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Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

Abstract

Cell growth (an increase in cell mass and size through macromolecular biosynthesis) and cell cycle progression are generally tightly coupled, allowing cells to proliferate continuously while maintaining their size. The target of rapamycin (TOR) is an evolutionarily conserved kinase that integrates signals from nutrients (amino acids and energy) and growth factors (in higher eukaryotes) to regulate cell growth and cell cycle progression coordinately. In mammals, TOR is best known to regulate translation through the ribosomal protein S6 kinases (S6Ks) and the eukaryotic translation initiation factor 4E-binding proteins. Consistent with the contribution of translation to growth, TOR regulates cell, organ, and organismal size. The identification of the tumor suppressor proteins tuberous sclerosis1 and 2 (TSC1 and 2) and Ras-homolog enriched in brain (Rheb) has biochemically linked the TOR and phosphatidylinositol 3-kinase (PI3K) pathways, providing a mechanism for the crosstalk that occurs between these pathways. TOR is emerging as a novel antitumor target, since the TOR inhibitor rapamycin appears to be effective against tumors resulting from aberrantly high PI3K signaling. Not only may inhibition of TOR be effective in cancer treatment, but rapamycin is an FDA-approved immunosuppressive and cardiology drug. We review here what is known (and not known) about the function of TOR in cellular and animal physiology.

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References

  • Abraham RT and Wiederrecht GJ . (1996). Annu. Rev. Immunol., 14, 483–510.

  • Abraham RT . (2002). Cell, 111, 9–12.

  • Alarcon CM, Heitman J and Cardenas ME . (1999). Mol. Cell. Biol., 10, 2531–2546.

  • Alessi DR, Kozlowski MT, Weng QP, Morrice N and Avruch J . (1998). Curr. Biol., 8, 69–81.

  • Alvarez B, Garrido E, Garcia-Sanz JA and Carrera AC . (2003). J. Biol. Chem., 278, 26466–26473.

  • Aoki M, Blazek E and Vogt PK . (2001). Proc. Natl. Acad. Sci. USA, 98, 136–141.

  • Araki E, Lipes MA, Patti ME, Bruning JC, Haag III B, Johnson RS and Kahn CR . (1994). Nature, 372, 186–190.

  • Barbet NC, Schneider U, Helliwell SB, Stansfield I, Tuite MF and Hall MN . (1996). Mol. Cell. Biol., 7, 25–42.

  • Beck T and Hall MN . (1999). Nature, 402, 689–692.

  • Beugnet A, Tee AR, Taylor PM and Proud CG . (2003). Biochem. J., 372, 555–566.

  • Biondi RM, Kieloch A, Currie RA, Deak M and Alessi DR . (2001). EMBO J., 20, 4380–4390.

  • Blommaart EF, Luiken JJ, Blommaart PJ, van Woerkom GM and Meijer AJ . (1995). J. Biol. Chem., 270, 2320–2326.

  • Bohni R, Riesgo-Escovar J, Oldham S, Brogiolo W, Stocker H, Andruss BF, Beckingham K and Hafen E . (1999). Cell, 97, 865–875.

  • Braun-Dullaeus RC, Mann MJ, Seay U, Zhang L, von Der Leyen HE, Morris RE and Dzau VJ . (2001). Arterioscler. Thromb. Vasc. Biol., 21, 1152–1158.

  • Brennan P, Babbage JW, Thomas G and Cantrell D . (1999). Mol. Cell. Biol., 19, 4729–4738.

  • Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS and Schreiber SL . (1994). Nature, 369, 756–758.

  • Brown EJ, Beal PA, Keith CT, Chen J, Shin TB and Schreiber SL . (1995). Nature, 377, 441–446.

  • Brunn GJ, Hudson CC, Sekulic A, Williams JM, Hosoi H, Houghton PJ, Lawrence Jr JC and Abraham RT . (1997). Science, 277, 99–101.

  • Brunn GJ, Williams J, Sabers C, Wiederrecht G, Lawrence Jr JC and Abraham RT . (1996). EMBO J., 15, 5256–5267.

  • Burnett PE, Barrow RK, Cohen NA, Snyder SH and Sabatini DM . (1998). Proc. Natl. Acad. Sci. USA, 95, 1432–1437.

  • Cafferkey R, Young PR, McLaughlin MM, Bergsma DJ, Koltin Y, Sathe GM, Faucette L, Eng WK, Johnson RK and Livi GP . (1993). Mol. Cell. Biol., 13, 6012–6023.

