Mammalian target of rapamycin
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The '''mammalian target of [[rapamycin]]''' ('''mTOR''') is a [[serine/threonine protein kinase]] that regulates cell growth, [[cell proliferation]], cell [[motility]], cell survival, [[protein synthesis]], and [[Transcription (genetics)|transcription]].<ref name=Hay>{{cite journal |author=Hay N, Sonenberg N |title=Upstream and downstream of mTOR |url=http://www.genesdev.org/cgi/content/full/18/16/1926| journal=Genes Dev |volume=18 |issue=16 |pages=1926–45 |year=2004 |pmid=15314020 |doi=10.1101/gad.1212704}}</ref><ref name=Beevers>{{cite journal |author=Beevers C, Li F, Liu L, Huang S |title=Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells |journal=Int J Cancer |volume=119 |issue=4 |pages=757–64 |year=2006 |pmid=16550606 |doi=10.1002/ijc.21932}}</ref>
==Function==
Current research indicates that mTOR integrates the input from multiple upstream pathways, including [[insulin]], [[growth factors]] (such as [[IGF-1]] and [[IGF-2]]), and [[mitogen]]s.<ref name=Hay/> mTOR also functions as a sensor of cellular nutrient and energy levels and [[redox]] status.<ref name=Tok>{{cite journal |author=Tokunaga C, Yoshino K, Yonezawa K |title=mTOR integrates amino acid- and energy-sensing pathways |journal=Biochem Biophys Res Commun |volume=313 |issue=2 |pages=443–6 |year=2004 |pmid=14684182 |doi=10.1016/j.bbrc.2003.07.019}}</ref> The dysregulation of the mTOR pathway is implicated as a contributing factor to various human disease processes, especially various types of [[cancer]].<ref name=Beevers/> [[Rapamycin]] is a bacterial natural product that can inhibit mTOR through association with its intracellular receptor [[FKBP|FKBP12]].<ref name=Huang2001>{{cite journal |author=Huang S, Houghton P |title=Mechanisms of resistance to rapamycins |journal=Drug Resist Updat |volume=4 |issue=6 |pages=378–91 |year=2001 |pmid=12030785 |doi=10.1054/drup.2002.0227}}</ref><ref name=Huang2003>{{cite journal |author=Huang S, Bjornsti M, Houghton P |title=Rapamycins: mechanism of action and cellular resistance |journal=Cancer Biol Ther |volume=2 |issue=3 |pages=222–32 |year=2003 |pmid=12878853}}</ref> The [[FKBP|FKBP12]]-[[rapamycin]] complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR.<ref name=Huang2003/>
mTOR has been shown to function as the [[catalytic]] subunit of two distinct molecular complexes in cells.<ref name=Wull>{{cite journal |author=Wullschleger S, Loewith R, Hall M |title=TOR signaling in growth and metabolism |journal=Cell |volume=124 |issue=3 |pages=471–84 |year=2006 |pmid=16469695 |doi=10.1016/j.cell.2006.01.016}}</ref>
==Complexes==
===mTORC1===
mTOR Complex 1 (mTORC1) is composed of mTOR, regulatory associated protein of mTOR (Raptor), and mammalian LST8/G-protein β-subunit like protein (mLST8/GβL).<ref name=Kim2002>{{cite journal |author=Kim D, Sarbassov D, Ali S, King J, Latek R, Erdjument-Bromage H, Tempst P, Sabatini D |title=mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery |journal=Cell |volume=110 |issue=2 |pages=163–75 |year=2002 |pmid=12150925 |doi=10.1016/S0092-8674(02)00808-5}}</ref><ref name=Kim2003>{{cite journal |author=Kim D, Sarbassov D, Ali S, Latek R, Guntur K, Erdjument-Bromage H, Tempst P, Sabatini D |title=GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR |journal=Mol Cell |volume=11 |issue=4 |pages=895–904 |year=2003 |pmid=12718876 |doi=10.1016/S1097-2765(03)00114-X}}</ref> This complex is characterized by the classic features of mTOR by functioning as a nutrient/energy/redox sensor and controlling protein synthesis.<ref name=Kim2002/><ref name=Hay/> The activity of this complex is stimulated by insulin, growth factors, [[serum]], [[phosphatidic acid]], [[amino acids]] (particularly [[leucine]]), and [[oxidative stress]].<ref name=Kim2002/><ref name=Fang>{{cite journal |author=Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J |title=Phosphatidic acid-mediated mitogenic activation of mTOR signaling |journal=Science |volume=294 |issue=5548 |pages=1942–5 |year=2001 |pmid=11729323 |doi=10.1126/science.1066015}}</ref>
mTORC1 is inhibited by low nutrient levels, growth factor deprivation, reductive stress, [[caffeine]], rapamycin, [[farnesylthiosalicylic acid]] (FTS) and [[curcumin]].<ref name=Kim2002/><ref name=McMahon>{{cite journal |author=McMahon L, Yue W, Santen R, Lawrence J |title=Farnesylthiosalicylic acid inhibits mammalian target of rapamycin (mTOR) activity both in cells and in vitro by promoting dissociation of the mTOR-raptor complex |url= http://mend.endojournals.org/cgi/content/full/19/1/175 |journal=Mol Endocrinol |volume=19 |issue=1 |pages=175–83 |year=2005 |pmid=15459249 |doi=10.1210/me.2004-0305}}</ref><ref name=Beevers/> The two best characterized targets of mTORC1 are [[p70-S6 Kinase 1]] (S6K1) and [[eIF4E|eukaryotic initiation factor 4E]] (eIF4E) binding protein 1 ([[4E-BP1]]).<ref name=Hay/>
