098

    PubMed  CAS  Google Scholar 

  • Dufner A, Andjelkovic M, Burgering BM, Hemmings BA, Thomas G (1999) Protein kinase B localization and activation differentially affect S6 kinase 1 activity and eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation. Mol Cell Biol 19:4525–4534

    PubMed  CAS  Google Scholar 

  • Dumont FJ, Melino MR, Staruch MJ, Koprak SL, Fischer PA, Sigal NH (1990a) The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells. J Immunol 144:1418–1424

    PubMed  CAS  Google Scholar 

  • Dumont FJ, Staruch MJ, Koprak SL, Melino MR, Sigal NH (1990b) Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J Immunol 144:251–258

    PubMed  CAS  Google Scholar 

  • Dumont FJ, Staruch MJ, Grammer T, Blenis J, Kastner CA, Rupprecht KM (1995) Dominant mutations confer resistance to the immunosuppressant, rapamycin, in variants of a T cell lymphoma. Cell Immunol 163:70–79

    PubMed  CAS  Google Scholar 

  • Eng CP, Sehgal SN, Vezina C (1984) Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo) 37:1231–1237

    CAS  Google Scholar 

  • Fadden P, Haystead TA, Lawrence JC Jr (1997) Identification of phosphorylation sites in the translational regulator, PHAS-I, that are controlled by insulin and rapamycin in rat adipocytes. J Biol Chem 272:10240–10247

    PubMed  CAS  Google Scholar 

  • Featherstone C, Jackson SP (1999) DNA double-strand break repair. Curr Biol 9:R759–761

    Google Scholar 

  • Fumagalli S, Thomas G (2000) S6 phosphorylation and signal transduction. In: Sonenberg N, Hershey JWB, Mathews MB (eds) Translational control of gene expression. Cold Spring Harbor Laboratory Press, Plainview, NY, pp 695–718

    Google Scholar 

  • Gallego C, Gari E, Colomina N, Herrero E, Aldea M (1997) The Cln3 cyclin is down-regulated by translational repression and degradation during the G 1 arrest caused by nitrogen deprivation in budding yeast. EMBO J 16:7196–7206

    PubMed  CAS  Google Scholar 

  • Geballe AP, Sachs MS (2000) Translational control by upstream open reading frames. In: Sonenberg N, Hershey JWB, Mathews MB (eds) Translational control of gene expression. Cold Spring Harbor Laboratory Press, Plainview, NY, pp 595–614

    Google Scholar 

  • Gingras A-C, Kennedy SG, O’Leary MA, Sonenberg N, Hay N (1998) 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev 12:502–513

    PubMed  CAS  Google Scholar 

  • Gingras A-C, Raught B, Sonenberg N (1999a) eIF4 Initiation Factors: Effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68:913–963

    PubMed  CAS  Google Scholar 

  • Gingras A-C, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, Aebersold R, Sonenberg N (1999b) Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev 13:1422–1437

    PubMed  CAS  Google Scholar 

  • Gingras A-C, Raught B, Gygi SP, Polakiewicz RD, Marcotrigiano J, Miron M, Poulin F, Burley SK, Aebersold R, Sonenberg N (2001) Serum-sensitive phosphorylation of a subset of sites in the translational inhibitor 4E-BP1 abrogates its binding to eIF4E. (in preparation)

    Google Scholar 

  • Gothel SF, Marahiel MA (1999) Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts. Cell Mol Life Sci 55:423–436

    PubMed  CAS  Google Scholar 

  • Graves LM, Bornfeldt KE, Argast GM, Krebs EG, Kong X, Lin TA, Lawrence JC Jr (1995) cAMPand rapamycin-sensitive regulation of the association of eukaryotic initiation factor 4E and the translational regulator PHAS-I in aortic smooth muscle cells. Proc Natl Acad Sci USA 92:7222–7226

    PubMed  CAS  Google Scholar 

  • Groves MR, Barford D (1999) Topological characteristics of helical repeat proteins. Curr Opin Struct Biol 9:383–389