  • Cantley LC . (2002). Science, 296, 1655–1657.

  • Castro AF, Rebhun JF, Clark GJ and Quilliam LA . (2003). J. Biol. Chem., 278, 32493–32496.

  • Cheatham L, Monfar M, Chou MM and Blenis J . (1995). Proc. Natl. Acad. Sci. USA, 92, 11696–11700.

  • Chen Y, Chen H, Rhoad AE, Warner L, Caggiano TJ, Failli A, Zhang H, Hsiao C-L, Nakanishi K and Molnar-Kimber KL . (1994). Biochem. Biophys. Res. Commun., 203, 1–7.

  • Chen Y-R, Meyer CF and Tan T-H . (1996). J. Biol. Chem., 271, 631–634.

  • Chen J, Zheng XF, Brown EJ and Schreiber SL . (1995). Proc. Natl. Acad. Sci. USA, 92, 4947–4951.

  • Chen Y, Zheng Y and Foster DA . (2003). Oncogene, 22, 3937–3942.

  • Chiu MI, Katz H and Berlin V . (1994). Proc. Natl. Acad. Sci., 91, 12574–12578.

  • Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw III EB, Kaestner KH, Bartolomei MS, Shulman GI and Birnbaum MJ . (2001a). Science, 292, 1728–1731.

  • Cho H, Thorvaldsen JL, Chu Q, Feng F and Birnbaum MJ . (2001b). J. Biol. Chem., 276, 38349–38352.

  • Choi J, Chen J, Schreiber SL and Clardy J . (1996). Science, 273, 239–242.

  • Choi KM, McMahon LP and Lawrence Jr JC . (2003). J. Biol. Chem., 278, 19667–19673.

  • Chou MM and Blenis J . (1996). Cell, 85, 573–583.

  • Colombani J, Raisin S, Pantalacci S, Radimerski T, Montagne J and Leopold P . (2003). Cell, 114, 739–749.

  • Conlon IJ, Dunn GA, Mudge AW and Raff MC . (2001). Nat. Cell. Biol., 3, 918–921.

  • Crespo JL and Hall MN . (2002). Microbiol. Mol. Biol. Rev., 66, 579–591 table of contents.

  • Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, Pledger WJ and Cheng JQ . (2002). J. Biol. Chem., 277, 35364–35370.

  • Datar SA, Jacobs HW, de la Cruz AF, Lehner CF and Edgar BA . (2000). EMBO J., 19, 4543–4554.

  • De Benedetti A and Harris AL . (1999). Int. J. Biochem. Cell. Biol., 31, 59–72.

  • de Groot RP, Ballou LM and Sasssone-Corsi P . (1994). Cell, 79, 81–91.

  • Dennis PB, Jaeschke A, Saitoh M, Fowler B, Kozma SC and Thomas G . (2001). Science, 294, 1102–1105.

  • Di Como CJ and Arndt KT . (1996). Genes Dev., 10, 1904–1916.

  • Diehl JA, Cheng M, Roussel MF and Sherr CJ . (1998). Genes Dev., 12, 3499–3511.

  • Dolinski K, Muir S, Cardenas M and Heitman J . (1997). Proc. Natl. Acad. Sci. USA, 94, 13093–13098.

  • Dufner A, Andjelkovic M, Burgering BM, Hemmings BA and Thomas G . (1999). Mol. Cell. Biol., 19, 4525–4534.

  • Edinger AL and Thompson CB . (2002). Mol. Cell. Biol., 13, 2276–2288.

  • Elit L . (2002). Curr. Opin. Invest. Drugs., 3, 1249–1253.

  • Fang Y, Park IH, Wu AL, Du G, Huang P, Frohman MA, Walker SJ, Brown HA and Chen J . (2003). Curr. Biol., 13, 2037–2044.

  • Fang Y, Vilella-Bach M, Bachmann R, Flanigan A and Chen J . (2001). Science, 294, 1942–1945.

  • Faridi J, Fawcett J, Wang L and Roth RA . (2003). Am. J. Physiol. Endocrinol. Metab., 285, E964–72.

  • Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C and Blenis J . (2004). Mol. Biol. Cell., 24, 200–216.

  • Fingar DC, Salama S, Tsou C, Harlow E and Blenis J . (2002). Genes Dev., 16, 1472–1487.