mTORC1 [[phosphorylate]]s S6K1 on at least two residues, with the most critical modification occurring on a [[threonine]] residue<!--Thr389-->.<ref name=Saitoh>{{cite journal |author=Saitoh M, Pullen N, Brennan P, Cantrell D, Dennis P, Thomas G |title=Regulation of an activated S6 kinase 1 variant reveals a novel mammalian target of rapamycin phosphorylation site| url= http://www.jbc.org/cgi/content/full/277/22/20104 |journal=J Biol Chem |volume=277 |issue=22 |pages=20104–12 |year=2002 |pmid=11914378 |doi=10.1074/jbc.M201745200}}</ref><ref name=Pullen1997>{{cite journal |author=Pullen N, Thomas G |title=The modular phosphorylation and activation of p70s6k |journal=FEBS Lett |volume=410 |issue=1 |pages=78–82 |year=1997 |pmid=9247127 |doi=10.1016/S0014-5793(97)00323-2}}</ref> This event stimulates the subsequent phosphorylation of S6K1 by [[PDK1]].<ref name=Pullen1997/><ref name=Pullen1998>{{cite journal |author=Pullen N, Dennis P, Andjelkovic M, Dufner A, Kozma S, Hemmings B, Thomas G |title=Phosphorylation and activation of p70s6k by PDK1 |journal=Science |volume=279 |issue=5351 |pages=707–10 |year=1998 |pmid=9445476 |doi=10.1126/science.279.5351.707}}</ref> Active S6K1 can in turn stimulate the initiation of protein synthesis through activation of S6 Ribosomal protein (a component of the [[ribosome]]) and other components of the translational machinery.<ref name=Peterson>{{cite journal |author=Peterson R, Schreiber S |title=Translation control: connecting mitogens and the ribosome |journal=Curr Biol |volume=8 |issue=7 |pages=R248–50 |year=1998 |pmid=9545190 |doi=10.1016/S0960-9822(98)70152-6}}</ref> S6K1 can also participate in a positive feedback loop with mTORC1 by phosphorylating mTOR's negative regulatory domain at two sites<!--threonine2446 and serine2448-->; phosphorylation at these sites appears to stimulate mTOR activity.<ref name=Chiang>{{cite journal |author=Chiang G, Abraham R |title=Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase |journal=J Biol Chem |volume=280 |issue=27 |pages=25485–90 |year=2005 |pmid=15899889 |doi=10.1074/jbc.M501707200}}</ref><ref name=Holz>{{cite journal |author=Holz M, Blenis J |title=Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase |url= http://www.jbc.org/cgi/content/full/280/28/26089|journal=J Biol Chem |volume=280 |issue=28 |pages=26089–93 |year=2005 |pmid=15905173 |doi=10.1074/jbc.M504045200}}</ref>
mTORC1 has been shown to phosphorylate at least four residues of 4E-BP1 in a hierarchical manner.<ref name=Gingras>{{cite journal |author=Gingras A, Gygi S, Raught B, Polakiewicz R, Abraham R, Hoekstra M, Aebersold R, Sonenberg N |title=Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism |url= http://www.genesdev.org/cgi/content/full/13/11/1422|journal=Genes Dev |volume=13 |issue=11 |pages=1422–37 |year=1999 |pmid=10364159 |doi=10.1101/gad.13.11.1422}}</ref><ref name=Huang2001/><ref name=Mothe>{{cite journal |author=Mothe-Satney I, Brunn G, McMahon L, Capaldo C, Abraham R, Lawrence J |title=Mammalian target of rapamycin-dependent phosphorylation of PHAS-I in four (S/T)P sites detected by phospho-specific antibodies |url= http://www.jbc.org/cgi/content/full/275/43/33836| journal=J Biol Chem |volume=275 |issue=43 |pages=33836–43 |year=2000 |pmid=10942774 |doi=10.1074/jbc.M006005200}}</ref> Non-phosphorylated 4E-BP1 binds tightly to the translation initiation factor eIF4E, preventing it from binding to 5'-capped [[mRNA]]s and recruiting them to the [[Eukaryotic translation|ribosomal initiation complex]].<ref name=Pause>{{cite journal |author=Pause A, Belsham G, Gingras A, Donzé O, Lin T, Lawrence J, Sonenberg N |title=Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function |journal=Nature |volume=371 |issue=6500 |pages=762–7 |year=1994 |pmid=7935836 |doi=10.1038/371762a0}}</ref> Upon phosphorylation by mTORC1, 4E-BP1 releases eIF4E, allowing it to perform its function.<ref name=Pause/> The activity of mTORC1 appears to be regulated through a dynamic interaction between mTOR and Raptor, one which is mediated by [[GβL]].<ref name=Kim2002/><ref name=Kim2003/> Raptor and mTOR share a strong [[N-terminal]] interaction and a weaker [[C-terminal]] interaction near mTOR's kinase domain.<ref name=Kim2002/> When stimulatory signals are sensed, such as high nutrient/energy levels, the mTOR-Raptor C-terminal interaction is weakened and possibly completely lost, allowing mTOR kinase activity to be turned on. When stimulatory signals are withdrawn, such as low nutrient levels, the mTOR-Raptor C-terminal interaction is strengthened, essentially shutting off kinase function of mTOR .<ref name=Kim2002/>
===mTORC2===
mTOR Complex 2 (mTORC2) is composed of mTOR, rapamycin-insensitive companion of mTOR (Rictor), GβL, and mammalian stress-activated protein kinase interacting protein 1 ([[mSIN1]]).<ref name=Frias>{{cite journal |author=Frias M, Thoreen C, Jaffe J, Schroder W, Sculley T, Carr S, Sabatini D |title=mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s |journal=Curr Biol |volume=16 |issue=18 |pages=1865–70 |year=2006 |pmid=16919458 |doi=10.1016/j.cub.2006.08.001}}</ref><ref name=Sarb1>{{cite journal |author=Sarbassov D, Ali S, Kim D, Guertin D, Latek R, Erdjument-Bromage H, Tempst P, Sabatini D |title=Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton |journal=Curr Biol |volume=14 |issue=14 |pages=1296–302 |year=2004 |pmid=15268862 |doi=10.1016/j.cub.2004.06.054}}</ref> mTORC2 has been shown to function as an important regulator of the [[cytoskeleton]] through its stimulation of F-[[actin]] stress fibers, [[paxillin]], [[RhoA]], [[Rac1]], [[Cdc42]], and [[protein kinase C]] α (PKCα).<ref name=Sarb1/> mTORC2 also appears to possess the activity of a previously elusive protein known as "[[PDK2]]." mTORC2 phosphorylates the serine/threonine protein kinase [[AKT|Akt/PKB]] at a serine residue<!--serine473-->. Phosphorylation of the serine stimulates Akt phosphorylation at a threonine<!--threonine308--> residue by [[PDK1]] and leads to full Akt activation<ref name=Sarb2>{{cite journal |author=Sarbassov D, Guertin D, Ali S, Sabatini D |title=Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex |journal=Science |volume=307 |issue=5712 |pages=1098–101 |year=2005 |pmid=15718470 |doi=10.1126/science.1106148}}</ref><ref name=Stephens>{{cite journal |author=Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter G, Holmes A, Gaffney P, Reese C, McCormick F, Tempst P, Coadwell J, Hawkins P |title=Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B |journal=Science |volume=279 |issue=5351 |pages=710–4 |year=1998 |pmid=9445477 |doi=10.1126/science.279.5351.710}}</ref>; curcumin inhibits both by preventing phosphorylation of the serine.<ref name=Beevers/>
mTORC2 appears to be regulated by insulin, growth factors, serum, and nutrient levels.<ref name=Frias/> Originally, mTORC2 was identified as a rapamycin-insensitive entity, as acute exposure to rapamycin did not affect mTORC2 activity or Akt phosphorylation.<ref name=Sarb2> However, subsequent studies have shown that chronic exposure to rapamycin, while not effecting pre-existing mTORC2s, can bind to free mTOR molecules, thus inhibiting the formation of new mTORC2.<ref name=Sarb3>{{cite journal |author=Sarbassov D, Ali S, Sengupta S, Sheen J, Hsu P, Bagley A, Markhard A, Sabatini D |title=Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB |journal=Mol Cell |volume=22 |issue=2 |pages=159–68 |year=2006 |pmid=16603397 |doi=10.1016/j.molcel.2006.03.029}}</ref>
==Aging==
[[Image:MTOR-pathway-betz.jpg|thumb|right|300px|mTOR signaling pathway.[http://www.betz.lu/] ]]
Decreased TOR activity has been found to slow [[aging]] in [[Cerevisiae | Saccharomcyes cerevisiae]], Caenorhabditis elegans, and Drosophila melanogaster <ref>Kaeberlein, M., Powers, R.W., 3rd, Steffen, K.K., Westman, E.A., Hu, D., Dang, N., Kerr, E.O., Kirkland, K.T., Fields, S., and Kennedy, B.K. (2005). Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193-1196.</ref><ref>Powers, R.W., 3rd, Kaeberlein, M., Caldwell, S.D., Kennedy, B.K., and Fields, S. (2006). Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev 20, 174-184.</ref><ref>Jia, K., Chen, D., and Riddle, D.L. (2004). The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131, 3897-3906.</ref><ref>Kapahi, P., Zid, B.M., Harper, T., Koslover, D., Sapin, V., and Benzer, S. (2004). Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 14, 885-890.</ref>. The [http://www.nia.nih.gov/ResearchInformation/ScientificResources/InterventionsTestingProgram.htm NIA Interventions Testing Program] is currently testing the mTOR inhibitor [[rapamycin]] to determine whether it increases lifespan in mice.
[[Matt Kaeberlein | Kaeberlein]] and colleagues have proposed the hypothesis that decreased TOR activity accounts for lifespan extension by [[caloric restriction]] <ref>Kaeberlein, M., Powers, R.W., 3rd, Steffen, K.K., Westman, E.A., Hu, D., Dang, N., Kerr, E.O., Kirkland, K.T., Fields, S., and Kennedy, B.K. (2005). Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193-1196.</ref>.
== mTOR inhibitors as therapies ==
mTOR inhibitors are already used in the treatment of [[transplant rejection]] . They are also beginning to be used in the treatment of cancer.<ref name=Easton>{{cite journal |author=Easton et al. |title=mTOR and cancer therapy |url=http://www.nature.com/onc/journal/v25/n48/abs/1209886a.html| journal=Oncogene |volume=25 |issue=48 |pages=6436–46 |year=2006 |doi=10.1038/sj.onc.1209886}}</ref>.
mTOR inhibitors may also be useful for treating several age-associated diseases.
==References==
{{reflist}}
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal | author=Huang S, Houghton PJ |title=Mechanisms of resistance to rapamycins. |journal=Drug Resist. Updat. |volume=4 |issue= 6 |pages= 378–91 |year= 2002 |pmid= 12030785 |doi= 10.1054/drup.2002.0227 }}
*{{cite journal | author=Harris TE, Lawrence JC |title=TOR signaling. |journal=Sci. STKE |volume=2003 |issue= 212 |pages= re15 |year= 2004 |pmid= 14668532 |doi= 10.1126/stke.2122003re15 }}
*{{cite journal | author=Easton JB, Houghton PJ |title=Therapeutic potential of target of rapamycin inhibitors. |journal=Expert Opin. Ther. Targets |volume=8 |issue= 6 |pages= 551–64 |year= 2005 |pmid= 15584862 |doi= 10.1517/14728222.8.6.551 }}
*{{cite journal | author=Deldicque L, Theisen D, Francaux M |title=Regulation of mTOR by amino acids and resistance exercise in skeletal muscle. |journal=Eur. J. Appl. Physiol. |volume=94 |issue= 1-2 |pages= 1–10 |year= 2005 |pmid= 15702344 |doi= 10.1007/s00421-004-1255-6 }}
*{{cite journal | author=Weimbs T |title=Regulation of mTOR by polycystin-1: is polycystic kidney disease a case of futile repair? |journal=Cell Cycle |volume=5 |issue= 21 |pages= 2425–9 |year= 2007 |pmid= 17102641 |doi= }}
*{{cite journal | author=Sun SY, Fu H, Khuri FR |title=Targeting mTOR signaling for lung cancer therapy. |journal=Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer |volume=1 |issue= 2 |pages= 109–11 |year= 2007 |pmid= 17409838 |doi= }}
*{{cite journal | author=Abraham RT, Gibbons JJ |title=The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. |journal=Clin. Cancer Res. |volume=13 |issue= 11 |pages= 3109–14 |year= 2007 |pmid= 17545512 |doi= 10.1158/1078-0432.CCR-06-2798 }}
}}
{{refend}}
==External links==
* {{MeshName|mTOR+protein}}
{{Serine/threonine-specific protein kinases}}
[[Category:Signal transduction]]
[[de:MTOR]]
[[fr:MTOR]]
[[pl:Kinaza mTOR]]
[[it:MTOR]]
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