    PubMed  CAS  Google Scholar 

  • Groves MR, Hanlon N, Turowski P, Hemmings BA, Barford D (1999) The structure of the protein phosphatase 2 A PR65/A subunit reveals the conformation of its 15 tandemly repeated HEAT motifs. Cell 96:99–110

    PubMed  CAS  Google Scholar 

  • Haendler B, Keller R, Hiestand PC, Kocher HP, Wegmann G, Movva NR (1989) Yeast cyclophilin: isolation and characterization of the protein, cDNA and gene. Gene 83:39–46

    PubMed  CAS  Google Scholar 

  • Hara K, Yonezawa K, Kozlowski MT, Sugimoto T, Andrabi K, Weng QP, Kasuga M, Nishimoto I, Avruch J (1997) Regulation of eIF-4E BP1 phosphorylation by mTOR. J Biol Chem 272: 26457–26463

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Harding MW, Galat A, Uehling DE, Schreiber SL (1989) A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature 341:758–760

    PubMed  CAS  Google Scholar 

  • Hardwick JS, Kuruvilla FG, Tong JK, Shamji AF, Schreiber SL (1999) Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. Proc Natl Acad Sci USA 96:14866–14870

    PubMed  CAS  Google Scholar 

  • Hartley KO, Gell D, Smith GC, Zhang H, Divecha N, Connelly MA, Admon A, Lees-Miller SP, Anderson CW, Jackson SP (1995) DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product. Cell 82:849–856

    PubMed  CAS  Google Scholar 

  • Heesom KJ, Avison MB, Diggle TA, Denton RM (1998) Insulin-stimulated kinase from rat fat cells that phosphorylates initiation factor-4E binding protein 1 on the rapamycin-insensitive site (serine-111). Biochem J 336:39–48

    PubMed  CAS  Google Scholar 

  • Heesom KJ, Denton RM (1999) Dissociation of the eukaryotic initiation factor-4E/4E-BP1 complex involves phosphorylation of 4E-BP1 by an mTOR-associated kinase. FEBS Lett 457:489–493

    PubMed  CAS  Google Scholar 

  • Heitman J, Movva NR, Hall MN (1991a) Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253:905–909

    PubMed  CAS  Google Scholar 

  • Heitman J, Movva NR, Hiestand PC, Hall MN (1991b) FK 506-binding protein proline rotamase is a target for the immunosuppressive agent FK 506 in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 88:1948–1952

    PubMed  CAS  Google Scholar 

  • Helliwell SB, Wagner P, Kunz J, Deuter-Reinhard M, Henriquez R, Hall MN (1994) TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast. Mol Biol Cell 5:105–118

    PubMed  CAS  Google Scholar 

  • Hershey JWB, Merrick WC (2000) Pathway and mechanism of initiation of protein synthesis. In: Sonenberg N, Hershey JWB, Mathews MB (eds) Translational control of gene expression. Cold Spring Harbor Laboratory Press, Plainview, NY, pp 33–88

    Google Scholar 

  • Hinnebusch AG (2000) Mechanism and regulation of initiator methionyl-tRNA binding to ribosomes. In: Sonenberg N, Hershey JWB, Mathews MB (eds) Translational control of gene expression. Cold Spring Harbor Laboratory Press, Plainview, NY, pp 185–244

    Google Scholar 

  • Hu C, Pang S, Kong X, Velleca M, Lawrence JC Jr (1994) Molecular cloning and tissue distribution of PHAS-I, an intracellular target for insulin and growth factors. Proc Natl Acad Sci USA 91:3730–3734

    PubMed  CAS  Google Scholar 

  • Iiboshi Y, Papst PJ, Kawasome H, Hosoi H, Abraham RT, Houghton PJ, Terada N (1999) Aminoacid-dependent control of p70s6k. J Biol Chem 274:1092–1099

    PubMed  CAS  Google Scholar 

  • Inui S, Sanjo H, Maeda K, Yamamoto H, Miyamoto E, Sakaguchi N (1998) Ig receptor binding protein 1 (α4) is associated with a rapamycin-sensitive signal transduction in lymphocytes through direct binding to the catalytic subunit of protein phosphatase 2 A. Blood 92:539–546

