Skip to main content
SpringerLink
Log in

Key factors in mTOR regulation

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Mammalian target of rapamycin (mTOR) is a protein serine/threonine kinase that controls a wide range of growth-related cellular processes. In the past several years, many factors have been identified that are involved in controlling mTOR activity. Those factors in turn are regulated by diverse signaling cascades responsive to changes in intracellular and environmental conditions. The molecular connections between mTOR and its regulators form a complex signaling network that governs cellular metabolism, growth and proliferation. In this review, we discuss some key factors in mTOR regulation and mechanisms by which these factors control mTOR activity.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. De Virgilio C, Loewith R (2006) Cell growth control: little eukaryotes make big contributions. Oncogene 25:6392–6415

    PubMed  Google Scholar 

  2. Jacinto E, Hall MN (2003) Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 4:117–126

    CAS  PubMed  Google Scholar 

  3. Heitman J, Movva NR, Hiestand PC, Hall MN (1991) 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

    CAS  PubMed  Google Scholar 

  4. 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

    CAS  PubMed  Google Scholar 

  5. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484

    CAS  PubMed  Google Scholar 

  6. Huang S, Bjornsti MA, Houghton PJ (2003) Rapamycins: mechanism of action and cellular resistance. Cancer Biol Ther 2:222–232

    CAS  PubMed  Google Scholar 

  7. Easton JB, Houghton PJ (2004) Therapeutic potential of target of rapamycin inhibitors. Expert Opin Ther Targets 8:551–564

    CAS  PubMed  Google Scholar 

  8. Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, Oppliger W, Jenoe P, Hall MN (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10:457–468

    CAS  PubMed  Google Scholar 

  9. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6:1122–1128

    CAS  PubMed  Google Scholar 

  10. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159–168

    CAS  PubMed  Google Scholar 

  11. Bhaskar PT, Hay N (2007) The two TORCs and Akt. Dev Cell 12:487–502

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  15. Dames SA, Mulet JM, Rathgeb-Szabo K, Hall MN, Grzesiek S (2005) The solution structure of the FATC domain of the protein kinase target of rapamycin suggests a role for redox-dependent structural and cellular stability. J Biol Chem 280:20558–20564

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  17. Chiang GG, Abraham RT (2005) Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. J Biol Chem 280:25485–25490

    CAS  PubMed  Google Scholar 

  18. Holz MK, Blenis J (2005) Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J Biol Chem 280:26089–26093

    CAS  PubMed  Google Scholar 

  19. Copp J, Manning G, Hunter T (2009) TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2. Cancer Res 69:1821–1827

    CAS  PubMed  Google Scholar 

  20. 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

    CAS  PubMed  Google Scholar 

  21. Cheng SW, Fryer LG, Carling D, Shepherd PR (2004) Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status. J Biol Chem 279:15719–15722

    CAS  PubMed  Google Scholar 

  22. Acosta-Jaquez HA, Keller JA, Foster KG, Ekim B, Soliman GA, Feener EP, Ballif BA, Fingar DC (2009) Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling and cell growth. Mol Cell Biol 29:4308–4324

    CAS  PubMed  Google Scholar 

  23. Rosner M, Siegel N, Valli A, Fuchs C, Hengstschlager M (2009) mTOR phosphorylated at S2448 binds to raptor and rictor. Amino Acids [Epub ahead of print]

  24. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110:163–175

    CAS  PubMed  Google Scholar 

  25. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM (2003) GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 11:895–904

    CAS  PubMed  Google Scholar 

  26. Smith TF, Gaitatzes C, Saxena K, Neer EJ (1999) The WD repeat: a common architecture for diverse functions. Trends Biochem Sci 24:181–185

    CAS  PubMed  Google Scholar 

  27. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11:859–871

    CAS  PubMed  Google Scholar 

  28. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110:177–189

    CAS  PubMed  Google Scholar 

  29. Adami A, Garcia-Alvarez B, Arias-Palomo E, Barford D, Llorca O (2007) Structure of TOR and its complex with KOG1. Mol Cell 27:509–516

    CAS  PubMed  Google Scholar 

  30. Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K, Hara K, Tanaka N, Avruch J, 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

    CAS  PubMed  Google Scholar 

  31. Schalm SS, Fingar DC, Sabatini DM, Blenis J (2003) TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol 13:797–806