  • Flick K, Chapman-Shimshoni D, Stuart D, Guaderrama M and Wittenberg C . (1998). Mol. Cell. Biol., 18, 2492–2501.

  • Gallo R, Padurean A, Jayaraman T, Marx S, Roque M, Adelman S, Chesebro J, Fallon J, Fuster V, Marks A and Badimon JJ . (1999). Circulation, 99, 2164–2170.

  • Gao X and Pan D . (2001). Genes Dev., 15, 1383–1392.

  • Gao X, Neufeld TP and Pan D . (2000). Dev. Biol., 221, 404–418.

  • Gao X, Zhang Y, Arrazola P, Hino O, Kobayashi T, Yeung RS, Ru B and Pan D . (2002). Nat. Cell. Biol., 4, 699–704.

  • Garami A, Zwartkruis FJT, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma S, Hafen E, Bos JL and Thomas G . (2003). Mol. Cell, 11, 1457–1466.

  • Gera JF, Mellinghoff IK, Shi Y, Rettig MB, Tran C, Hsu JH, Sawyers CL and Lichtenstein AK . (2003). J. Biol. Chem., 279, 2737–2746.

  • Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, Aebersold R and Sonenberg N . (1999a). Genes Dev., 13, 1422–1437.

  • Gingras AC, Kennedy SG, O’Leary MA, Sonenberg N and Hay N . (1998). Genes Dev., 12, 502–513.

  • Gingras AC, Raught B and Sonenberg N . (2001b). Genes Dev., 15, 807–826.

  • Gingras AC, Raught B, Gygi SP, Niedzwiecka A, Miron M, Burley SK, Polakiewicz RD, Wyslouch-Cieszynska A, Aebersold R and Sonenberg N . (2001a). Genes Dev., 15, 2852–2864.

  • Goberdhan DC, Paricio N, Goodman EC, Mlodzik M and Wilson C . (1999). Genes Dev., 13, 3244–3258.

  • Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, Yeung RS, Walker CL, Noonan D, Kwiatkowski DJ, Chou MM, Panettieri Jr RA and Krymskaya VP . (2002). J. Biol. Chem., 277, 30958–30967.

  • Gstaiger M, Luke B, Hess D, Oakeley EJ, Wirbelauer C, Blondel M, Vigneron M, Peter M and Krek W . (2003). Science, 302, 1208–1212.

  • Hahn WC and Weinberg RA . (2002). N. Engl. J. Med., 347, 1593–1603.

  • Hanahan D and Weinberg RA . (2000). Cell, 100, 57–70.

  • Hannan KM, Brandenburger Y, Jenkins A, Sharkey K, Cavanaugh A, Rothblum L, Moss T, Poortinga G, McArthur GA, Pearson RB and Hannan RD . (2003). Mol. Cell. Biol., 23, 8862–8877.

  • Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J and Yonezawa K . (2002). Cell, 110, 177–189.

  • Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C and Avruch J . (1998). J. Biol. Chem., 273, 14484–14494.

  • Harada H, Andersen JS, Mann M, Terada N and Korsmeyer SJ . (2001). Proc. Natl. Acad. Sci. USA, 98, 9666–9670.

  • Hardie DG and Hawley SA . (2001). BioEssays, 23, 1112–1119.

  • Harding MW, Galat A, Uehling DE and Schreiber SL . (1989). Nature, 341, 758–760.

  • Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR and Hardie DG . (2003). J. Biol., 2, 28.

  • Haystead TA, Haystead CM, Hu C, Lin TA and Lawrence Jr JC . (1994). J. Biol. Chem., 269, 23185–23191.

  • Heesom KJ and Denton RM . (1999). FEBS Lett., 457, 489–493.

  • Heitman J, Movva NR and Hall MN . (1991). Science, 253, 905–909.

  • Helliwell SB, Wagner P, Kunz J, Deuter-Reinhard M, Henriquez R and Hall MN . (1994). Mol. Cell. Biol., 5, 105–118.

  • Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Hoglund P, Jarvinen H, Kristo P, Pelin K, Ridanpaa M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A and Aaltonen LA . (1998). Nature, 391, 184–187.

  • Hentges KE, Sirry B, Gingeras AC, Sarbassov D, Sonenberg N, Sabatini D and Peterson AS . (2001). Proc. Natl. Acad. Sci. USA, 98, 13796–13801.

  • Herbert TP, Tee AR and Proud CG . (2002). J. Biol. Chem., 277, 11591–11596.