    PubMed  CAS  Google Scholar 

  • Jefferies HB, Thomas G (1996) Ribosomal protein S6 phosphorylation and signal transduction. In: Sonenberg N, Hershey JWB, Mathews MB (eds) Translational control of gene expression. Cold Spring Harbor Laboratory Press, Plainview, NY, pp 389–409

    Google Scholar 

  • Jefferies HB, Reinhard C, Kozma SC, Thomas G (1994) Rapamycin selectively represses translation of the “polypyrimidine tract” mRNA family. Proc Natl Acad Sci USA 91:4441–4445

    PubMed  CAS  Google Scholar 

  • Jeggo PA, Carr AM, Lehmann AR (1998) Splitting the ATM: distinct repair and checkpoint defects in ataxia-telangiectasia. Trends Genet 14:312–316

    PubMed  CAS  Google Scholar 

  • Jiang Y, Broach JR (1999) Tor proteins and protein phosphatase 2 A reciprocally regulate Tap42 in controlling cell growth in yeast. EMBO J 18:2782–2792

    PubMed  CAS  Google Scholar 

  • Kay JE, Kromwel L, Doe SE, Denyer M (1991) Inhibition of T and B lymphocyte proliferation by rapamycin. Immunology 72:544–549

    PubMed  CAS  Google Scholar 

  • Kay JE, Smith MC, Frost V, Morgan GY (1996) Hypersensitivity to rapamycin of BJAB B lymphoblastoid cells. Immunology 87:390–395

    PubMed  CAS  Google Scholar 

  • Khaleghpour K, Pyronnet S, Gingras A-C, Sonenberg N (1999) Translational homeostasis: eukaryotic translation initiation factor 4E control of 4E-binding protein 1 and p70 S6 kinase activities. Mol Cell Biol 19:4302–4310

    PubMed  CAS  Google Scholar 

  • Kimball SR, Jefferson LS (2000) Regulation of translation initiation in mammalian cells by amino acids. In: Sonenberg N, Hershey JWB, Mathews MB (eds) Translational control of gene expression. Cold Spring Harbor Laboratory Press, Plainview, NY, pp 561–580

    Google Scholar 

  • Kimball SR, Shantz LM, Horetsky RL, Jefferson LS (1999) Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6. J Biol Chem 274:11647–11652

    PubMed  CAS  Google Scholar 

  • Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H (1987a) FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 40:1249–1255

    CAS  Google Scholar 

  • Kino T, Hatanaka H, Miyata S, Inamura N, Nishiyama M, Yajima T, Goto T, Okuhara M, Kohsaka M, Aoki H et al. (1987b) FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 40:1256–1265

    CAS  Google Scholar 

  • Kohn AD, Barthel A, Kovacina KS, Boge A, Wallach B, Summers SA, Birnbaum MJ, Scott PH, Lawrence JC, Jr, Roth RA (1998) Construction and characterization of a conditionally active version of the serine/threonine kinase Akt. J Biol Chem 273:11937–11943

    PubMed  CAS  Google Scholar 

  • Koltin Y, Faucette L, Bergsma DJ, Levy MA, Cafferkey R, Koser PL, Johnson RK, Livi GP (1991) Rapamycin sensitivity in Saccharomyces cerevisiae is mediated by a peptidyl-prolyl cis-trans isomerase related to human FK506-binding protein. Mol Cell Biol 11:1718–1723

    PubMed  CAS  Google Scholar 

  • Kumar V, Pandey P, Sabatini D, Kumar M, Majumder PK, Bharti A, Carmichael G, Kufe D, Kharbanda S (2000a) Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of translation. EMBO J 19:1087–1097

    PubMed  CAS  Google Scholar 

  • Kumar V, Sabatini D, Pandey P, Gingras A-C, Majumder PK, Kumar M, Yuan ZM, Carmichael G, Weichselbaum R, Sonenberg N, Kufe D, Kharbanda S (2000b) Regulation of the rapamycin and FKBP-target 1/mammalian target of rapamycin and cap-dependent initiation of translation by the c-Abl protein-tyrosine kinase. J Biol Chem 275:10779–10787