    CAS  PubMed  Google Scholar 

  32. Hornberger TA, Chu WK, Mak YW, Hsiung JW, Huang SA, Chien S (2006) The role of phospholipase D and phosphatidic acid in the mechanical activation of mTOR signaling in skeletal muscle. Proc Natl Acad Sci USA 103:4741–4746

    CAS  PubMed  Google Scholar 

  33. Lee VH, Healy T, Fonseca BD, Hayashi A, Proud CG (2008) Analysis of the regulatory motifs in eukaryotic initiation factor 4E-binding protein 1. Febs J 275:2185–2199

    CAS  PubMed  Google Scholar 

  34. Tzatsos A (2009) Raptor binds the SAIN (Shc and IRS-1 NPXY-binding) domain of IRS-1 and regulates the phosphorylation of IRS-1 at Ser636/639 by mTOR. J Biol Chem 284(34):22525–22534

    CAS  PubMed  Google Scholar 

  35. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214–226

    CAS  PubMed  Google Scholar 

  36. Carriere A, Cargnello M, Julien LA, Gao H, Bonneil E, Thibault P, Roux PP (2008) Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation. Curr Biol 18:1269–1277

    CAS  PubMed  Google Scholar 

  37. Wang L, Lawrence JC Jr, Sturgill TW, Harris TE (2009) Mammalian target of rapamycin complex 1 (mTORC1) activity is associated with phosphorylation of raptor by mTOR. J Biol Chem 284:14693–14697

    CAS  PubMed  Google Scholar 

  38. Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10:307–318

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  40. 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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  43. Pearson RB, Dennis PB, Han JW, Williamson NA, Kozma SC, Wettenhall RE, Thomas G (1995) The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. EMBO J 14:5279–5287

    CAS  PubMed  Google Scholar 

  44. 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

    CAS  PubMed  Google Scholar 

  45. Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G (1998) Phosphorylation and activation of p70s6k by PDK1. Science 279:707–710

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  47. Fingar DC, Salama S, Tsou C, Harlow E, Blenis J (2002) Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev 16:1472–1487

    CAS  PubMed  Google Scholar 

  48. Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ (2001) p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci USA 98:9666–9670

    CAS  PubMed  Google Scholar 

  49. Tremblay F, Marette A (2001) Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem 276:38052–38060

    CAS  PubMed  Google Scholar 

  50. Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, Barnett J, Leslie NR, Cheng S, Shepherd PR, Gout I, Downes CP, Lamb RF (2004) The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 166:213–223

    CAS  PubMed  Google Scholar 

  51. Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG (2001) Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J 20:4370–4379

    CAS  PubMed  Google Scholar 

  52. Zhang HH, Lipovsky AI, Dibble CC, Sahin M, Manning BD (2006) S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt. Mol Cell 24:185–197

    CAS  PubMed  Google Scholar 

  53. Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, Cahill DA, Goldstein BJ, White MF (1991) Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352:73–77

    CAS  PubMed  Google Scholar 

  54. Craparo A, Freund R, Gustafson TA (1997) 14-3-3 (epsilon) interacts with the insulin-like growth factor I receptor and insulin receptor substrate I in a phosphoserine-dependent manner. J Biol Chem 272:11663–11669

    CAS  PubMed  Google Scholar 

  55. Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127:125–137

    CAS  PubMed  Google Scholar 

  56. Pearce LR, Huang X, Boudeau J, Pawlowski R, Wullschleger S, Deak M, Ibrahim AF, Gourlay R, Magnuson MA, Alessi DR (2007) Identification of protor as a novel rictor-binding component of mTOR complex-2. Biochem J 405:513–522

    CAS  PubMed  Google Scholar 

  57. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (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

    CAS  PubMed  Google Scholar 

  58. Thedieck K, Polak P, Kim ML, Molle KD, Cohen A, Jeno P, Arrieumerlou C, Hall MN (2007) PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS One 2:e1217

    PubMed  Google Scholar 

  59. Woo SY, Kim DH, Jun CB, Kim YM, Haar EV, Lee SI, Hegg JW, Bandhakavi S, Griffin TJ, Kim DH (2007) PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J Biol Chem 282:25604–25612