  • Hidalgo M and Rowinsky EK . (2000). Oncogene, 19, 6680–6686.

  • Hong SP, Leiper FC, Woods A, Carling D and Carlson M . (2003). Proc. Natl. Acad. Sci. USA, 100, 8839–8843.

  • Huang S and Houghton PJ . (2003). Curr. Opin. Pharmacol., 3, 371–377.

  • Huang H, Potter CJ, Tao W, Li DM, Brogiolo W, Hafen E, Sun H and Xu T . (1999). Development, 126, 5365–5372.

  • Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ and Abraham RT . (2002). Mol. Cell. Biol., 22, 7004–7014.

  • Iiboshi Y, Papst PJ, Kawasome H, Hosoi H, Abraham RT, Houghton PJ and Terada N . (1999). J. Biol. Chem., 274, 1092–1099.

  • Inoki K, Li Y, Xu T and Guan KL . (2003a). Genes Dev., 17, 1829–1834.

  • Inoki K, Li Y, Zhu T, Wu J and Guan KL . (2002). Nat. Cell. Biol., 4, 648–657.

  • Inoki K, Zhu T and Guan KL . (2003b). Cell, 115, 577–590.

  • Isotani S, Hara K, Tokunaga C, Inoue H, Avruch J and Yonezawa K . (1999). J. Biol. Chem., 274, 34493–34498.

  • Jacinto E, Guo B, Arndt KT, Schmelzle T and Hall MN . (2001). Mol. Cell, 8, 1017–1026.

  • Jefferies HB, Fumagalli S, Dennis PB, Reinhard C, Pearson RB and Thomas G . (1997). EMBO J., 16, 3693–3704.

  • Jefferies HBJ, Reinhard C, Kozma SC and Thomas G . (1994). Proc. Natl. Acad. Sci., 91, 4441–4445.

  • Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Muller O, Back W and Zimmer M . (1998). Nat. Genet., 18, 38–43.

  • Jeno P, Ballou LM, Novak-Hofer I and Thomas G . (1988). Proc. Natl. Acad. Sci. USA, 85, 406–410.

  • Jiang Y and Broach JR . (1999). EMBO J., 18, 2782–2792.

  • Johnston GC, Pringle JR and Hartwell LH . (1977). Exp. Cell. Res., 105, 79–98.

  • Kawasome H, Papst P, Webb S, Keller GM, Johnson GL, Gelfand EW and Terada N . (1998). Proc. Natl. Acad. Sci. USA, 95, 5033–5038.

  • Keith CT and Schreiber SL . (1995). Science, 270, 50–51.

  • Kenyon C, Chang J, Gensch E, Rudner A and Tabtiang R . (1993). Nature, 366, 461–464.

  • Kim JE and Chen J . (2000). Proc. Natl. Acad. Sci. USA, 97, 14340–14345.

  • Kim DH, Sarbassov dos D, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P and Sabatini DM . (2003). Mol. Cell, 11, 895–904.

  • Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P and Sabatini DM . (2002). Cell, 110, 163–175.

  • Kimura N, Tokunaga C, Dalal S, Richardson C, Yoshino K, Hara K, Kemp BE, Witters LA, Mimura O and Yonezawa K . (2003). Genes Cells, 8, 65–79.

  • Kobayashi T, Minowa O, Kuno J, Mitani H, Hino O and Noda T . (1999). Cancer Res., 59, 1206–1211.

  • Kobayashi T, Minowa O, Sugitami Y, Takai S, Mitani H, Kobayashi E, Noda T and Hino O . (2001). PNAS, 98, 8762–8767.

  • Koltin Y, Faucette L, Bergsma DJ, Levy MA, Cafferkey R, Koser PL, Johnson RK and Livi GP . (1991). Mol. Cell. Biol., 11, 1718–1723.

  • Kozma SC and Thomas G . (2002). BioEssays, 24, 65–71.

  • Kunz J, Henriquez R, Schneider U, Deuter-Reinhard M, Movva NR and Hall MN . (1993). Cell, 73, 585–596.

  • Kwiatkowski DJ . (2003). Ann. Hum. Genet., 67, 87–96.

  • Lawlor MA, Mora A, Ashby PR, Williams MR, Murray-Tait V, Malone L, Prescott AR, Lucocq JM and Alessi DR . (2002). EMBO J., 21, 3728–3738.

  • Lazaris-Karatzas A, Montine KS and Sonenberg N . (1990). Nature, 345, 544–547.

  • Leevers SJ, Weinkove D, MacDougall LK, Hafen E and Waterfield MD . (1996). EMBO J., 15, 6584–6594.

  • Li S, Sonenberg N, Gingras AC, Peterson M, Avdulov S, Polunovsky VA and Bitterman PB . (2002). Mol. Cell. Biol., 22, 2853–2861.

  • Lin TA, Kong X, Haystead TA, Pause A, Belsham G, Sonenberg N and Lawrence Jr JC . (1994). Science, 266, 653–656.

  • Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, Oppliger W, Jenoe P and Hall MN . (2002). Mol. Cell, 10, 457–468.

  • Long X, Spycher C, Han ZS, Rose AM, Muller F and Avruch J . (2002). Curr. Biol., 12, 1448–1461.

  • Luo J, Manning BD and Cantley LC . (2003). Cancer Cell, 4, 257–262.

  • Ly C, Arechiga AF, Melo JV, Walsh CM and Ong ST . (2003). Cancer Res., 63, 5716–5722.

  • Mach KE, Furge KA and Albright CF . (2000). Genetics, 155, 611–622.

  • Mahalingam M and Templeton DJ . (1996). Mol. Cell. Biol., 16, 405–413.

  • Manning BD and Cantley LC . (2003a). Trends Biochem. Sci., 28, 573–576.

  • Manning BD and Cantley LC . (2003b). Biochem. Soc. Trans., 31, 573–578.

  • Manning BD, Tee AR, Logsdon MN, Blenis J and Cantley LC . (2002). Mol. Cell, 10, 151–162.

  • Marcotrigiano J, Gingras AC, Sonenberg N and Burley SK . (1999). Mol. Cell, 3, 707–716.

  • Marks AR . (2003). N. Engl. J. Med., 349, 1307–1309.

  • Martin KA and Blenis J . (2002). Adv. Cancer Res., 86, 1–39.

  • Martin KA, Rzucidlo EM, Merenick BL, Fingar DC, Brown DJ, Wagner RJ and Powell RJ . (2003). Am. J. Physiol. Cell. Physiol., 286, C507–C517.

  • Matsumoto S, Bandyopadhyay A, Kwiatkowski DJ, Maitra U and Matsumoto T . (2002). Genetics, 161, 1053–1063.

  • Meyer CA, Jacobs HW, Datar SA, Du W, Edgar BA and Lehner CF . (2000). EMBO J., 19, 4533–4542.

  • Miron M, Verdu J, Lachance PE, Birnbaum MJ, Lasko PF and Sonenberg N . (2001). Nat. Cell. Biol., 3, 596–601.

  • Mohi GM, Boulton C, Gu TL, Sternberg DW, Neuberg D, Griffin JD, Gilliland DG and Neel BG . (2004). Proc. Natl. Acad. Sci. USA, 101, 3130–3135.

  • Montagne J, Stewart MJ, Stocker H, Hafen E, Kozma SC and Thomas G . (1999). Science, 285, 2126–2129.

  • Mora A, Davies AM, Bertrand L, Sharif I, Budas GR, Jovanovic S, Mouton V, Kahn CR, Lucocq JM, Gray GA, Jovanovic A and Alessi DR . (2003). EMBO J., 22, 4666–4676.

  • Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F and Falotico R . (2002). N. Engl. J. Med., 346, 1773–1780.

  • Moser BA, Dennis PB, Pullen N, Pearson RB, Williamson NA, Wettenhall RE, Kozma SC and Thomas G . (1997). Mol. Cell. Biol., 17, 5648–5655.

  • Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL and Kuntz RE . (2003). N. Engl. J. Med., 349, 1315–1323.

  • Mothe-Satney I, Brunn GJ, McMahon LP, Capaldo CT, Abraham RT and Lawrence Jr JC . (2000a). J. Biol. Chem., 275, 33836–33843.

  • Mothe-Satney I, Yang D, Fadden P, Haystead TA and Lawrence Jr JC . (2000b). Mol. Cell. Biol., 20, 3558–3567.

  • Murata K, Wu J and Brautigan DL . (1997). Proc. Natl. Acad. Sci. USA, 94, 10624–10629.

  • Nanahoshi M, Nishiuma T, Tsujishita Y, Hara K, Inui S, Sakaguchi N and Yonezawa K . (1998). Biochem. Biophys. Res. Commun., 251, 520–526.

  • Nave BT, Ouwens M, Withers DJ, Alessi DR and Shepherd PR . (1999). Biochem. J., 344 (Part 2), 427–431.

  • Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H and Sawyers CL . (2001). Proc. Natl. Acad. Sci. USA, 98, 10314–10319.

  • Neufeld TP, de la Cruz AF, Johnston LA and Edgar BA . (1998). Cell, 93, 1183–1193.

  • Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K, Hara K, Tanaka N, Avruch J and Yonezawa K . (2003). J. Biol. Chem., 278, 15461–15464.

  • Oldham S and Hafen E . (2003). Trends Cell. Biol., 13, 79–85.

  • Oldham S, Montagne J, Radimerski T, Thomas G and Hafen E . (2000). Genes Dev., 14, 2689–2694.

  • Onda H, Lueck A, Morks PW, Warren HB and Kwiatkowski DJ . (1999). J. Clin. invest., 104, 687–695.

  • Owens GK . (1995). Physiol. Rev., 75, 487–517.

  • Pearson RB, Dennis PB, Han JW, Williamson NA, Kozma SC, Wettenhall RE and Thomas G . (1995). EMBO J., 14, 5279–5287.

  • Pende M, Kozma SC, Jaquet M, Oorschot V, Burcelin R, Le Marchand-Brustel Y, Klumperman J, Thorens B and Thomas G . (2000). Nature, 408, 994–997.

  • Peng T, Golub TR and Sabatini DM . (2002). Mol. Cell. Biol., 22, 5575–5584.

  • Perry J and Kleckner N . (2003). Cell, 112, 151–155.

  • Peterson RT, Beal PA, Comb MJ and Schreiber SL . (2000). J. Biol. Chem., 275, 7416–7423.

  • Peterson RT, Desai BN, Hardwick JS and Schreiber SL . (1999). Proc. Natl. Acad. Sci. USA, 96, 4438–4442.

  • Podsypanina K, Lee RT, Politis C, Hennessy I, Crane A, Puc J, Neshat M, Wang H, Yang L, Gibbons J, Frost P, Dreisbach V, Blenis J, Gaciong Z, Fisher P, Sawyers C, Hedrick-Ellenson L and Parsons R . (2001). Proc. Natl. Acad. Sci. USA, 98, 10320–10325.

  • Polymenis M and Schmidt EV . (1997). Genes Dev., 11, 2522–2531.

  • Poon M, Marx SO, Gallo R, Badimon JJ, Taubman MB and Marks AR . (1996). J. Clin. Invest., 98, 2277–2283.

  • Potter CJ, Huang H and Xu T . (2001). Cell, 105, 357–368.

  • Potter CJ, Pedraza LG and Xu T . (2002). Nat. Cell. Biol., 4, 658–665.

  • Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA and Thomas G . (1998). Science, 279, 707–710.

  • Radimerski T, Montagne J, Hemmings-Mieszczak M and Thomas G . (2002). Genes Dev., 16, 2627–2632.

  • Rajasekhar VK, Viale A, Socci ND, Wiedmann M, Hu X and Holland EC . (2003). Mol. Cell, 12, 889–901.

  • Rameh LE and Cantley LC . (1999). J. Biol. Chem., 274, 8347–8350.

  • Richardson CR, Broenstrup M, Fingar DC, Juelich K, Gygi S and Blenis J Submitted.

  • Rintelen F, Stocker H, Thomas G and Hafen E . (2001). Proc. Natl. Acad. Sci. USA, 98, 15020–15025.

  • Rohde J, Heitman J and Cardenas ME . (2001). J. Biol. Chem., 276, 9583–9586.

  • Romanelli A, Dreisbach VC and Blenis J . (2002). J. Biol. Chem., 277, 40281–40289.

  • Romanelli A, Martin KA, Toker A and Blenis J . (1999). Mol. Cell. Biol., 19, 2921–2928.

  • Rommel C, Bodine SC, Clarke BA, Rossman R, Nunez L, Stitt TN, Yancopoulos GD and Glass DJ . (2001). Nat. Cell Biol., 3, 1009–1013.

  • Roque M, Cordon-Cardo C, Fuster V, Reis ED, Drobnjak M and Badimon JJ . (2000). Atherosclerosis, 153, 315–322.

  • Rosner M, Hofer K, Kubista M and Hengstschlager M . (2003). Oncogene, 22, 4786–4798.

  • Rossig L, Jadidi AS, Urbich C, Badorff C, Zeiher AM and Dimmeler S . (2001). Mol. Cell. Biol., 21, 5644–5657.

  • Ruggero D and Pandolfi PP . (2003). Nat. Rev. Cancer, 3, 179–192.

  • Sabatini DM, Barrow RK, Blackshaw S, Burnett PE, Lai MM, Field ME, Bahr BA, Kirsch J, Betz H and Snyder SH . (1999). Science, 284, 1161–1164.

  • Sabatini DM, Pierchala BA, Barrow RK, Schell MJ and Snyder SH . (1995). J. Biol. Chem., 270, 20875–20878.

  • Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G and Abraham RT . (1995). J. Biol. Chem., 270, 815–822.

  • Saltiel AR and Kahn CR . (2001). Nature, 414, 799–806.

  • Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D and Edgar BA . (2003). Nat. Cell Biol., 5, 566–571.

  • Schalm SS and Blenis J . (2002). Curr. Biol., 12, 632–639.

  • Schalm SS, Fingar DC, Sabatini DM and Blenis J . (2003). Curr. Biol., 13, 797–806.

  • Schmelzle T and Hall MN . (2000). Cell., 103, 253–262.

  • Schmidt A, Kunz J and Hall MN . (1996). Proc. Natl. Acad. Sci. USA., 93, 13780–13785.

  • Schreiber SL . (1991). Science, 251, 283–287.

  • Sehgal SN . (2003). Transplant Proc., 35, 7S–14S.

  • Sekulic A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM and Abraham RT . (2000). Cancer Res., 60, 3504–3513.

  • Shamji AF, Nghiem P and Schreiber SL . (2003). Mol. Cell., 12, 271–280.

  • Shaw R, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA and Cantley LC . (2004). Proc. Natl. Acad. Sci. USA., 101, 3329–3335.

  • Shigemitsu K, Tsujishita Y, Hara K, Nanahoshi M, Avruch J and Yonezawa K . (1999). J. Biol. Chem., 274, 1058–1065.

  • Shima H, Pende M, Chen Y, Fumagalli S, Thomas G and Kozma SC . (1998). Embo J., 17, 6649–6659.

  • Shioi T, Kang PM, Douglas PS, Hampe J, Yballe CM, Lawitts J, Cantley LC and Izumo S . (2000). Embo J., 19, 2537–2548.

  • Shioi T, McMullen JR, Kang PM, Douglas PS, Obata T, Franke TF, Cantley LC and Izumo S . (2002). Mol. Cell. Biol., 22, 2799–2809.

  • Shiojima I, Yefremashvili M, Luo Z, Kureishi Y, Takahashi A, Tao J, Rosenzweig A, Kahn CR, Abel ED and Walsh K . (2002). J. Biol. Chem., 277, 37670–37677.

  • Siekierka JJ, Hung SH, Poe M, Lin CS and Sigal NH . (1989). Nature, 341, 755–757.

  • Siekierka JJ, Wiederrecht G, Greulich H, Boulton D, Hung SH, Cryan J, Hodges PJ and Sigal NH . (1990). J. Biol. Chem., 265, 21011–21015.

  • Sonenberg N and Gingras AC . (1998). Curr. Opin. Cell. Biol., 10, 268–275.

  • Stan R, McLaughlin MM, Cafferkey R, Johnson RK, Rosenberg M and Livi GP . (1994). J. Biol. Chem., 269, 32027–32030.

  • Stocker H and Hafen E . (2000). Curr. Opin. Genet. Dev., 10, 529–535.

  • Stocker H, Radimerski T, Schindelholz B, Wittwer F, Belawat P, Daram P, Breuer S, Thomas G and Hafen E . (2003). Nat. Cell. Biol., 5, 559–565.

  • Stolovich M, Tang H, Hornstein E, Levy G, Cohen R, Bae SS, Birnbaum MJ and Meyuhas O . (2002). Mol. Cell. Biol., 22, 8101–8113.

  • Takata M, Ogawa W, Kitamura T, Hino Y, Kuroda S, Kotani K, Klip A, Gingras AC, Sonenberg N and Kasuga M . (1999). J. Biol. Chem., 274, 20611–20618.

  • Tang H, Hornstein E, Stolovich M, Levy G, Livingstone M, Templeton D, Avruch J and Meyuhas O . (2001). Mol. Cell. Biol., 21, 8671–8683.