    PubMed  CAS  Google Scholar 

  • Kunz J, Henriquez R, Schneider U, Deuter-Reinhard M, Movva NR, Hall MN (1993) Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73:585–596

    PubMed  CAS  Google Scholar 

  • Lavin MF, Shiloh Y (1997) The genetic defect in ataxia-telangiectasia. Annu Rev Immunol 15:177–202

    PubMed  CAS  Google Scholar 

  • Lazaris-Karatzas A, Montine KS, Sonenberg N (1990) Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5’ cap. Nature 345:544–547

    PubMed  CAS  Google Scholar 

  • Lin TA, Kong X, Haystead TA, Pause A, Belsham G, Sonenberg N, Lawrence JC Jr (1994) PHAS-I as a link between mitogen-activated protein kinase and translation initiation. Science 266:653–656

    PubMed  CAS  Google Scholar 

  • Lin TA, Lawrence JC Jr (1996) Control of the translational regulators PHAS-I and PHAS-II by insulin and cAMP in 3T3-L1 adipocytes. J Biol Chem 271:30199–30204

    PubMed  CAS  Google Scholar 

  • Lorenz MC, Heitman J (1995) TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin. J Biol Chem 270:27531–27537

    PubMed  CAS  Google Scholar 

  • Lu KP (2000) Phosphorylation-dependent prolyl isomerization: a novel cell cycle regulatory mechanism. Prog Cell Cycle Res 4:83–96

    PubMed  CAS  Google Scholar 

  • Luo H, Chen H, Daloze P, St-Louis G, Wu J (1993) Anti-CD28 antibody- and IL-4-induced human T cell proliferation is sensitive to rapamycin. Clin Exp Immunol 94:371–376

    PubMed  CAS  Google Scholar 

  • Marcotrigiano J, Gingras A-C, Sonenberg N, Burley SK (1999) Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. Mol Cell 3:707–716

    PubMed  CAS  Google Scholar 

  • Martel RR, Klicius J, Galet S (1977) Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can J Physiol Pharmacol 55:48–51

    PubMed  CAS  Google Scholar 

  • Meyuhas O, Hornstein E (2000) Translational control of TOP mRNAs. In: Sonenberg N, Hershey JWB, Mathews MB (eds) Translational control of gene expression. Cold Spring Harbor Laboratory Press, Plainview, NY, pp 671–694

    Google Scholar 

  • Meyuhas O, Avni D, Shama S (1996) Translational control of ribosomal protein mRNAs in eukaryotes. In: Sonenberg N, Hershey JWB, Mathews MB (eds) Translational control. Cold Spring Harbor Laboratory Press, Plainview, NY, pp 363–388

    Google Scholar 

  • Murata K, Wu J, Brautigan DL (1997) B cell receptor-associated protein alpha4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2 A. Proc Natl Acad Sci USA 94:10624–10629

    PubMed  CAS  Google Scholar 

  • Nanahoshi M, Nishiuma T, Tsujishita Y, Hara K, Inui S, Sakaguchi N, Yonezawa K (1998) Regulation of protein phosphatase 2 A catalytic activity by alpha4 protein and its yeast homolog TAP42. Biochem Biophys Res Commun 251:52–526

    Google Scholar 

  • Nanahoshi M, Tsujishita Y, Tokunaga C, Inui S, Sakaguchi N, Hara K, Yonezawa K (1999) Alpha4 protein as a common regulator of type 2A-related serine/threonine protein phosphatases. FEBS Lett 446:108–112

    PubMed  CAS  Google Scholar 

  • Navé BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR (1999) Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 344:427–431

    PubMed  Google Scholar 

  • Nielsen FC, Christiansen J (1995) Posttranscriptional regulation of insulin-like growth factor II mRNA. Scand J Clin Lab Invest Suppl 220:37–46

    PubMed  CAS  Google Scholar 

  • Nielsen FC, Ostergaard L, Nielsen J, Christiansen J (1995) Growth-dependent translation of IGFII mRNA by a rapamycin-sensitive pathway. Nature 377:358–362