    CAS  PubMed  Google Scholar 

  60. Yang Q, Inoki K, Ikenoue T, Guan KL (2006) Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 20:2820–2832

    CAS  PubMed  Google Scholar 

  61. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101

    CAS  PubMed  Google Scholar 

  62. Hagan GN, Lin Y, Magnuson MA, Avruch J, Czech MP (2008) A rictor-myo1c complex participates in dynamic cortical actin events in 3T3-L1 adipocytes. Mol Cell Biol 28:4215–4226

    CAS  PubMed  Google Scholar 

  63. Martin J, Masri J, Bernath A, Nishimura RN, Gera J (2008) Hsp70 associates with rictor and is required for mTORC2 formation and activity. Biochem Biophys Res Commun 372:578–583

    CAS  PubMed  Google Scholar 

  64. McDonald PC, Oloumi A, Mills J, Dobreva I, Maidan M, Gray V, Wederell ED, Bally MB, Foster LJ, Dedhar S (2008) Rictor and integrin-linked kinase interact and regulate Akt phosphorylation and cancer cell survival. Cancer Res 68:1618–1624

    CAS  PubMed  Google Scholar 

  65. Zeng Z, Sarbassov dos D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C, Giles FJ, Sabatini DM, Andreeff M, Konopleva M (2007) Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109:3509–3512

    CAS  PubMed  Google Scholar 

  66. Akcakanat A, Singh G, Hung MC, Meric-Bernstam F (2007) Rapamycin regulates the phosphorylation of rictor. Biochem Biophys Res Commun 362:330–333

    CAS  PubMed  Google Scholar 

  67. Rosner M, Hengstschlager M (2008) Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1. Hum Mol Genet 17:2934–2948

    CAS  PubMed  Google Scholar 

  68. Facchinetti V, Ouyang W, Wei H, Soto N, Lazorchak A, Gould C, Lowry C, Newton AC, Mao Y, Miao RQ, Sessa WC, Qin J, Zhang P, Su B, Jacinto E (2008) The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J 27:1932–1943

    CAS  PubMed  Google Scholar 

  69. Ikenoue T, Inoki K, Yang Q, Zhou X, Guan KL (2008) Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J 27:1919–1931

    CAS  PubMed  Google Scholar 

  70. Garcia-Martinez JM, Alessi DR (2008) mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 416:375–385

    CAS  PubMed  Google Scholar 

  71. Rosner M, Fuchs C, Siegel N, Valli A, Hengstschlager M (2009) Functional interaction of mTOR complexes in regulating mammalian cell size and cell cycle. Hum Mol Genet 18(17):3298–3310

    CAS  PubMed  Google Scholar 

  72. Leung AK, Robson WL (2007) Tuberous sclerosis complex: a review. J Pediatr Health Care 21:108–114

    PubMed  Google Scholar 

  73. Mak BC, Yeung RS (2004) The tuberous sclerosis complex genes in tumor development. Cancer Invest 22:588–603

    CAS  PubMed  Google Scholar 

  74. Plank TL, Yeung RS, Henske EP (1998) Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer Res 58:4766–4770

    CAS  PubMed  Google Scholar 

  75. van Slegtenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R, van den Ouweland A, Reuser A, Sampson J, Halley D, van der Sluijs P (1998) Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 7:1053–1057

    PubMed  Google Scholar 

  76. Wienecke R, Konig A, DeClue JE (1995) Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity. J Biol Chem 270:16409–16414

    CAS  PubMed  Google Scholar 

  77. Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK (2001) The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105:345–355

    CAS  PubMed  Google Scholar 

  78. Gao X, Pan D (2001) TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev 15:1383–1392

    CAS  PubMed  Google Scholar 

  79. Potter CJ, Pedraza LG, Xu T (2002) Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 4:658–665

    CAS  PubMed  Google Scholar 

  80. Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA (2003) Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 5:566–571

    CAS  PubMed  Google Scholar 

  81. Stocker H, Radimerski T, Schindelholz B, Wittwer F, Belawat P, Daram P, Breuer S, Thomas G, Hafen E (2003) Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 5:559–565

    CAS  PubMed  Google Scholar 

  82. Inoki K, Li Y, Xu T, Guan KL (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17:1829–1834

    CAS  PubMed  Google Scholar 

  83. Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D (2003) Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 5:578–581

    CAS  PubMed  Google Scholar 

  84. Castro AF, Rebhun JF, Clark GJ, Quilliam LA (2003) Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J Biol Chem 278:32493–32496

    CAS  PubMed  Google Scholar 

  85. Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G (2003) Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 11:1457–1466

    CAS  PubMed  Google Scholar 

  86. Li Y, Inoki K, Guan KL (2004) Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity. Mol Cell Biol 24:7965–7975

    CAS  PubMed  Google Scholar 

  87. Nellist M, Sancak O, Goedbloed MA, Rohe C, van Netten D, Mayer K, Tucker-Williams A, van den Ouweland AM, Halley DJ (2005) Distinct effects of single amino-acid changes to tuberin on the function of the tuberin-hamartin complex. Eur J Hum Genet 13:59–68

    CAS  PubMed  Google Scholar 

  88. Cai SL, Tee AR, Short JD, Bergeron JM, Kim J, Shen J, Guo R, Johnson CL, Kiguchi K, Walker CL (2006) Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning. J Cell Biol 173:279–289

    CAS  PubMed  Google Scholar 

  89. Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, Pledger WJ, Cheng JQ (2002) Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 277:35364–35370

    CAS  PubMed  Google Scholar 

  90. Inoki K, Li Y, Zhu T, Wu J, Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648–657

    CAS  PubMed  Google Scholar 

  91. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC (2002) Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 10:151–162

    CAS  PubMed  Google Scholar 

  92. Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590

    CAS  PubMed  Google Scholar 

  93. Kahn BB, Alquier T, Carling D, Hardie DG (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1:15–25

    CAS  PubMed  Google Scholar 

  94. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL (2006) TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126:955–968

    CAS  PubMed  Google Scholar 

  95. Moon RT (2005) Wnt/beta-catenin pathway. Sci STKE (271):cm1. Accessed 15 Feb 2005

  96. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121:179–193

    CAS  PubMed  Google Scholar 

  97. Ma L, Teruya-Feldstein J, Bonner P, Bernardi R, Franz DN, Witte D, Cordon-Cardo C, Pandolfi PP (2007) Identification of S664 TSC2 phosphorylation as a marker for extracellular signal-regulated kinase mediated mTOR activation in tuberous sclerosis and human cancer. Cancer Res 67:7106–7112

    CAS  PubMed  Google Scholar 

  98. Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J (2004) Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci USA 101:13489–13494

    CAS  PubMed  Google Scholar 

  99. Ballif BA, Roux PP, Gerber SA, MacKeigan JP, Blenis J, Gygi SP (2005) Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors. Proc Natl Acad Sci USA 102:667–672

    CAS  PubMed  Google Scholar 

  100. Yamagata K, Sanders LK, Kaufmann WE, Yee W, Barnes CA, Nathans D, Worley PF (1994) rheb, a growth factor- and synaptic activity-regulated gene, encodes a novel Ras-related protein. J Biol Chem 269:16333–16339

    CAS  PubMed  Google Scholar 

  101. Kinouchi H, Arai S, Kamii H, Izaki K, Kunizuka H, Mizoi K, Yoshimoto T (1999) Induction of Rheb mRNA following middle cerebral artery occlusion in the rat. Neuroreport 10:1055–1059

    CAS  PubMed  Google Scholar 

  102. Bos JL (1997) Ras-like GTPases. Biochim Biophys Acta 1333:M19–M31

    CAS  PubMed  Google Scholar 

  103. Aspuria PJ, Tamanoi F (2004) The Rheb family of GTP-binding proteins. Cell Signal 16:1105–1112

    CAS  PubMed  Google Scholar 

  104. Im E, von Lintig FC, Chen J, Zhuang S, Qui W, Chowdhury S, Worley PF, Boss GR, Pilz RB (2002) Rheb is in a high activation state and inhibits B-Raf kinase in mammalian cells. Oncogene 21:6356–6365

    CAS  PubMed  Google Scholar 

  105. Yu Y, Li S, Xu X, Li Y, Guan K, Arnold E, Ding J (2005) Structural basis for the unique biological function of small GTPase RHEB. J Biol Chem 280:17093–17100

    CAS  PubMed  Google Scholar 

  106. Hsu YC, Chern JJ, Cai Y, Liu M, Choi KW (2007) Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase. Nature 445:785–788

    CAS  PubMed  Google Scholar 

  107. Dong X, Yang B, Li Y, Zhong C, Ding J (2009) Molecular basis of the acceleration of the GDP-GTP exchange of human Rheb by human TCTP. J Biol Chem 284(35):23754–23764

    CAS  PubMed  Google Scholar 

  108. Smith EM, Finn SG, Tee AR, Browne GJ, Proud CG (2005) The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J Biol Chem 280:18717–18727

    CAS  PubMed  Google Scholar 

  109. Roccio M, Bos JL, Zwartkruis FJ (2006) Regulation of the small GTPase Rheb by amino acids. Oncogene 25:657–664

    CAS  PubMed  Google Scholar 

  110. Long X, Ortiz-Vega S, Lin Y, Avruch J (2005) Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J Biol Chem 280:23433–23436

    CAS  PubMed  Google Scholar 

  111. Nobukuni T, Joaquin M, Roccio M, Dann SG, Kim SY, Gulati P, Byfield MP, Backer JM, Natt F, Bos JL, Zwartkruis FJ, Thomas G (2005) Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci USA 102:14238–14243

    CAS  PubMed  Google Scholar 

  112. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (2005) Rheb binds and regulates the mTOR kinase. Curr Biol 15:702–713

    CAS  PubMed  Google Scholar 

  113. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25:903–915

    CAS  PubMed  Google Scholar 

  114. Sato T, Nakashima A, Guo L, Tamanoi F (2009) Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J Biol Chem 284:12783–12791

    CAS  PubMed  Google Scholar 

  115. Tee AR, Blenis J, Proud CG (2005) Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1. FEBS Lett 579:4763–4768

    CAS  PubMed  Google Scholar 

  116. Marks AR (1996) Cellular functions of immunophilins. Physiol Rev 76:631–649

    CAS  PubMed  Google Scholar 

  117. Nielsen JV, Mitchelmore C, Pedersen KM, Kjaerulff KM, Finsen B, Jensen NA (2004) Fkbp8: novel isoforms, genomic organization, and characterization of a forebrain promoter in transgenic mice. Genomics 83:181–192

    CAS  PubMed  Google Scholar 

  118. Fischer G, Aumuller T (2003) Regulation of peptide bond cis/trans isomerization by enzyme catalysis and its implication in physiological processes. Rev Physiol Biochem Pharmacol 148:105–150

    CAS  PubMed  Google Scholar 

  119. Ratajczak T, Ward BK, Minchin RF (2003) Immunophilin chaperones in steroid receptor signalling. Curr Top Med Chem 3:1348–1357

    CAS  PubMed  Google Scholar 

  120. Griffith JP, Kim JL, Kim EE, Sintchak MD, Thomson JA, Fitzgibbon MJ, Fleming MA, Caron PR, Hsiao K, Navia MA (1995) X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex. Cell 82:507–522

    CAS  PubMed  Google Scholar 

  121. Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kalish VJ, Tucker KD, Showalter RE, Moomaw EW et al (1995) Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex. Nature 378:641–644

    CAS  PubMed  Google Scholar 

  122. Maestre-Martinez M, Edlich F, Jarczowski F, Weiwad M, Fischer G, Lucke C (2006) Solution structure of the FK506-binding domain of human FKBP38. J Biomol NMR 34:197–202

    CAS  PubMed  Google Scholar 

  123. Pedersen KM, Finsen B, Celis JE, Jensen NA (1999) muFKBP38: a novel murine immunophilin homolog differentially expressed in Schwannoma cells and central nervous system neurons in vivo. Electrophoresis 20:249–255

    CAS  PubMed  Google Scholar 

  124. Shirane M, Nakayama KI (2003) Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis. Nat Cell Biol 5:28–37

    CAS  PubMed  Google Scholar 

  125. Edlich F, Weiwad M, Erdmann F, Fanghanel J, Jarczowski F, Rahfeld JU, Fischer G (2005) Bcl-2 regulator FKBP38 is activated by Ca2+/calmodulin. EMBO J 24:2688–2699

    CAS  PubMed  Google Scholar 

  126. Bai X, Ma D, Liu A, Shen X, Wang QJ, Liu Y, Jiang Y (2007) Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 318:977–980

    CAS  PubMed  Google Scholar 

  127. Uhlenbrock K, Weiwad M, Wetzker R, Fischer G, Wittinghofer A, Rubio I (2009) Reassessment of the role of FKBP38 in the Rheb/mTORC1 pathway. FEBS Lett 583:965–970