  • Tapon N, Ito N, Dickson BJ, Treisman JE and Hariharan IK . (2001a). Cell., 105, 345–355.

  • Tapon N, Moberg KH and Hariharan IK . (2001b). Curr. Opin. Cell. Biol., 13, 731–737.

  • Tee AR, Anjum R and Blenis J . (2003a). J. Biol. Chem., 278, 37288–37296.

  • Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC and Blenis J . (2002). Proc. Natl. Acad. Sci. USA., 99, 13571–13576.

  • Tee AR, Manning BD, Roux PP, Cantley LC and Blenis J . (2003b). Curr. Biol., 13, 1259–1268.

  • Terada N, Patel HR, Takase K, Kohno K, Nairn AC and Gelfand EW . (1994). PNAS., 91, 11477–11481.

  • Urano J, Tabancay AP, Yang W and Tamanoi F . (2000). J. Biol. Chem., 275, 11198–11206.

  • Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L and Muller F . (2003). Nature, 426, 620.

  • Verdu J, Buratovich MA, Wilder EL and Birnbaum MJ . (1999). Nat. Cell. Biol., 1, 500–506.

  • Vilella-Bach M, Nuzzi P, Fang Y and Chen J . (1999). J. Biol. Chem., 274, 4266–4272.

  • Vinals F, Chambard JC and Pouyssegur J . (1999). J. Biol. Chem., 274, 26776–26782.

  • Vivanco I and Sawyers CL . (2002). Nat. Rev. Cancer, 2, 489–501.

  • Vogt PK . (2001). Trends Mol. Med., 7, 482–484.

  • von Manteuffel SR, Dennis PB, Pullen N, Gingras AC, Sonenberg N and Thomas G . (1997). Mol. Cell. Biol., 17, 5426–5436.

  • von Manteuffel SR, Gingras AC, Ming XF, Sonenberg N and Thomas G . (1996). Proc. Natl. Acad. Sci. USA., 93, 4076–4080.

  • Wang X, Li W, Williams M, Terada N, Alessi DR and Proud CG . (2001). Embo J., 20, 4370–4379.

  • Weigmann K, Cohen SM and Lehner CF . (1997). Development, 124, 3555–3563.

  • Weinkove D and Leevers SJ . (2000). Curr. Opin. Genet. Dev., 10, 75–80.

  • Weng Q-p, Andrabi K, Kozlowski MT, Grove JR and Avruch J . (1995). M.C.B., 15, 2333–2340.

  • Weng QP, Kozlowski M, Belham C, Zhang A, Comb MJ and Avruch J . (1998). J. Biol. Chem., 273, 16621–16629.

  • Westphal RS, Coffee RL, Jr, Marotta A, Pelech SL and Wadzinski BE . (1999). J. Biol. Chem., 274, 687–692.

  • Wiederrecht G, Brizuela L, Elliston K, Sigal NH and Siekierka JJ . (1991). Proc. Natl. Acad. Sci. USA., 88, 1029–1033.

  • Williams MR, Arthur JS, Balendran A, van der Kaay J, Poli V, Cohen P and Alessi DR . (2000). Curr. Biol., 10, 439–448.

  • Wilson KF, Wu WJ and Cerione RA . (2000). J. Biol. Chem., 275, 37307–37310.

  • Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner-Weir S and White MF . (1998). Nature, 391, 900–904.

  • Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M and Carling D . (2003). Curr. Biol., 13, 2004–2008.

  • Yokogami K, Wakisaka S, Avruch J and Reeves SA . (2000). Curr. Biol., 10, 47–50.

  • Zhang H, Stallock JP, Ng JC, Reinhard C and Neufeld TP . (2000). Genes. Dev., 14, 2712–2724.

  • Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA and Pan D . (2003). Nat.Cell. Biol., 5, 578–581.

  • Zhou BP, Liao Y, Xia W, Spohn B, Lee MH and Hung MC . (2001). Nat. Cell. Biol., 3, 245–252.

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Acknowledgements

We thank Celeste J Richardson, Kathy A Martin, and Martin Myers Jr for critical reading of the paper. This work was supported by NIH Grant #GM051405. We are also thankful for the support of the Tuberous Sclerosis Alliance and The Rothberg Courage Fund.

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Fingar, D., Blenis, J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 23, 3151–3171 (2004). https://doi.org/10.1038/sj.onc.1207542

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