    PubMed  CAS  Google Scholar 

  • Nielsen J, Christiansen J, Lykke-Andersen J, Johnsen AH, Wewer UM, Nielsen FC (1999) A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development. Mol Cell Biol 19:1262–1270

    PubMed  CAS  Google Scholar 

  • Noda T, Ohsumi Y (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273:3963–3966

    PubMed  CAS  Google Scholar 

  • Patti ME, Brambilla E, Luzi L, Landaker EJ, Kahn CR (1998) Bidirectional modulation of insulin action by amino acids. J Clin Invest 101:1519–1529

    PubMed  CAS  Google Scholar 

  • Pause A, Belsham GJ, Gingras A-C, Donzé O, Lin TA, Lawrence JC Jr, Sonenberg N (1994) Insulindependent stimulation of protein synthesis by phosphorylation of a regulator of 5’-cap function. Nature 371:762–767

    PubMed  CAS  Google Scholar 

  • Pedersen S, Celis JE, Nielsen J, Christiansen J, Nielsen FC (1997) Distinct repression of translation by wortmannin and rapamycin. Eur J Biochem 247:449–456

    PubMed  CAS  Google Scholar 

  • Peterson RT, Desai BN, Hardwick JS, Schreiber SL (1999) Protein phosphatase 2 A interacts with the 70-kDa S6 kinase and is inactivated by inhibition of FKBP12-rapamycin-associated protein. Proc Natl Acad Sci USA 96:4438–4442

    PubMed  CAS  Google Scholar 

  • Peterson RT, Beal PA, Comb MJ, Schreiber SL (2000) FKBP12-rapamycin-associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions. J Biol Chem 275:7416–7423

    PubMed  CAS  Google Scholar 

  • Polymenis M, Schmidt EV (1997) Coupling of cell division to cell growth by translational control of the G1 cyclin CLN3 in yeast. Genes Dev 11:2522–2531

    PubMed  CAS  Google Scholar 

  • Poulin F, Gingras A-C, Olsen H, Chevalier S, Sonenberg N (1998) 4E-BP3, a new member of the eukaryotic initiation factor 4E-binding protein family. J Biol Chem 273:14002–14007

    PubMed  CAS  Google Scholar 

  • Powers T, Walter P(1999) Regulation of ribosome biogenesis by the rapamycin-sensitive TORsignaling pathway in Saccharomyces cerevisiae. Mol Biol Cell 10:987–1000

    PubMed  CAS  Google Scholar 

  • Powis G, Bonjouklian R, Berggren MM, Gallegos A, Abraham R, Ashendel C, Zalkow L, Matter WF, Dodge J, Grindey G (1994) Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res 54:2419–2423

    PubMed  CAS  Google Scholar 

  • Raught B, Gingras A-C, James A, Medina D, Sonenberg N, Rosen JM (1996) Expression of a translationally regulated, dominant-negative CCAAT/enhancer-binding protein beta isoform and up-regulation of the eukaryotic translation initiation factor 2/alpha are correlated with neoplastic transformation of mammary epithelial cells. Cancer Res 56:4382–4386

    PubMed  CAS  Google Scholar 

  • Raught B, Gingras A-C, Sonenberg N (2000a) Regulation of ribosomal recruitment in eukaryotes. In: Sonenberg N, Hershey JWB, Mathews MB (eds) Translational control of gene expression. Cold Spring Harbor Laboratory Press, Plainview, NY, pp 245–294

    Google Scholar 

  • Raught B, Gingras A-C, Gygi SP, Imataka H, Morino S, Gradi A, Aebersold R, Sonenberg N (2000b) Serum-stimulated, rapamycin-sensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI. EMBO J 19:434–444

    PubMed  CAS  Google Scholar 

  • Rosenwald IB, Chen JJ, Wang S, Savas L, London IM, Pullman J (1999) Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene 18:2507–2517

    PubMed  CAS  Google Scholar 

  • Rotman G, Shiloh Y (1998) ATM: from gene to function. Hum Mol Genet 7:1555–1563