    CAS  PubMed  Google Scholar 

  128. Dunlop EA, Dodd KM, Seymour LA, Tee AR (2009) Mammalian target of rapamycin complex 1-mediated phosphorylation of eukaryotic initiation factor 4E-binding protein 1 requires multiple protein–protein interactions for substrate recognition. Cell Signal 21:1073–1084

    CAS  PubMed  Google Scholar 

  129. Ma D, Bai X, Guo S, Jiang Y (2008) The switch I region of Rheb is critical for its interaction with FKBP38. J Biol Chem 283:25963–25970

    CAS  PubMed  Google Scholar 

  130. Wang X, Fonseca BD, Tang H, Liu R, Elia A, Clemens MJ, Bommer UA, Proud CG (2008) Re-evaluating the roles of proposed modulators of mammalian target of rapamycin complex 1 (mTORC1) signaling. J Biol Chem 283:30482–30492

    CAS  PubMed  Google Scholar 

  131. Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A, Dai N (2009) Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab 296:E592–E602

    CAS  PubMed  Google Scholar 

  132. Telerman A, Amson R (2009) The molecular programme of tumour reversion: the steps beyond malignant transformation. Nat Rev Cancer 9:206–216

    CAS  PubMed  Google Scholar 

  133. Chen SH, Wu PS, Chou CH, Yan YT, Liu H, Weng SY, Yang-Yen HF (2007) A knockout mouse approach reveals that TCTP functions as an essential factor for cell proliferation and survival in a tissue- or cell type-specific manner. Mol Biol Cell 18:2525–2532

    CAS  PubMed  Google Scholar 

  134. Rehmann H, Bruning M, Berghaus C, Schwarten M, Kohler K, Stocker H, Stoll R, Zwartkruis FJ, Wittinghofer A (2008) Biochemical characterisation of TCTP questions its function as a guanine nucleotide exchange factor for Rheb. FEBS Lett 582:3005–3010

    CAS  PubMed  Google Scholar 

  135. Kovacina KS, Park GY, Bae SS, Guzzetta AW, Schaefer E, Birnbaum MJ, Roth RA (2003) Identification of a proline-rich Akt substrate as a 14-3-3 binding partner. J Biol Chem 278:10189–10194

    CAS  PubMed  Google Scholar 

  136. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH (2007) Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 9:316–323

    CAS  PubMed  Google Scholar 

  137. Wang L, Harris TE, Roth RA, Lawrence JC Jr (2007) PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 282:20036–20044

    CAS  PubMed  Google Scholar 

  138. Oshiro N, Takahashi R, Yoshino K, Tanimura K, Nakashima A, Eguchi S, Miyamoto T, Hara K, Takehana K, Avruch J, Kikkawa U, 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

    CAS  PubMed  Google Scholar 

  139. Wang L, Harris TE, Lawrence JC 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

    CAS  PubMed  Google Scholar 

  140. Fonseca BD, Smith EM, Lee VH, MacKintosh C, Proud CG (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

    CAS  PubMed  Google Scholar 

  141. Dong J, Pan D (2004) Tsc2 is not a critical target of Akt during normal Drosophila development. Genes Dev 18:2479–2484

    CAS  PubMed  Google Scholar 

  142. Shah N, Pang B, Yeoh KG, Thorn S, Chen CS, Lilly MB, Salto-Tellez M (2008) Potential roles for the PIM1 kinase in human cancer—a molecular and therapeutic appraisal. Eur J Cancer 44:2144–2151

    CAS  PubMed  Google Scholar 

  143. Zhang F, Beharry ZM, Harris TE, Lilly MB, Smith CD, Mahajan S, Kraft AS (2009) PIM1 protein kinase regulates PRAS40 phosphorylation and mTOR activity in FDCP1 cells. Cancer Biol Ther 8:846–853

    CAS  PubMed  Google Scholar 

  144. Li H, Lin X (2008) Positive and negative signaling components involved in TNFalpha-induced NF-kappaB activation. Cytokine 41:1–8

    PubMed  Google Scholar 

  145. Häcker H, Karin M (2006) Regulation and function of IKK and IKK-related kinases. Sci STKE (357):re13. Accessed 17 Oct 2006

  146. Karin M (1999) How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex. Oncogene 18:6867–6874

    CAS  PubMed  Google Scholar 

  147. Ozes ON, Akca H, Mayo LD, Gustin JA, Maehama T, Dixon JE, Donner DB (2001) A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proc Natl Acad Sci USA 98:4640–4645

    CAS  PubMed  Google Scholar 

  148. Lee DF, Kuo HP, Chen CT, Hsu JM, Chou CK, Wei Y, Sun HL, Li LY, Ping B, Huang WC, He X, Hung JY, Lai CC, Ding Q, Su JL, Yang JY, Sahin AA, Hortobagyi GN, Tsai FJ, Tsai CH, Hung MC (2007) IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130:440–455

    CAS  PubMed  Google Scholar 

  149. Dan HC, Baldwin AS (2008) Differential involvement of IkappaB kinases alpha and beta in cytokine- and insulin-induced mammalian target of rapamycin activation determined by Akt. J Immunol 180:7582–7589

    CAS  PubMed  Google Scholar 

  150. Dan HC, Adli M, Baldwin AS (2007) Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells by I kappa B kinase alpha. Cancer Res 67:6263–6269

    CAS  PubMed  Google Scholar 

  151. Singer WD, Brown HA, Sternweis PC (1997) Regulation of eukaryotic phosphatidylinositol-specific phospholipase C and phospholipase D. Annu Rev Biochem 66:475–509

    CAS  PubMed  Google Scholar 

  152. McDermott M, Wakelam MJ, Morris AJ (2004) Phospholipase D. Biochem Cell Biol 82:225–253

    CAS  PubMed  Google Scholar 

  153. Andresen BT, Rizzo MA, Shome K, Romero G (2002) The role of phosphatidic acid in the regulation of the Ras/MEK/Erk signaling cascade. FEBS Lett 531:65–68

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  155. Sun Y, Chen J (2008) mTOR signaling: PLD takes center stage. Cell Cycle 7:3118–3123

    CAS  PubMed  Google Scholar 

  156. Toschi A, Lee E, Xu L, Garcia A, Gadir N, Foster DA (2009) Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid: competition with rapamycin. Mol Cell Biol 29:1411–1420

    CAS  PubMed  Google Scholar 

  157. Fang Y, Park IH, Wu AL, Du G, Huang P, Frohman MA, Walker SJ, Brown HA, Chen J (2003) PLD1 regulates mTOR signaling and mediates Cdc42 activation of S6K1. Curr Biol 13:2037–2044

    CAS  PubMed  Google Scholar 

  158. Ha SH, Kim DH, Kim IS, Kim JH, Lee MN, Lee HJ, Kim JH, Jang SK, Suh PG, Ryu SH (2006) PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals. Cell Signal 18:2283–2291

    CAS  PubMed  Google Scholar 

  159. Lehman N, Ledford B, Di Fulvio M, Frondorf K, McPhail LC, Gomez-Cambronero J (2007) Phospholipase D2-derived phosphatidic acid binds to and activates ribosomal p70 S6 kinase independently of mTOR. Faseb J 21:1075–1087

    CAS  PubMed  Google Scholar 

  160. Sun Y, Fang Y, Yoon MS, Zhang C, Roccio M, Zwartkruis FJ, Armstrong M, Brown HA, Chen J (2008) Phospholipase D1 is an effector of Rheb in the mTOR pathway. Proc Natl Acad Sci USA 105:8286–8291

    CAS  PubMed  Google Scholar 

  161. Exton JH (2002) Regulation of phospholipase D. FEBS Lett 531:58–61

    CAS  PubMed  Google Scholar 

  162. Chou MM, Blenis J (1996) The 70 kDa S6 kinase complexes with and is activated by the Rho family G proteins Cdc42 and Rac1. Cell 85:573–583

    CAS  PubMed  Google Scholar 

  163. Nishimoto T (2000) Upstream and downstream of ran GTPase. Biol Chem 381:397–405

    CAS  PubMed  Google Scholar 

  164. Schurmann A, Brauers A, Massmann S, Becker W, Joost HG (1995) Cloning of a novel family of mammalian GTP-binding proteins (RagA, RagBs, RagB1) with remote similarity to the Ras-related GTPases. J Biol Chem 270:28982–28988

    CAS  PubMed  Google Scholar 

  165. Sekiguchi T, Hirose E, Nakashima N, Ii M, Nishimoto T (2001) Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B. J Biol Chem 276:7246–7257

    CAS  PubMed  Google Scholar 

  166. Nakashima N, Noguchi E, Nishimoto T (1999) Saccharomyces cerevisiae putative G protein, Gtr1p, which forms complexes with itself and a novel protein designated as Gtr2p, negatively regulates the Ran/Gsp1p G protein cycle through Gtr2p. Genetics 152:853–867

    CAS  PubMed  Google Scholar 

  167. Wang Y, Nakashima N, Sekiguchi T, Nishimoto T (2005) Saccharomyces cerevisiae GTPase complex: Gtr1p-Gtr2p regulates cell-proliferation through Saccharomyces cerevisiae Ran-binding protein, Yrb2p. Biochem Biophys Res Commun 336:639–645

    CAS  PubMed  Google Scholar 

  168. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320:1496–1501

    CAS  PubMed  Google Scholar 

  169. Gao M, Kaiser CA (2006) A conserved GTPase-containing complex is required for intracellular sorting of the general amino-acid permease in yeast. Nat Cell Biol 8:657–667

    CAS  PubMed  Google Scholar 

  170. Buerger C, DeVries B, Stambolic V (2006) Localization of Rheb to the endomembrane is critical for its signaling function. Biochem Biophys Res Commun 344:869–880

    CAS  PubMed  Google Scholar 

  171. Takahashi K, Nakagawa M, Young SG, Yamanaka S (2005) Differential membrane localization of ERas and Rheb, two Ras-related proteins involved in the phosphatidylinositol 3-kinase/mTOR pathway. J Biol Chem 280:32768–32774

    CAS  PubMed  Google Scholar 

  172. Schu PV, Takegawa K, Fry MJ, Stack JH, Waterfield MD, Emr SD (1993) Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science 260:88–91

    CAS  PubMed  Google Scholar 

  173. Kapeller R, Cantley LC (1994) Phosphatidylinositol 3-kinase. Bioessays 16:565–576

    CAS  PubMed  Google Scholar 

  174. Stack JH, Herman PK, Schu PV, Emr SD (1993) A membrane-associated complex containing the Vps15 protein kinase and the Vps34 PI 3-kinase is essential for protein sorting to the yeast lysosome-like vacuole. EMBO J 12:2195–2204

    CAS  PubMed  Google Scholar 

  175. Byfield MP, Murray JT, Backer JM (2005) hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem 280:33076–33082

    CAS  PubMed  Google Scholar 

  176. Gulati P, Gaspers LD, Dann SG, Joaquin M, Nobukuni T, Natt F, Kozma SC, Thomas AP, Thomas G (2008) Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab 7:456–465

    CAS  PubMed  Google Scholar 

  177. Stein MP, Feng Y, Cooper KL, Welford AM, Wandinger-Ness A (2003) Human VPS34 and p150 are Rab7 interacting partners. Traffic 4:754–771

    CAS  PubMed  Google Scholar 

  178. Drenan RM, Liu X, Bertram PG, Zheng XF (2004) FKBP12-rapamycin-associated protein or mammalian target of rapamycin (FRAP/mTOR) localization in the endoplasmic reticulum and the Golgi apparatus. J Biol Chem 279:772–778

    CAS  PubMed  Google Scholar 

  179. Zhang X, Shu L, Hosoi H, Murti KG, Houghton PJ (2002) Predominant nuclear localization of mammalian target of rapamycin in normal and malignant cells in culture. J Biol Chem 277:28127–28134

    CAS  PubMed  Google Scholar 

  180. Desai BN, Myers BR, Schreiber SL (2002) FKBP12-rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. Proc Natl Acad Sci USA 99:4319–4324

    CAS  PubMed  Google Scholar 

  181. Liu X, Zheng XF (2007) Endoplasmic reticulum and Golgi localization sequences for mammalian target of rapamycin. Mol Biol Cell 18:1073–1082

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank their colleagues for stimulating discussion and critical reading of this manuscript. This work was supported by NIH grants CA129821 and GM068832 to YJ.

Author information

Authors and Affiliations

  1. Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China

    Xiaochun Bai

  2. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Yu Jiang

Authors
  1. Xiaochun Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xiaochun Bai or Yu Jiang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bai, X., Jiang, Y. Key factors in mTOR regulation. Cell. Mol. Life Sci. 67, 239–253 (2010). https://doi.org/10.1007/s00018-009-0163-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-009-0163-7

Keywords

Search

Navigation