    PubMed  CAS  Google Scholar 

  • Rotman G, Shiloh Y(1999) ATM: a mediator of multiple responses to genotoxic stress. Oncogene 18:6135–6144

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Sarkaria JN, Tibbetts RS, Busby EC, Kennedy AP, Hill DE, Abraham RT (1998) Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res 58:4375–4382

    PubMed  CAS  Google Scholar 

  • Schmidt A, Kunz J, Hall MN (1996) TOR2 is required for organization of the actin cytoskeleton in yeast. Proc Natl Acad Sci USA 93:13780–13785

    PubMed  CAS  Google Scholar 

  • Schmidt A, Bickle M, Beck T, Hall MN (1997) The yeast phosphatidylinositol kinase homolog TOR2 activates RHO1 and RHO2 via the exchange factor ROM2. Cell 88:531–542

    PubMed  CAS  Google Scholar 

  • Schmidt A, Beck T, Koller A, Kunz J, Hall MN (1998) The TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease. EMBO J 17:6924–6931

    PubMed  CAS  Google Scholar 

  • Scott PH, Lawrence JC Jr (1998) Attenuation of mammalian target of rapamycin activity by increased cAMP in 3T3-L1 cells. J Biol Chem 272:34496–34501

    Google Scholar 

  • Scott PH, Brunn GJ, Kohn AD, Roth RA, Lawrence JC Jr (1998) Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc Natl Acad Sci USA 95:7772–7777

    PubMed  CAS  Google Scholar 

  • Sehgal SN, Baker H, Vezina C (1975) Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo) 28:727–732

    CAS  Google Scholar 

  • Sekulic A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, Abraham RT (2000) A direct linkage between the phosphoinositide 3-Kinase-AKT signaling pathway and the mammalian target of rapamycin. Cancer Res 60:3504–3513

    PubMed  CAS  Google Scholar 

  • Shigemitsu K, Tsujishita Y, Hara K, Nanahoshi M, Avruch J, Yonezawa K (1999) Regulation of translational effectors by amino acid and mammalian target of rapamycin signaling pathways. Possible involvement of autophagy in cultured hepatoma cells. J Biol Chem 274:1058–1065

    PubMed  CAS  Google Scholar 

  • Shiloh Y (1997) Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu Rev Genet 31:635–662

    PubMed  CAS  Google Scholar 

  • Siekierka JJ, Hung SH, Poe M, Lin CS, Sigal NH (1989) A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature 341:755–757

    PubMed  CAS  Google Scholar 

  • Siekierka JJ, Wiederrecht G, Greulich H, Boulton D, Hung SH, Cryan J, Hodges PJ, Sigal NH (1990) The cytosolic-binding protein for the immunosuppressant FK-506 is both a ubiquitous and highly conserved peptidyl-prolyl cis-trans isomerase. J Biol Chem 265:21011–21015

    PubMed  CAS  Google Scholar 

  • Singh K, Sun S, Vezina C (1979) Rapamycin (AY-22,989), a new antifungal antibiotic. IV. Mechanism of action. J Antibiot (Tokyo) 32:630–645

    CAS  Google Scholar 

  • Smith GC, Jackson SP (1999) The DNA-dependent protein kinase. Genes Dev 13:916–934

    PubMed  CAS  Google Scholar 

  • Smith GC, Divecha N, Lakin ND, Jackson SP (1999) DNA-dependent protein kinase and related proteins. Biochem Soc Symp 64:91–104

    PubMed  CAS  Google Scholar 

  • Stan R, McLaughlin MM, Cafferkey R, Johnson RK, Rosenberg M, Livi GP (1994) Interaction between FKBP12-rapamycin and TOR involves a conserved serine residue. J Biol Chem 269:32027–32030

    PubMed  CAS  Google Scholar 

  • Sykes K, Gething MJ, Sambrook J (1993) Proline isomerases function during heat shock. Proc Natl Acad Sci USA 90:5853–5857

    PubMed  CAS  Google Scholar 

  • Takata M, Ogawa W, Kitamura T, Hino Y, Kuroda S, Kotani K, Klip A, Gingras A-C, Sonenberg N, Kasuga M (1999) Requirement for Akt (protein kinase B) in insulin-induced activation of glycogen synthase and phosphorylation of 4E-BP 1(PHAS-1). J Biol Chem 274:20611–20618

    PubMed  CAS  Google Scholar 

  • Tropschug M, Barthelmess IB, Neupert W (1989) Sensitivity to cyclosporin A is mediated by cyclophilin in Neurospora crassa and Saccharomyces cerevisiae. Nature 342:953–955

    PubMed  CAS  Google Scholar 

  • Ui M, Okada T, Hazeki K, Hazeki O (1995) Wortmannin as a unique probe for an intracellular signalling protein, phosphoinositide 3-kinase. Trends Biochem Sci 20:303–307

    PubMed  CAS  Google Scholar 

  • Vezina C, Kudelski A, Sehgal SN (1975) Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 28:721–726

    CAS  Google Scholar 

  • Vilella-Bach M, Nuzzi P, Fang Y, Chen J (1999) The FKBP12-rapamycin-binding domain is required for FKBP12-rapamycin-associated protein kinase activity and G1 progression. J Biol Chem 274:4266–4272

    PubMed  CAS  Google Scholar 

  • Vlahos CJ, Matter WF, Hui KY, Brown RF (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 2169:5241–5248

    Google Scholar 

  • von Manteuffel SR, Gingras A-C, Ming XF, Sonenberg N, Thomas G (1996) 4E-BP1 phosphorylation is mediated by the FRAP-p70s6 k pathway and is independent of mitogen-activated protein kinase. Proc Natl Acad Sci USA 93:4076–4080

    Google Scholar 

  • Wang X, Campbell LE, Miller CM, Proud CG (1998) Amino acid availability regulates p70 S6 kinase and multiple translation factors. Biochem J 334:261–267

    PubMed  CAS  Google Scholar 

  • Wiederrecht G, Brizuela L, Elliston K, Sigal NH, Siekierka JJ (1991) FKB1 encodes a nonessential FK 506-binding protein in Saccharomyces cerevisiae and contains regions suggesting homology to the cyclophilins. Proc Natl Acad Sci USA 88:1029–1033

    PubMed  CAS  Google Scholar 

  • Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, Pirola L, Vanhaesebroeck B, Waterfield MD, Panayotou G (1996) Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol Cell Biol 16:1722–1733

    PubMed  CAS  Google Scholar 

  • Xu G, Kwon G, Marshall CA, Lin TA, Lawrence JC Jr, McDaniel ML (1998a) 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

    PubMed  CAS  Google Scholar 

  • Xu G, Marshall CA, Lin TA, Kwon G, Munivenkatappa RB, Hill JR, Lawrence JC Jr, McDaniel ML (1998b) Insulin mediates glucose-stimulated phosphorylation of PHAS-I by pancreatic beta cells. An insulin-receptor mechanism for autoregulation of protein synthesis by translation. J Biol Chem 273:4485–4491

    PubMed  CAS  Google Scholar 

  • Zaragoza D, Ghavidel A, Heitman J, Schultz MC (1998) Rapamycin induces the G(0) program of transcriptional repression in yeast by interfering with the TOR signaling pathway. Mol Cell Biol 18:4463–4470

    PubMed  CAS  Google Scholar 

  • Zheng XF, Florentino D, Chen J, Crabtree GR, Schreiber SL (1995) TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell 82:121–130

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and McGill Cancer Centre, McGill University, 3655 Dummond Street, Montréal, Québec, H3G 1Y6, Canada

    Anne-Claude Gingras, Brian Raught & Nahum Sonenberg

Authors
  1. Anne-Claude Gingras
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brian Raught
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nahum Sonenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA

    Robert E. Rhoads

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Gingras, AC., Raught, B., Sonenberg, N. (2001). Control of Translation by the Target of Rapamycin Proteins. In: Rhoads, R.E. (eds) Signaling Pathways for Translation. Progress in Molecular and Subcellular Biology, vol 27. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-09889-9_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-09889-9_6

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-07505-6

  • Online ISBN: 978-3-662-09889-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation