RBCC Red Blood Cell Collection

MTOR (FRAP, FRAP1, FRAP2, RAFT1, RAPT1) [Confidence: low (only semi-automatic identification from reviews)]
Serine/threonine-protein kinase mTOR; 2.7.11.1 (FK506-binding protein 12-rapamycin complex-associated protein 1; FKBP12-rapamycin complex-associated protein; Mammalian target of rapamycin; mTOR; Mechanistic target of rapamycin; Rapamycin and FKBP12 target 1; Rapamycin target protein 1)

UniProt P42345
ID MTOR_HUMAN Reviewed; 2549 AA.
AC P42345; Q4LE76; Q5TER1; Q6LE87; Q96QG3; Q9Y4I3;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1995, sequence version 1.
DT 22-JAN-2014, entry version 146.
DE RecName: Full=Serine/threonine-protein kinase mTOR;
DE EC=2.7.11.1;
DE AltName: Full=FK506-binding protein 12-rapamycin complex-associated protein 1;
DE AltName: Full=FKBP12-rapamycin complex-associated protein;
DE AltName: Full=Mammalian target of rapamycin;
DE Short=mTOR;
DE AltName: Full=Mechanistic target of rapamycin;
DE AltName: Full=Rapamycin and FKBP12 target 1;
DE AltName: Full=Rapamycin target protein 1;
GN Name=MTOR; Synonyms=FRAP, FRAP1, FRAP2, RAFT1, RAPT1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=8008069; DOI=10.1038/369756a0;
RA Brown E.J., Albers M.W., Shin T.B., Ichikawa K., Keith C.T.,
RA Lane W.S., Schreiber S.L.;
RT "A mammalian protein targeted by G1-arresting rapamycin-receptor
RT complex.";
RL Nature 369:756-758(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9653645; DOI=10.1006/geno.1997.5186;
RA Onyango P., Lubyova B., Gardellin P., Kurzbauer R., Weith A.;
RT "Molecular cloning and expression analysis of five novel genes in
RT chromosome 1p36.";
RL Genomics 50:187-198(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Nakajima D., Saito K., Yamakawa H., Kikuno R.F., Nakayama M.,
RA Ohara R., Okazaki N., Koga H., Nagase T., Ohara O.;
RT "Preparation of a set of expression-ready clones of mammalian long
RT cDNAs encoding large proteins by the ORF trap cloning method.";
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cerebellum;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1362-2549.
RX PubMed=11426320; DOI=10.1038/sj.gene.6363745;
RA Stover C., Endo Y., Takahashi M., Lynch N., Constantinescu C.,
RA Vorup-Jensen T., Thiel S., Friedl H., Hankeln T., Hall R., Gregory S.,
RA Fujita T., Schwaeble W.;
RT "The human gene for mannan-binding lectin-associated serine protease-2
RT (MASP-2), the effector component of the lectin route of complement
RT activation, is part of a tightly linked gene cluster on chromosome
RT 1p36.2-3.";
RL Genes Immun. 2:119-127(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1987-2146, AND TISSUE SPECIFICITY.
RC TISSUE=B-cell;
RX PubMed=7809080; DOI=10.1073/pnas.91.26.12574;
RA Chiu M.I., Katz H., Berlin V.;
RT "RAPT1, a mammalian homolog of yeast Tor, interacts with the
RT FKBP12/rapamycin complex.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:12574-12578(1994).
RN [8]
RP SUBCELLULAR LOCATION, AND AUTOPHOSPHORYLATION.
RX PubMed=9434772; DOI=10.1006/bbrc.1997.7878;
RA Withers D.J., Ouwens D.M., Nave B.T., van der Zon G.C.M.,
RA Alarcon C.M., Cardenas M.E., Heitman J., Maassen J.A., Shepherd P.R.;
RT "Expression, enzyme activity, and subcellular localization of
RT mammalian target of rapamycin in insulin-responsive cells.";
RL Biochem. Biophys. Res. Commun. 241:704-709(1997).
RN [9]
RP INTERACTION WITH UBQLN1.
RX PubMed=11853878; DOI=10.1016/S0167-4889(01)00164-1;
RA Wu S., Mikhailov A., Kallo-Hosein H., Hara K., Yonezawa K., Avruch J.;
RT "Characterization of ubiquilin 1, an mTOR-interacting protein.";
RL Biochim. Biophys. Acta 1542:41-56(2002).
RN [10]
RP FUNCTION IN NUTRIENT-DEPENDENT CELL GROWTH, FUNCTION IN
RP PHOSPHORYLATION OF RPS6KB1, AND INTERACTION WITH RPTOR.
RX PubMed=12150925; DOI=10.1016/S0092-8674(02)00808-5;
RA Kim D.-H., Sarbassov D.D., Ali S.M., King J.E., Latek R.R.,
RA Erdjument-Bromage H., Tempst P., Sabatini D.M.;
RT "mTOR interacts with raptor to form a nutrient-sensitive complex that
RT signals to the growth machinery.";
RL Cell 110:163-175(2002).
RN [11]
RP FUNCTION, AND INTERACTION WITH RPTOR.
RX PubMed=12150926; DOI=10.1016/S0092-8674(02)00833-4;
RA Hara K., Maruki Y., Long X., Yoshino K., Oshiro N., Hidayat S.,
RA Tokunaga C., Avruch J., Yonezawa K.;
RT "Raptor, a binding partner of target of rapamycin (TOR), mediates TOR
RT action.";
RL Cell 110:177-189(2002).
RN [12]
RP INTERACTION WITH CLIP1, AND FUNCTION IN PHOSPHORYLATION OF CLIP1.
RX PubMed=12231510; DOI=10.1093/embo-reports/kvf197;
RA Choi J.H., Bertram P.G., Drenan R., Carvalho J., Zhou H.H.,
RA Zheng X.F.;
RT "The FKBP12-rapamycin-associated protein (FRAP) is a CLIP-170
RT kinase.";
RL EMBO Rep. 3:988-994(2002).
RN [13]
RP FUNCTION IN PHOSPHORYLATION OF RPS6KB2.
RX PubMed=12087098; DOI=10.1074/jbc.M204080200;
RA Park I.H., Bachmann R., Shirazi H., Chen J.;
RT "Regulation of ribosomal S6 kinase 2 by mammalian target of
RT rapamycin.";
RL J. Biol. Chem. 277:31423-31429(2002).
RN [14]
RP INTERACTION WITH MLST8 AND RPTOR, IDENTIFICATION IN THE MTORC1
RP COMPLEX, AND TISSUE SPECIFICITY.
RX PubMed=12408816; DOI=10.1016/S1097-2765(02)00636-6;
RA Loewith R., Jacinto E., Wullschleger S., Lorberg A., Crespo J.L.,
RA Bonenfant D., Oppliger W., Jenoe P., Hall M.N.;
RT "Two TOR complexes, only one of which is rapamycin sensitive, have
RT distinct roles in cell growth control.";
RL Mol. Cell 10:457-468(2002).
RN [15]
RP SUBCELLULAR LOCATION.
RX PubMed=11930000; DOI=10.1073/pnas.261702698;
RA Desai B.N., Myers B.R., Schreiber S.L.;
RT "FKBP12-rapamycin-associated protein associates with mitochondria and
RT senses osmotic stress via mitochondrial dysfunction.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:4319-4324(2002).
RN [16]
RP ENZYME REGULATION, AND FUNCTION IN RESPONSE TO LOW CELLULAR ENERGY.
RX PubMed=14651849; DOI=10.1016/S0092-8674(03)00929-2;
RA Inoki K., Zhu T., Guan K.L.;
RT "TSC2 mediates cellular energy response to control cell growth and
RT survival.";
RL Cell 115:577-590(2003).
RN [17]
RP FUNCTION, AND INTERACTION WITH MLST8.
RX PubMed=12718876; DOI=10.1016/S1097-2765(03)00114-X;
RA Kim D.-H., Sarbassov D.D., Ali S.M., Latek R.R., Guntur K.V.P.,
RA Erdjument-Bromage H., Tempst P., Sabatini D.M.;
RT "GbetaL, a positive regulator of the rapamycin-sensitive pathway
RT required for the nutrient-sensitive interaction between raptor and
RT mTOR.";
RL Mol. Cell 11:895-904(2003).
RN [18]
RP FUNCTION IN PHOSPHORYLATION OF PRKCA, FUNCTION IN REGULATION OF THE
RP ACTIN CYTOSKELETON, IDENTIFICATION IN THE MTORC2 COMPLEX, AND
RP INTERACTION WITH RICTOR.
RX PubMed=15268862; DOI=10.1016/j.cub.2004.06.054;
RA Sarbassov D.D., Ali S.M., Kim D.-H., Guertin D.A., Latek R.R.,
RA Erdjument-Bromage H., Tempst P., Sabatini D.M.;
RT "Rictor, a novel binding partner of mTOR, defines a rapamycin-
RT insensitive and raptor-independent pathway that regulates the
RT cytoskeleton.";
RL Curr. Biol. 14:1296-1302(2004).
RN [19]
RP ENZYME REGULATION, AND FUNCTION IN RESPONSE TO HYPOXIA.
RX PubMed=15545625; DOI=10.1101/gad.1256804;
RA Brugarolas J., Lei K., Hurley R.L., Manning B.D., Reiling J.H.,
RA Hafen E., Witters L.A., Ellisen L.W., Kaelin W.G. Jr.;
RT "Regulation of mTOR function in response to hypoxia by REDD1 and the
RT TSC1/TSC2 tumor suppressor complex.";
RL Genes Dev. 18:2893-2904(2004).
RN [20]
RP SUBCELLULAR LOCATION.
RX PubMed=14578359; DOI=10.1074/jbc.M305912200;
RA Drenan R.M., Liu X., Bertram P.G., Zheng X.F.S.;
RT "FKBP12-rapamycin-associated protein or mammalian target of rapamycin
RT (FRAP/mTOR) localization in the endoplasmic reticulum and the Golgi
RT apparatus.";
RL J. Biol. Chem. 279:772-778(2004).
RN [21]
RP FUNCTION IN REGULATION OF THE ACTIN CYTOSKELETON, FUNCTION IN
RP PHOSPHORYLATION OF PXN, IDENTIFICATION IN THE MTORC2 COMPLEX,
RP INTERACTION WITH RICTOR, AND AUTOPHOSPHORYLATION.
RX PubMed=15467718; DOI=10.1038/ncb1183;
RA Jacinto E., Loewith R., Schmidt A., Lin S., Ruegg M.A., Hall A.,
RA Hall M.N.;
RT "Mammalian TOR complex 2 controls the actin cytoskeleton and is
RT rapamycin insensitive.";
RL Nat. Cell Biol. 6:1122-1128(2004).
RN [22]
RP PHOSPHORYLATION AT THR-2446 AND SER-2448.
RX PubMed=15905173; DOI=10.1074/jbc.M504045200;
RA Holz M.K., Blenis J.;
RT "Identification of S6 kinase 1 as a novel mammalian target of
RT rapamycin (mTOR)-phosphorylating kinase.";
RL J. Biol. Chem. 280:26089-26093(2005).
RN [23]
RP FUNCTION IN PHOSPHORYLATION OF AKT1.
RX PubMed=15718470; DOI=10.1126/science.1106148;
RA Sarbassov D.D., Guertin D.A., Ali S.M., Sabatini D.M.;
RT "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR
RT complex.";
RL Science 307:1098-1101(2005).
RN [24]
RP IDENTIFICATION IN THE MTORC2 COMPLEX, AND INTERACTION WITH PRR5.
RX PubMed=17599906; DOI=10.1074/jbc.M704343200;
RA Woo S.-Y., Kim D.-H., Jun C.-B., Kim Y.-M., Haar E.V., Lee S.-I.,
RA Hegg J.W., Bandhakavi S., Griffin T.J., Kim D.-H.;
RT "PRR5, a novel component of mTOR complex 2, regulates platelet-derived
RT growth factor receptor beta expression and signaling.";
RL J. Biol. Chem. 282:25604-25612(2007).
RN [25]
RP INTERACTION WITH AKT1S1, AND ENZYME REGULATION.
RX PubMed=17386266; DOI=10.1016/j.molcel.2007.03.003;
RA Sancak Y., Thoreen C.C., Peterson T.R., Lindquist R.A., Kang S.A.,
RA Spooner E., Carr S.A., Sabatini D.M.;
RT "PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein
RT kinase.";
RL Mol. Cell 25:903-915(2007).
RN [26]
RP IDENTIFICATION IN THE MTORC1 AND MTORC2 COMPLEXES, AND FUNCTION IN
RP PHOSPHORYLATION OF RPS6KB1 AND SGK1.
RX PubMed=18925875; DOI=10.1042/BJ20081668;
RA Garcia-Martinez J.M., Alessi D.R.;
RT "mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation
RT and activation of serum- and glucocorticoid-induced protein kinase 1
RT (SGK1).";
RL Biochem. J. 416:375-385(2008).
RN [27]
RP FUNCTION IN LIPID SYNTHESIS AND CELL GROWTH.
RX PubMed=18762023; DOI=10.1016/j.cmet.2008.07.007;
RA Porstmann T., Santos C.R., Griffiths B., Cully M., Wu M., Leevers S.,
RA Griffiths J.R., Chung Y.L., Schulze A.;
RT "SREBP activity is regulated by mTORC1 and contributes to Akt-
RT dependent cell growth.";
RL Cell Metab. 8:224-236(2008).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-567, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [29]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2478 AND SER-2481, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [30]
RP FUNCTION, ENZYME REGULATION, AND SUBCELLULAR LOCATION.
RX PubMed=18497260; DOI=10.1126/science.1157535;
RA Sancak Y., Peterson T.R., Shaul Y.D., Lindquist R.A., Thoreen C.C.,
RA Bar-Peled L., Sabatini D.M.;
RT "The Rag GTPases bind raptor and mediate amino acid signaling to
RT mTORC1.";
RL Science 320:1496-1501(2008).
RN [31]
RP INTERACTION WITH DEPTOR, AND ENZYME REGULATION.
RX PubMed=19446321; DOI=10.1016/j.cell.2009.03.046;
RA Peterson T.R., Laplante M., Thoreen C.C., Sancak Y., Kang S.A.,
RA Kuehl W.M., Gray N.S., Sabatini D.M.;
RT "DEPTOR is an mTOR inhibitor frequently overexpressed in multiple
RT myeloma cells and required for their survival.";
RL Cell 137:873-886(2009).
RN [32]
RP PHOSPHORYLATION AT SER-1261.
RX PubMed=19487463; DOI=10.1128/MCB.01665-08;
RA Acosta-Jaquez H.A., Keller J.A., Foster K.G., Ekim B., Soliman G.A.,
RA Feener E.P., Ballif B.A., Fingar D.C.;
RT "Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling
RT and cell growth.";
RL Mol. Cell. Biol. 29:4308-4324(2009).
RN [33]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-567, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [34]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-1218, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [35]
RP PHOSPHORYLATION AT SER-2448.
RX PubMed=19145465; DOI=10.1007/s00726-008-0230-7;
RA Rosner M., Siegel N., Valli A., Fuchs C., Hengstschlager M.;
RT "mTOR phosphorylated at S2448 binds to raptor and rictor.";
RL Amino Acids 38:223-228(2010).
RN [36]
RP SUBCELLULAR LOCATION.
RX PubMed=20381137; DOI=10.1016/j.cell.2010.02.024;
RA Sancak Y., Bar-Peled L., Zoncu R., Markhard A.L., Nada S.,
RA Sabatini D.M.;
RT "Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is
RT necessary for its activation by amino acids.";
RL Cell 141:290-303(2010).
RN [37]
RP FUNCTION IN PHOSPHORYLATION OF DAP, AND FUNCTION IN AUTOPHAGY.
RX PubMed=20537536; DOI=10.1016/j.cub.2010.04.041;
RA Koren I., Reem E., Kimchi A.;
RT "DAP1, a novel substrate of mTOR, negatively regulates autophagy.";
RL Curr. Biol. 20:1093-1098(2010).
RN [38]
RP INTERACTION WITH TTI1.
RX PubMed=20810650; DOI=10.1101/gad.1934210;
RA Hurov K.E., Cotta-Ramusino C., Elledge S.J.;
RT "A genetic screen identifies the Triple T complex required for DNA
RT damage signaling and ATM and ATR stability.";
RL Genes Dev. 24:1939-1950(2010).
RN [39]
RP INTERACTION WITH TELO2.
RX PubMed=20801936; DOI=10.1101/gad.1956410;
RA Takai H., Xie Y., de Lange T., Pavletich N.P.;
RT "Tel2 structure and function in the Hsp90-dependent maturation of mTOR
RT and ATR complexes.";
RL Genes Dev. 24:2019-2030(2010).
RN [40]
RP INTERACTION WITH TELO2 AND TTI1.
RX PubMed=20427287; DOI=10.1074/jbc.M110.121699;
RA Kaizuka T., Hara T., Oshiro N., Kikkawa U., Yonezawa K., Takehana K.,
RA Iemura S., Natsume T., Mizushima N.;
RT "Tti1 and Tel2 are critical factors in mammalian target of rapamycin
RT complex assembly.";
RL J. Biol. Chem. 285:20109-20116(2010).
RN [41]
RP FUNCTION IN REGULATION OF RNA POLYMERASE III TRANSCRIPTION, AND
RP FUNCTION IN PHOSPHORYLATION OF MAF1.
RX PubMed=20516213; DOI=10.1128/MCB.00319-10;
RA Michels A.A., Robitaille A.M., Buczynski-Ruchonnet D., Hodroj W.,
RA Reina J.H., Hall M.N., Hernandez N.;
RT "mTORC1 directly phosphorylates and regulates human MAF1.";
RL Mol. Cell. Biol. 30:3749-3757(2010).
RN [42]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-567 AND THR-1162, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [43]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [44]
RP PHOSPHORYLATION AT SER-2159; THR-2164 AND SER-2481, AND MUTAGENESIS OF
RP SER-2159 AND THR-2164.
RX PubMed=21576368; DOI=10.1128/MCB.05437-11;
RA Ekim B., Magnuson B., Acosta-Jaquez H.A., Keller J.A., Feener E.P.,
RA Fingar D.C.;
RT "mTOR kinase domain phosphorylation promotes mTORC1 signaling, cell
RT growth, and cell cycle progression.";
RL Mol. Cell. Biol. 31:2787-2801(2011).
RN [45]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [46]
RP FUNCTION IN PHOSPHORYLATION OF GRB10, AND FUNCTION IN INSR-DEPENDENT
RP SIGNALING.
RX PubMed=21659604; DOI=10.1126/science.1199498;
RA Hsu P.P., Kang S.A., Rameseder J., Zhang Y., Ottina K.A., Lim D.,
RA Peterson T.R., Choi Y., Gray N.S., Yaffe M.B., Marto J.A.,
RA Sabatini D.M.;
RT "The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-
RT mediated inhibition of growth factor signaling.";
RL Science 332:1317-1322(2011).
RN [47]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [48]
RP INTERACTION WITH NBN.
RX PubMed=23762398; DOI=10.1371/journal.pone.0065586;
RA Wang J.Q., Chen J.H., Chen Y.C., Chen M.Y., Hsieh C.Y., Teng S.C.,
RA Wu K.J.;
RT "Interaction between NBS1 and the mTOR/Rictor/SIN1 complex through
RT specific domains.";
RL PLoS ONE 8:E65586-E65586(2013).
RN [49]
RP FUNCTION, PHOSPHORYLATION OF RPS6KB1, AND REGULATION OF PYRIMIDINE
RP SYNTHESIS.
RX PubMed=23429704; DOI=10.1126/science.1228771;
RA Robitaille A.M., Christen S., Shimobayashi M., Cornu M., Fava L.L.,
RA Moes S., Prescianotto-Baschong C., Sauer U., Jenoe P., Hall M.N.;
RT "Quantitative phosphoproteomics reveal mTORC1 activates de novo
RT pyrimidine synthesis.";
RL Science 339:1320-1323(2013).
RN [50]
RP FUNCTION, PHOSPHORYLATION OF RPS6KB1, AND REGULATION OF PYRIMIDINE
RP SYNTHESIS.
RX PubMed=23429703; DOI=10.1126/science.1228792;
RA Ben-Sahra I., Howell J.J., Asara J.M., Manning B.D.;
RT "Stimulation of de novo pyrimidine synthesis by growth signaling
RT through mTOR and S6K1.";
RL Science 339:1323-1328(2013).
RN [51]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 2018-2112 IN COMPLEX WITH
RP FKBP1A AND INHIBITOR RAPAMYCIN.
RX PubMed=8662507; DOI=10.1126/science.273.5272.239;
RA Choi J., Chen J., Schreiber S.L., Clardy J.;
RT "Structure of the FKBP12-rapamycin complex interacting with the
RT binding domain of human FRAP.";
RL Science 273:239-242(1996).
RN [52]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 2018-2112 IN COMPLEX WITH
RP FKBP1A AND INHIBITOR RAPAMYCIN.
RX PubMed=10089303; DOI=10.1107/S0907444998014747;
RA Liang J., Choi J., Clardy J.;
RT "Refined structure of the FKBP12-rapamycin-FRB ternary complex at 2.2
RT A resolution.";
RL Acta Crystallogr. D 55:736-744(1999).
RN [53]
RP 3D-STRUCTURE MODELING, HEAT-REPEATS, AND TPR-REPEATS.
RX PubMed=20060908; DOI=10.1016/j.jsb.2010.01.002;
RA Knutson B.A.;
RT "Insights into the domain and repeat architecture of target of
RT rapamycin.";
RL J. Struct. Biol. 170:354-363(2010).
RN [54]
RP CRYO-ELECTRON MICROSCOPY (26 ANGSTROMS) OF MTORC1 COMPLEX, AND
RP SUBUNIT.
RX PubMed=20542007; DOI=10.1016/j.molcel.2010.05.017;
RA Yip C.K., Murata K., Walz T., Sabatini D.M., Kang S.A.;
RT "Structure of the human mTOR complex I and its implications for
RT rapamycin inhibition.";
RL Mol. Cell 38:768-774(2010).
RN [55]
RP X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS) OF 1376-2549 IN COMPLEX WITH
RP MLST8, SUBUNIT, TPR-REPEATS, DOMAINS, AND MUTAGENESIS OF HIS-2340.
RX PubMed=23636326; DOI=10.1038/nature12122;
RA Yang H., Rudge D.G., Koos J.D., Vaidialingam B., Yang H.J.,
RA Pavletich N.P.;
RT "mTOR kinase structure, mechanism and regulation.";
RL Nature 497:217-223(2013).
RN [56]
RP VARIANTS [LARGE SCALE ANALYSIS] SER-8; THR-135; VAL-1083; VAL-1134;
RP PHE-1178; VAL-2011; TYR-2215 AND LEU-2476.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [57]
RP VARIANTS PHE-2220 AND ALA-2406.
RX PubMed=21248752; DOI=10.1038/nature09639;
RA Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P.,
RA Davies H., Jones D., Lin M.L., Teague J., Bignell G., Butler A.,
RA Cho J., Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C.,
RA Jia M., Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A.,
RA Mudie L., Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S.,
RA Kahnoski R.J., Anema J., Tuveson D.A., Perez-Mancera P.A.,
RA Mustonen V., Fischer A., Adams D.J., Rust A., Chan-On W., Subimerb C.,
RA Dykema K., Furge K., Campbell P.J., Teh B.T., Stratton M.R.,
RA Futreal P.A.;
RT "Exome sequencing identifies frequent mutation of the SWI/SNF complex
RT gene PBRM1 in renal carcinoma.";
RL Nature 469:539-542(2011).
CC -!- FUNCTION: Serine/threonine protein kinase which is a central
CC regulator of cellular metabolism, growth and survival in response
CC to hormones, growth factors, nutrients, energy and stress signals.
CC MTOR directly or indirectly regulates the phosphorylation of at
CC least 800 proteins. Functions as part of 2 structurally and
CC functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR
CC complex 1 and 2). Activated mTORC1 up-regulates protein synthesis
CC by phosphorylating key regulators of mRNA translation and ribosome
CC synthesis. This includes phosphorylation of EIF4EBP1 and release
CC of its inhibition toward the elongation initiation factor 4E
CC (eiF4E). Moreover, phosphorylates and activates RPS6KB1 and
CC RPS6KB2 that promote protein synthesis by modulating the activity
CC of their downstream targets including ribosomal protein S6,
CC eukaryotic translation initiation factor EIF4B, and the inhibitor
CC of translation initiation PDCD4. Stimulates the pyrimidine
CC biosynthesis pathway, both by acute regulation through RPS6KB1-
CC mediated phosphorylation of the biosynthetic enzyme CAD, and
CC delayed regulation, through transcriptional enhancement of the
CC pentose phosphate pathway which produces 5-phosphoribosyl-1-
CC pyrophosphate (PRPP), an allosteric activator of CAD at a later
CC step in synthesis, this function is dependent on the mTORC1
CC complex. Regulates ribosome synthesis by activating RNA polymerase
CC III-dependent transcription through phosphorylation and inhibition
CC of MAF1 a RNA polymerase III-repressor. In parallel to protein
CC synthesis, also regulates lipid synthesis through SREBF1/SREBP1
CC and LPIN1. To maintain energy homeostasis mTORC1 may also regulate
CC mitochondrial biogenesis through regulation of PPARGC1A. mTORC1
CC also negatively regulates autophagy through phosphorylation of
CC ULK1. Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-
CC 758', disrupting the interaction with AMPK and preventing
CC activation of ULK1. Also prevents autophagy through
CC phosphorylation of the autophagy inhibitor DAP. mTORC1 exerts a
CC feedback control on upstream growth factor signaling that includes
CC phosphorylation and activation of GRB10 a INSR-dependent signaling
CC suppressor. Among other potential targets mTORC1 may phosphorylate
CC CLIP1 and regulate microtubules. As part of the mTORC2 complex
CC MTOR may regulate other cellular processes including survival and
CC organization of the cytoskeleton. Plays a critical role in the
CC phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of
CC phosphoinositide 3-kinase, facilitating its activation by PDK1.
CC mTORC2 may regulate the actin cytoskeleton, through
CC phosphorylation of PRKCA, PXN and activation of the Rho-type
CC guanine nucleotide exchange factors RHOA and RAC1A or RAC1B.
CC mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422'.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- ENZYME REGULATION: Activation of mTORC1 by growth factors such as
CC insulin involves AKT1-mediated phosphorylation of TSC1-TSC2, which
CC leads to the activation of the RHEB GTPase a potent activator of
CC the protein kinase activity of mTORC1. Insulin-stimulated and
CC amino acid-dependent phosphorylation at Ser-1261 promotes
CC autophosphorylation and the activation of mTORC1. Activation by
CC amino acids requires relocalization of the mTORC1 complex to
CC lysosomes that is mediated by the Ragulator complex and the Rag
CC GTPases RRAGA, RRAGB, RRAGC and RRAGD. On the other hand, low
CC cellular energy levels can inhibit mTORC1 through activation of
CC PRKAA1 while hypoxia inhibits mTORC1 through a REDD1-dependent
CC mechanism which may also require PRKAA1. The kinase activity of
CC MTOR within the mTORC1 complex is positively regulated by MLST8
CC and negatively regulated by DEPTOR and AKT1S1. MTOR phosphorylates
CC RPTOR which in turn inhibits mTORC1. MTOR is the target of the
CC immunosuppressive and anti-cancer drug rapamycin which acts in
CC complex with FKBP1A/FKBP12, and specifically inhibits its kinase
CC activity. mTORC2 is also activated by growth factors, but seems to
CC be nutrient-insensitive. It may be regulated by RHEB but in an
CC indirect manner through the PI3K signaling pathway.
CC -!- SUBUNIT: Part of the mammalian target of rapamycin complex 1
CC (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and
CC DEPTOR. The mTORC1 complex is a 1 Md obligate dimer of two
CC stoichiometric heterotetramers with overall dimensions of 290 A x
CC 210 A x 135 A. It has a rhomboid shape and a central cavity, the
CC dimeric interfaces are formed by interlocking interactions between
CC the two MTOR and the two RPTOR subunits. the MLST8 subunits forms
CC distal foot-like protuberances, and contacts only one MTOR within
CC the complex, while the small PRAS40 localizes to the midsection of
CC the central core, in close proximity to RPTOR. Part of the
CC mammalian target of rapamycin COmplex 2 (mTORC2) which contains
CC MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Interacts with
CC PPAPDC3 and PML. Interacts with PRR5 and RICTOR; the interaction
CC is direct within the mTORC2 complex. Interacts with UBQLN1.
CC Interacts with TTI1 and TELO2. Interacts with CLIP1;
CC phosphorylates and regulates CLIP1. Interacts with NBN.
CC -!- INTERACTION:
CC Q8TB45:DEPTOR; NbExp=5; IntAct=EBI-359260, EBI-2359040;
CC Q13541:EIF4EBP1; NbExp=2; IntAct=EBI-359260, EBI-74090;
CC Q9BVC4:MLST8; NbExp=4; IntAct=EBI-359260, EBI-1387471;
CC Q8TCU6:PREX1; NbExp=11; IntAct=EBI-359260, EBI-1046542;
CC Q6R327:RICTOR; NbExp=23; IntAct=EBI-359260, EBI-1387196;
CC Q8N122:RPTOR; NbExp=18; IntAct=EBI-359260, EBI-1567928;
CC Q96EB6:SIRT1; NbExp=2; IntAct=EBI-359260, EBI-1802965;
CC Q8NHX9:TPCN2; NbExp=2; IntAct=EBI-359260, EBI-5239949;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Peripheral
CC membrane protein; Cytoplasmic side. Golgi apparatus membrane;
CC Peripheral membrane protein; Cytoplasmic side. Mitochondrion outer
CC membrane; Peripheral membrane protein; Cytoplasmic side. Lysosome.
CC Cytoplasm (By similarity). Nucleus, PML body (By similarity).
CC Note=Shuttles between cytoplasm and nucleus. Accumulates in the
CC nucleus in response to hypoxia (By similarity). Targeting to
CC lysosomes depends on amino acid availability and RRAGA and RRAGB.
CC -!- TISSUE SPECIFICITY: Expressed in numerous tissues, with highest
CC levels in testis.
CC -!- DOMAIN: The kinase domain (PI3K/PI4K) is intrinsically active but
CC has a highly restricted catalytic center (PubMed:23636326).
CC -!- DOMAIN: The FAT domain forms three discontinuous subdomains of
CC alpha-helical TPR repeats plus a single subdomain of HEAT repeats.
CC The four domains pack sequentially to form a C-shaped a-solenoid
CC that clamps onto the kinase domain (PubMed:23636326).
CC -!- PTM: Autophosphorylates when part of mTORC1 or mTORC2.
CC Phosphorylation at Ser-1261, Ser-2159 and Thr-2164 promotes
CC autophosphorylation. Phosphorylation in the kinase domain
CC modulates the interactions of MTOR with RPTOR and PRAS40 and leads
CC to increased intrinsic mTORC1 kinase activity.
CC -!- SIMILARITY: Belongs to the PI3/PI4-kinase family.
CC -!- SIMILARITY: Contains 1 FAT domain.
CC -!- SIMILARITY: Contains 1 FATC domain.
CC -!- SIMILARITY: Contains 32 HEAT repeats.
CC -!- SIMILARITY: Contains 1 PI3K/PI4K domain.
CC -!- SIMILARITY: Contains 16 TPR repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC39933.1; Type=Frameshift; Positions=956, 999;
CC Sequence=BAE06077.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/FRAP1ID40639ch1p36.html";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Mammalian target of rapamycin
CC entry;
CC URL="http://en.wikipedia.org/wiki/Mammalian_target_of_rapamycin";
CC -!- WEB RESOURCE: Name=Target mTOR; Note=mTOR signaling pathway and
CC mTOR inhibition resource;
CC URL="http://www.targetmtor.com/index.jsp";
CC -----------------------------------------------------------------------
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DR EMBL; L34075; AAA58486.1; -; mRNA.
DR EMBL; U88966; AAC39933.1; ALT_FRAME; mRNA.
DR EMBL; AB209995; BAE06077.1; ALT_INIT; mRNA.
DR EMBL; AL109811; CAI22105.1; -; Genomic_DNA.
DR EMBL; AL049653; CAI22105.1; JOINED; Genomic_DNA.
DR EMBL; AL391561; CAI22105.1; JOINED; Genomic_DNA.
DR EMBL; AL391561; CAI17228.1; -; Genomic_DNA.
DR EMBL; AL049653; CAI17228.1; JOINED; Genomic_DNA.
DR EMBL; AL109811; CAI17228.1; JOINED; Genomic_DNA.
DR EMBL; AL049653; CAI22145.1; -; Genomic_DNA.
DR EMBL; AL109811; CAI22145.1; JOINED; Genomic_DNA.
DR EMBL; AL391561; CAI22145.1; JOINED; Genomic_DNA.
DR EMBL; BC117166; AAI17167.1; -; mRNA.
DR EMBL; AJ300188; CAC15570.1; -; Genomic_DNA.
DR EMBL; L35478; AAC41713.1; -; mRNA.
DR PIR; S45340; S45340.
DR RefSeq; NP_004949.1; NM_004958.3.
DR RefSeq; XP_005263495.1; XM_005263438.1.
DR UniGene; Hs.338207; -.
DR PDB; 1AUE; X-ray; 2.33 A; A/B=2015-2114.
DR PDB; 1FAP; X-ray; 2.70 A; B=2018-2112.
DR PDB; 1NSG; X-ray; 2.20 A; B=2019-2112.
DR PDB; 2FAP; X-ray; 2.20 A; B=2019-2112.
DR PDB; 2GAQ; NMR; -; A=2015-2114.
DR PDB; 2NPU; NMR; -; A=2015-2114.
DR PDB; 2RSE; NMR; -; B=2019-2112.
DR PDB; 3FAP; X-ray; 1.85 A; B=2019-2112.
DR PDB; 4DRH; X-ray; 2.30 A; B/E=2025-2114.
DR PDB; 4DRI; X-ray; 1.45 A; B=2025-2114.
DR PDB; 4DRJ; X-ray; 1.80 A; B=2025-2114.
DR PDB; 4FAP; X-ray; 2.80 A; B=2019-2112.
DR PDB; 4JSN; X-ray; 3.20 A; A/B=1376-2549.
DR PDB; 4JSP; X-ray; 3.30 A; A/B=1376-2549.
DR PDB; 4JSV; X-ray; 3.50 A; A/B=1376-2549.
DR PDB; 4JSX; X-ray; 3.50 A; A/B=1376-2549.
DR PDB; 4JT5; X-ray; 3.45 A; A/B=1376-2549.
DR PDB; 4JT6; X-ray; 3.60 A; A/B=1376-2549.
DR PDBsum; 1AUE; -.
DR PDBsum; 1FAP; -.
DR PDBsum; 1NSG; -.
DR PDBsum; 2FAP; -.
DR PDBsum; 2GAQ; -.
DR PDBsum; 2NPU; -.
DR PDBsum; 2RSE; -.
DR PDBsum; 3FAP; -.
DR PDBsum; 4DRH; -.
DR PDBsum; 4DRI; -.
DR PDBsum; 4DRJ; -.
DR PDBsum; 4FAP; -.
DR PDBsum; 4JSN; -.
DR PDBsum; 4JSP; -.
DR PDBsum; 4JSV; -.
DR PDBsum; 4JSX; -.
DR PDBsum; 4JT5; -.
DR PDBsum; 4JT6; -.
DR ProteinModelPortal; P42345; -.
DR SMR; P42345; 662-719, 752-783, 1109-1181, 2025-2114, 2140-2422, 2517-2549.
DR DIP; DIP-790N; -.
DR IntAct; P42345; 47.
DR MINT; MINT-121301; -.
DR STRING; 9606.ENSP00000354558; -.
DR BindingDB; P42345; -.
DR ChEMBL; CHEMBL2221341; -.
DR GuidetoPHARMACOLOGY; 2109; -.
DR PhosphoSite; P42345; -.
DR DMDM; 1169735; -.
DR PaxDb; P42345; -.
DR PRIDE; P42345; -.
DR Ensembl; ENST00000361445; ENSP00000354558; ENSG00000198793.
DR GeneID; 2475; -.
DR KEGG; hsa:2475; -.
DR UCSC; uc001asd.3; human.
DR CTD; 2475; -.
DR GeneCards; GC01M011166; -.
DR HGNC; HGNC:3942; MTOR.
DR HPA; CAB005057; -.
DR MIM; 601231; gene.
DR neXtProt; NX_P42345; -.
DR PharmGKB; PA28360; -.
DR eggNOG; COG5032; -.
DR HOGENOM; HOG000163215; -.
DR HOVERGEN; HBG005744; -.
DR InParanoid; P42345; -.
DR KO; K07203; -.
DR OMA; DPYKHKM; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P42345; -.
DR ChiTaRS; MTOR; human.
DR EvolutionaryTrace; P42345; -.
DR GeneWiki; Mammalian_target_of_rapamycin; -.
DR GenomeRNAi; 2475; -.
DR NextBio; 9805; -.
DR PRO; PR:P42345; -.
DR ArrayExpress; P42345; -.
DR Bgee; P42345; -.
DR CleanEx; HS_FRAP1; -.
DR Genevestigator; P42345; -.
DR GO; GO:0012505; C:endomembrane system; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0070438; C:mTOR-FKBP12-rapamycin complex; IEA:Ensembl.
DR GO; GO:0005942; C:phosphatidylinositol 3-kinase complex; NAS:UniProtKB.
DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell.
DR GO; GO:0031931; C:TORC1 complex; IDA:UniProtKB.
DR GO; GO:0031932; C:TORC2 complex; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008144; F:drug binding; IEA:InterPro.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0043022; F:ribosome binding; IEA:Ensembl.
DR GO; GO:0001030; F:RNA polymerase III type 1 promoter DNA binding; IDA:UniProtKB.
DR GO; GO:0001031; F:RNA polymerase III type 2 promoter DNA binding; IDA:UniProtKB.
DR GO; GO:0001032; F:RNA polymerase III type 3 promoter DNA binding; IDA:UniProtKB.
DR GO; GO:0001156; F:TFIIIC-class transcription factor binding; IDA:UniProtKB.
DR GO; GO:0016049; P:cell growth; IDA:UniProtKB.
DR GO; GO:0071456; P:cellular response to hypoxia; ISS:UniProtKB.
DR GO; GO:0031669; P:cellular response to nutrient levels; ISS:UniProtKB.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007281; P:germ cell development; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0010507; P:negative regulation of autophagy; ISS:UniProtKB.
DR GO; GO:0045792; P:negative regulation of cell size; IEA:Ensembl.
DR GO; GO:0016242; P:negative regulation of macroautophagy; IEA:Ensembl.
DR GO; GO:0051534; P:negative regulation of NFAT protein import into nucleus; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IMP:UniProtKB.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IEA:Ensembl.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
DR GO; GO:0030838; P:positive regulation of actin filament polymerization; IEA:Ensembl.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IEA:Ensembl.
DR GO; GO:0010592; P:positive regulation of lamellipodium assembly; IEA:Ensembl.
DR GO; GO:0046889; P:positive regulation of lipid biosynthetic process; IMP:UniProtKB.
DR GO; GO:0010831; P:positive regulation of myotube differentiation; IEA:Ensembl.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IEA:Ensembl.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling cascade; IEA:Ensembl.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0051496; P:positive regulation of stress fiber assembly; IEA:Ensembl.
DR GO; GO:0045945; P:positive regulation of transcription from RNA polymerase III promoter; IMP:UniProtKB.
DR GO; GO:0045727; P:positive regulation of translation; IDA:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:MGI.
DR GO; GO:0030163; P:protein catabolic process; TAS:UniProtKB.
DR GO; GO:0032956; P:regulation of actin cytoskeleton organization; IMP:UniProtKB.
DR GO; GO:0043610; P:regulation of carbohydrate utilization; IEA:Ensembl.
DR GO; GO:0031998; P:regulation of fatty acid beta-oxidation; IEA:Ensembl.
DR GO; GO:0005979; P:regulation of glycogen biosynthetic process; IEA:Ensembl.
DR GO; GO:0045859; P:regulation of protein kinase activity; IEA:Ensembl.
DR GO; GO:0032314; P:regulation of Rac GTPase activity; IEA:Ensembl.
DR GO; GO:0032095; P:regulation of response to food; IEA:Ensembl.
DR GO; GO:0043200; P:response to amino acid stimulus; IDA:UniProtKB.
DR GO; GO:0007584; P:response to nutrient; NAS:UniProtKB.
DR GO; GO:0031529; P:ruffle organization; IEA:Ensembl.
DR GO; GO:0031295; P:T cell costimulation; TAS:Reactome.
DR GO; GO:0031929; P:TOR signaling cascade; IMP:UniProtKB.
DR Gene3D; 1.10.1070.11; -; 3.
DR Gene3D; 1.25.10.10; -; 4.
DR Gene3D; 1.25.40.10; -; 2.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR024585; DUF3385_TOR.
DR InterPro; IPR003152; FATC.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000403; PI3/4_kinase_cat_dom.
DR InterPro; IPR018936; PI3/4_kinase_CS.
DR InterPro; IPR003151; PIK-rel_kinase_FAT.
DR InterPro; IPR014009; PIK_FAT.
DR InterPro; IPR009076; Rapamycin-bd_dom.
DR InterPro; IPR026683; TOR.
DR InterPro; IPR011990; TPR-like_helical.
DR PANTHER; PTHR11139:SF9; PTHR11139:SF9; 1.
DR Pfam; PF11865; DUF3385; 1.
DR Pfam; PF02259; FAT; 1.
DR Pfam; PF02260; FATC; 1.
DR Pfam; PF00454; PI3_PI4_kinase; 1.
DR Pfam; PF08771; Rapamycin_bind; 1.
DR SMART; SM00146; PI3Kc; 1.
DR SUPFAM; SSF47212; SSF47212; 1.
DR SUPFAM; SSF48371; SSF48371; 5.
DR SUPFAM; SSF56112; SSF56112; 2.
DR PROSITE; PS51189; FAT; 1.
DR PROSITE; PS51190; FATC; 1.
DR PROSITE; PS50077; HEAT_REPEAT; FALSE_NEG.
DR PROSITE; PS00915; PI3_4_KINASE_1; 1.
DR PROSITE; PS00916; PI3_4_KINASE_2; 1.
DR PROSITE; PS50290; PI3_4_KINASE_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ATP-binding; Complete proteome; Cytoplasm;
KW Endoplasmic reticulum; Golgi apparatus; Kinase; Lysosome; Membrane;
KW Mitochondrion; Mitochondrion outer membrane; Nucleotide-binding;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW Serine/threonine-protein kinase; TPR repeat; Transferase.
FT CHAIN 1 2549 Serine/threonine-protein kinase mTOR.
FT /FTId=PRO_0000088808.
FT REPEAT 16 53 HEAT 1.
FT REPEAT 55 99 HEAT 2.
FT REPEAT 100 137 HEAT 3.
FT REPEAT 138 179 HEAT 4.
FT REPEAT 180 220 HEAT 5.
FT REPEAT 222 276 HEAT 6.
FT REPEAT 277 313 HEAT 7.
FT REPEAT 314 364 HEAT 8.
FT REPEAT 365 409 HEAT 9.
FT REPEAT 410 445 HEAT 10.
FT REPEAT 446 494 HEAT 11.
FT REPEAT 495 529 HEAT 12.
FT REPEAT 530 563 HEAT 13.
FT REPEAT 564 596 HEAT 14.
FT REPEAT 597 636 HEAT 15.
FT REPEAT 637 683 HEAT 16.
FT REPEAT 686 724 HEAT 17.
FT REPEAT 727 766 HEAT 18.
FT REPEAT 769 811 HEAT 19.
FT REPEAT 814 853 HEAT 20.
FT REPEAT 857 893 HEAT 21.
FT REPEAT 894 942 HEAT 22.
FT REPEAT 943 988 HEAT 23.
FT REPEAT 989 1027 HEAT 24.
FT REPEAT 1029 1068 HEAT 25.
FT REPEAT 1069 1105 HEAT 26.
FT REPEAT 1106 1144 HEAT 27.
FT REPEAT 1145 1188 HEAT 28.
FT REPEAT 1189 1225 HEAT 29.
FT REPEAT 1226 1273 HEAT 30.
FT REPEAT 1274 1311 HEAT 31.
FT REPEAT 1312 1345 HEAT 32.
FT REPEAT 1346 1382 TPR 1.
FT DOMAIN 1382 1982 FAT.
FT REPEAT 1383 1408 TPR 2.
FT REPEAT 1409 1442 TPR 3.
FT REPEAT 1443 1473 TPR 4.
FT REPEAT 1474 1507 TPR 5.
FT REPEAT 1508 1541 TPR 6.
FT REPEAT 1542 1574 TPR 7.
FT REPEAT 1575 1614 TPR 8.
FT REPEAT 1615 1649 TPR 9.
FT REPEAT 1650 1693 TPR 10.
FT REPEAT 1694 1731 TPR 11.
FT REPEAT 1732 1786 TPR 12.
FT REPEAT 1787 1846 TPR 13.
FT REPEAT 1898 1930 TPR 14.
FT REPEAT 1931 1970 TPR 15.
FT REPEAT 1971 2005 TPR 16.
FT DOMAIN 2182 2516 PI3K/PI4K.
FT DOMAIN 2517 2549 FATC.
FT REGION 1 651 Interaction with NBN.
FT REGION 2012 2144 Sufficient for interaction with the
FT FKBP1A/rapamycin complex (By similarity).
FT REGION 2258 2296 Interaction with MLST8.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 567 567 Phosphoserine.
FT MOD_RES 1162 1162 Phosphothreonine.
FT MOD_RES 1218 1218 N6-acetyllysine.
FT MOD_RES 1261 1261 Phosphoserine.
FT MOD_RES 2159 2159 Phosphoserine.
FT MOD_RES 2164 2164 Phosphothreonine.
FT MOD_RES 2446 2446 Phosphothreonine; by RPS6KB1.
FT MOD_RES 2448 2448 Phosphoserine; by RPS6KB1.
FT MOD_RES 2478 2478 Phosphoserine.
FT MOD_RES 2481 2481 Phosphoserine; by autocatalysis.
FT VARIANT 8 8 A -> S (in a lung large cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_041537.
FT VARIANT 135 135 M -> T (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_041538.
FT VARIANT 1083 1083 M -> V (in dbSNP:rs56164650).
FT /FTId=VAR_041539.
FT VARIANT 1134 1134 A -> V (in dbSNP:rs28730685).
FT /FTId=VAR_041540.
FT VARIANT 1178 1178 S -> F (in dbSNP:rs55975118).
FT /FTId=VAR_041541.
FT VARIANT 2011 2011 M -> V (in an ovarian mucinous carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_041542.
FT VARIANT 2215 2215 S -> Y (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_041543.
FT VARIANT 2220 2220 L -> F (found in a renal cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_064733.
FT VARIANT 2406 2406 V -> A (found in a renal cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_064734.
FT VARIANT 2476 2476 P -> L (in a glioblastoma multiforme
FT sample; somatic mutation).
FT /FTId=VAR_041544.
FT MUTAGEN 2159 2159 S->A: Reduces mTORC1-associated S-2481
FT autophosphorylation; when associated with
FT A-2164.
FT MUTAGEN 2159 2159 S->D: Stronger phosphorylation of
FT RPS6KB1; when associated with E-2164.
FT MUTAGEN 2164 2164 T->A: Reduces mTORC1-associated S-2481
FT autophosphorylation; when associated with
FT A-2159.
FT MUTAGEN 2164 2164 T->E: Stronger phosphorylation of
FT RPS6KB1; when associated with D-2159.
FT MUTAGEN 2340 2340 H->A: Barely detectable kinase activity.
FT CONFLICT 353 353 K -> N (in Ref. 2; AAC39933).
FT CONFLICT 359 359 S -> N (in Ref. 2; AAC39933).
FT CONFLICT 364 364 D -> N (in Ref. 2; AAC39933).
FT CONFLICT 390 390 M -> L (in Ref. 2; AAC39933).
FT CONFLICT 430 430 R -> L (in Ref. 2; AAC39933).
FT CONFLICT 455 457 VLD -> GVE (in Ref. 2; AAC39933).
FT CONFLICT 461 461 A -> G (in Ref. 2; AAC39933).
FT CONFLICT 482 484 VFT -> FFN (in Ref. 2; AAC39933).
FT CONFLICT 489 489 L -> V (in Ref. 2; AAC39933).
FT CONFLICT 513 513 L -> I (in Ref. 2; AAC39933).
FT CONFLICT 539 539 L -> V (in Ref. 2; AAC39933).
FT CONFLICT 553 553 R -> C (in Ref. 2; AAC39933).
FT CONFLICT 857 857 P -> L (in Ref. 3; BAE06077).
FT CONFLICT 1075 1075 I -> S (in Ref. 2; AAC39933).
FT HELIX 1387 1406
FT HELIX 1410 1422
FT HELIX 1426 1439
FT HELIX 1446 1452
FT HELIX 1456 1469
FT HELIX 1474 1486
FT HELIX 1490 1498
FT STRAND 1501 1503
FT HELIX 1506 1521
FT TURN 1522 1524
FT HELIX 1526 1533
FT HELIX 1541 1553
FT HELIX 1557 1572
FT TURN 1573 1577
FT TURN 1584 1586
FT HELIX 1587 1605
FT STRAND 1606 1608
FT HELIX 1609 1611
FT HELIX 1612 1624
FT HELIX 1630 1640
FT TURN 1641 1643
FT TURN 1646 1648
FT HELIX 1650 1663
FT HELIX 1666 1677
FT STRAND 1681 1684
FT HELIX 1694 1706
FT HELIX 1710 1729
FT HELIX 1737 1762
FT TURN 1766 1768
FT HELIX 1769 1782
FT TURN 1783 1785
FT HELIX 1787 1813
FT HELIX 1868 1893
FT STRAND 1896 1898
FT HELIX 1900 1913
FT HELIX 1917 1929
FT HELIX 1933 1938
FT HELIX 1939 1943
FT TURN 1944 1947
FT HELIX 1951 1966
FT HELIX 1970 1980
FT HELIX 1985 2020
FT HELIX 2025 2039
FT HELIX 2044 2058
FT HELIX 2065 2091
FT HELIX 2094 2111
FT HELIX 2115 2117
FT STRAND 2119 2122
FT HELIX 2123 2126
FT HELIX 2128 2132
FT STRAND 2137 2139
FT STRAND 2152 2156
FT STRAND 2158 2162
FT STRAND 2165 2167
FT STRAND 2170 2176
FT STRAND 2181 2189
FT HELIX 2193 2211
FT HELIX 2213 2217
FT STRAND 2227 2229
FT STRAND 2231 2233
FT STRAND 2235 2238
FT STRAND 2243 2245
FT HELIX 2246 2256
FT HELIX 2263 2271
FT HELIX 2275 2277
FT HELIX 2280 2291
FT HELIX 2298 2306
FT HELIX 2310 2334
FT TURN 2341 2343
FT STRAND 2344 2347
FT TURN 2348 2350
FT STRAND 2353 2355
FT HELIX 2364 2367
FT STRAND 2369 2371
FT HELIX 2381 2386
FT TURN 2389 2394
FT HELIX 2395 2409
FT HELIX 2411 2422
FT TURN 2425 2427
FT HELIX 2428 2435
FT HELIX 2493 2507
FT TURN 2508 2510
FT STRAND 2512 2516
FT HELIX 2521 2533
FT HELIX 2535 2538
FT HELIX 2543 2545
SQ SEQUENCE 2549 AA; 288892 MW; 7D9AD6E784882AB4 CRC64;
MLGTGPAAAT TAATTSSNVS VLQQFASGLK SRNEETRAKA AKELQHYVTM ELREMSQEES
TRFYDQLNHH IFELVSSSDA NERKGGILAI ASLIGVEGGN ATRIGRFANY LRNLLPSNDP
VVMEMASKAI GRLAMAGDTF TAEYVEFEVK RALEWLGADR NEGRRHAAVL VLRELAISVP
TFFFQQVQPF FDNIFVAVWD PKQAIREGAV AALRACLILT TQREPKEMQK PQWYRHTFEE
AEKGFDETLA KEKGMNRDDR IHGALLILNE LVRISSMEGE RLREEMEEIT QQQLVHDKYC
KDLMGFGTKP RHITPFTSFQ AVQPQQSNAL VGLLGYSSHQ GLMGFGTSPS PAKSTLVESR
CCRDLMEEKF DQVCQWVLKC RNSKNSLIQM TILNLLPRLA AFRPSAFTDT QYLQDTMNHV
LSCVKKEKER TAAFQALGLL SVAVRSEFKV YLPRVLDIIR AALPPKDFAH KRQKAMQVDA
TVFTCISMLA RAMGPGIQQD IKELLEPMLA VGLSPALTAV LYDLSRQIPQ LKKDIQDGLL
KMLSLVLMHK PLRHPGMPKG LAHQLASPGL TTLPEASDVG SITLALRTLG SFEFEGHSLT
QFVRHCADHF LNSEHKEIRM EAARTCSRLL TPSIHLISGH AHVVSQTAVQ VVADVLSKLL
VVGITDPDPD IRYCVLASLD ERFDAHLAQA ENLQALFVAL NDQVFEIREL AICTVGRLSS
MNPAFVMPFL RKMLIQILTE LEHSGIGRIK EQSARMLGHL VSNAPRLIRP YMEPILKALI
LKLKDPDPDP NPGVINNVLA TIGELAQVSG LEMRKWVDEL FIIIMDMLQD SSLLAKRQVA
LWTLGQLVAS TGYVVEPYRK YPTLLEVLLN FLKTEQNQGT RREAIRVLGL LGALDPYKHK
VNIGMIDQSR DASAVSLSES KSSQDSSDYS TSEMLVNMGN LPLDEFYPAV SMVALMRIFR
DQSLSHHHTM VVQAITFIFK SLGLKCVQFL PQVMPTFLNV IRVCDGAIRE FLFQQLGMLV
SFVKSHIRPY MDEIVTLMRE FWVMNTSIQS TIILLIEQIV VALGGEFKLY LPQLIPHMLR
VFMHDNSPGR IVSIKLLAAI QLFGANLDDY LHLLLPPIVK LFDAPEAPLP SRKAALETVD
RLTESLDFTD YASRIIHPIV RTLDQSPELR STAMDTLSSL VFQLGKKYQI FIPMVNKVLV
RHRINHQRYD VLICRIVKGY TLADEEEDPL IYQHRMLRSG QGDALASGPV ETGPMKKLHV
STINLQKAWG AARRVSKDDW LEWLRRLSLE LLKDSSSPSL RSCWALAQAY NPMARDLFNA
AFVSCWSELN EDQQDELIRS IELALTSQDI AEVTQTLLNL AEFMEHSDKG PLPLRDDNGI
VLLGERAAKC RAYAKALHYK ELEFQKGPTP AILESLISIN NKLQQPEAAA GVLEYAMKHF
GELEIQATWY EKLHEWEDAL VAYDKKMDTN KDDPELMLGR MRCLEALGEW GQLHQQCCEK
WTLVNDETQA KMARMAAAAA WGLGQWDSME EYTCMIPRDT HDGAFYRAVL ALHQDLFSLA
QQCIDKARDL LDAELTAMAG ESYSRAYGAM VSCHMLSELE EVIQYKLVPE RREIIRQIWW
ERLQGCQRIV EDWQKILMVR SLVVSPHEDM RTWLKYASLC GKSGRLALAH KTLVLLLGVD
PSRQLDHPLP TVHPQVTYAY MKNMWKSARK IDAFQHMQHF VQTMQQQAQH AIATEDQQHK
QELHKLMARC FLKLGEWQLN LQGINESTIP KVLQYYSAAT EHDRSWYKAW HAWAVMNFEA
VLHYKHQNQA RDEKKKLRHA SGANITNATT AATTAATATT TASTEGSNSE SEAESTENSP
TPSPLQKKVT EDLSKTLLMY TVPAVQGFFR SISLSRGNNL QDTLRVLTLW FDYGHWPDVN
EALVEGVKAI QIDTWLQVIP QLIARIDTPR PLVGRLIHQL LTDIGRYHPQ ALIYPLTVAS
KSTTTARHNA ANKILKNMCE HSNTLVQQAM MVSEELIRVA ILWHEMWHEG LEEASRLYFG
ERNVKGMFEV LEPLHAMMER GPQTLKETSF NQAYGRDLME AQEWCRKYMK SGNVKDLTQA
WDLYYHVFRR ISKQLPQLTS LELQYVSPKL LMCRDLELAV PGTYDPNQPI IRIQSIAPSL
QVITSKQRPR KLTLMGSNGH EFVFLLKGHE DLRQDERVMQ LFGLVNTLLA NDPTSLRKNL
SIQRYAVIPL STNSGLIGWV PHCDTLHALI RDYREKKKIL LNIEHRIMLR MAPDYDHLTL
MQKVEVFEHA VNNTAGDDLA KLLWLKSPSS EVWFDRRTNY TRSLAVMSMV GYILGLGDRH
PSNLMLDRLS GKILHIDFGD CFEVAMTREK FPEKIPFRLT RMLTNAMEVT GLDGNYRITC
HTVMEVLREH KDSVMAVLEA FVYDPLLNWR LMDTNTKGNK RSRTRTDSYS AGQSVEILDG
VELGEPAHKK TGTTVPESIH SFIGDGLVKP EALNKKAIQI INRVRDKLTG RDFSHDDTLD
VPTQVELLIK QATSHENLCQ CYIGWCPFW
//

MIM 601231
*RECORD*
*FIELD* NO
601231
*FIELD* TI
*601231 MECHANISTIC TARGET OF RAPAMYCIN; MTOR
;;MAMMALIAN TARGET OF RAPAMYCIN;;
FKBP12-RAPAMYCIN COMPLEX-ASSOCIATED PROTEIN 1; FRAP1;;
read moreFK506-BINDING PROTEIN 12-RAPAMYCIN COMPLEX-ASSOCIATED PROTEIN 1;;
FRAP;;
FRAP2;;
RAFT1
MTOR COMPLEX, INCLUDED; MTORC, INCLUDED;;
MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1, INCLUDED; MTORC1, INCLUDED;;
MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 2, INCLUDED; MTORC2, INCLUDED
*FIELD* TX

DESCRIPTION

MTOR is a highly conserved protein kinase that is found in 2
structurally and functionally distinct protein complexes: TOR complex-1
(TORC1) and TORC2. TORC1 is a key regulator of cell growth and
proliferation and mRNA translation, whereas TORC2 promotes actin
cytoskeletal rearrangement, cell survival, and cell cycle progression
(summary by Jacinto et al. (2004) and Thoreen et al. (2012)).

CLONING

To identify the target for the FKBP12-rapamycin complex in human, Brown
et al. (1994) used a FKBP12/glutathione-S-transferase fusion protein and
glutathione affinity chromatography to purify a 220-kD bovine brain
protein which bound the FKBP12-rapamycin complex. They designed
oligonucleotide probes based on the bovine protein sequence and screened
a human Jurkat T-cell cDNA library. Their complete human cDNA for FRAP
encoded a predicted 2,549-amino acid protein with a calculated molecular
mass of approximately 300 kD. Brown et al. (1994) showed by Northern
blot analysis that the 7.6-kb gene transcript was present in a variety
of human tissues. They noted that, while the precise functions of FRAP
and its yeast homologs TOR1/TOR2 are unknown, the C-terminal regions of
these proteins share amino acid homology (approximately 21% identity on
average) with several phosphatidylinositol kinases; see 171834.

In a review, Hay and Sonenberg (2004) described the domain structure of
MTOR. The N-terminal half of the protein contains 20 tandem HEAT
repeats, which are implicated in protein-protein interactions. Each HEAT
repeat consists of 2 alpha helices of about 40 amino acids. The
C-terminal half contains a large FRAP-ATM (607585)-TRRAP (603015) (FAT)
domain, followed by the FKB12- and rapamycin-binding domain, a
serine/threonine kinase catalytic domain, a negative regulatory domain,
and a C-terminal FAT (FATC) domain necessary for MTOR activity.

GENE FUNCTION

FKBP12-rapamycin associated protein (FRAP) is one of a family of
proteins involved in cell cycle progression, DNA recombination, and DNA
damage detection. In rat, it is a 245-kD protein (symbolized RAFT1) with
significant homology to the Saccharomyces cerevisiae protein TOR1 and
has been shown to associate with the immunophilin FKBP12 (186945) in a
rapamycin-dependent fashion (Sabatini et al., 1994). Brown et al. (1994)
noted that the FKBP12-rapamycin complex was known to inhibit progression
through the G1 cell cycle stage by interfering with mitogenic signaling
pathways involved in G1 progression in several cell types, as well as in
yeast. The authors stated that the binding of FRAP to FKBP12-rapamycin
correlated with the ability of these ligands to inhibit cell cycle
progression.

Rapamycin is an efficacious anticancer agent against solid tumors. In a
hypoxic environment, the increase in mass of solid tumors is dependent
on the recruitment of mitogens and nutrients. When nutrient
concentrations change, particularly those of essential amino acids, the
mammalian target of rapamycin (mTOR/FRAP) functions in regulatory
pathways that control ribosome biogenesis and cell growth. In bacteria,
ribosome biogenesis is independently regulated by amino acids and ATP.
Dennis et al. (2001) demonstrated that the human mTOR pathway is
influenced by the intracellular concentration of ATP, independent of the
abundance of amino acids, and that mTOR/FRAP itself is an ATP sensor.

Castedo et al. (2001) delineated the apoptotic pathway resulting from
human immunodeficiency virus (HIV)-1 envelope glycoprotein (Env)-induced
syncytia formation in vitro and in vivo. Immunohistochemical analysis
demonstrated the presence of phosphorylated ser15 of p53 (191170) as
well as the preapoptotic marker tissue transglutaminase (TGM2; 190196)
in syncytium in the apical light zone (T-cell area) of lymph nodes, as
well as in peripheral blood mononuclear cells, from HIV-1-positive but
not HIV-1-negative donors. The presence of these markers correlated with
viral load (HIV-1 RNA levels). Quantitative immunoblot analysis showed
that phosphorylation of ser15 of p53 in response to HIV-1 Env is
mediated by FRAP and not by other phosphatidylinositol kinase-related
kinases, and it is accompanied by downregulation of protein phosphatase
2A (see 176915). The phosphorylation is significantly inhibited by
rapamycin. Immunofluorescence microscopy indicated that FRAP is enriched
in syncytial nuclei and that the nuclear accumulation precedes the
phosphorylation of ser15 of p53. Castedo et al. (2001) concluded that
HIV-1 Env-induced syncytium formation leads to apoptosis via a pathway
that involves phosphorylation of ser15 of p53 by FRAP, followed by
activation of BAX (600040), mitochondrial membrane permeabilization,
release of cytochrome C, and caspase activation.

Fang et al. (2001) identified phosphatidic acid as a critical component
of mTOR signaling. In their study, mitogenic stimulation of mammalian
cells led to a phospholipase D-dependent accumulation of cellular
phosphatidic acid, which was required for activation of mTOR downstream
effectors. Phosphatidic acid directly interacted with the domain in mTOR
that is targeted by rapamycin, and this interaction was positively
correlated with mTOR's ability to activate downstream effectors. The
involvement of phosphatidic acid in mTOR signaling reveals an important
function of this lipid in signal transduction and protein synthesis, as
well as a direct link between mTOR and mitogens. Fang et al. (2001)
concluded that their study suggested a potential mechanism for the in
vivo actions of the immunosuppressant rapamycin.

Kim et al. (2002) and Hara et al. (2002) reported that MTOR binds with
RAPTOR (607130), an evolutionarily conserved protein with at least 2
roles in the MTOR pathway. Kim et al. (2002) showed that RAPTOR has a
positive role in nutrient-stimulated signaling to the downstream
effector S6K1 (608938), maintenance of cell size, and MTOR protein
expression. The association of RAPTOR with MTOR also negatively
regulates MTOR kinase activity. Conditions that repress the pathway,
such as nutrient deprivation and mitochondrial uncoupling, stabilize the
MTOR-RAPTOR association and inhibit MTOR kinase activity. Kim et al.
(2002) proposed that RAPTOR is a component of the MTOR pathway that,
through its association with MTOR, regulates cell size in response to
nutrient levels.

In mammals, MTOR cooperates with PI3K (see 171834)-dependent effectors
in a biochemical signaling pathway to regulate the size of proliferating
cells. Fingar et al. (2002) presented evidence that rat S6k1 alpha-II,
Eif4e (133440), and Eif4ebp1 (602223) mediate Mtor-dependent cell size
control.

Hara et al. (2002) showed that the binding of RAPTOR to MTOR is
necessary for the MTOR-catalyzed phosphorylation of 4EBP1 in vitro and
that it strongly enhances the MTOR kinase activity toward p70-alpha
(S6K1). Rapamycin or amino acid withdrawal increased, whereas insulin
strongly inhibited, the recovery of 4EBP1 and RAPTOR on 7-methyl-GTP
sepharose. Partial inhibition of RAPTOR expression by RNA interference
reduced MTOR-catalyzed 4EBP1 phosphorylation in vitro. RNA interference
of C. elegans Raptor yielded an array of phenotypes that closely
resembled those produced by inactivation of CE-Tor. Thus, the authors
concluded that RAPTOR is an essential scaffold for the MTOR-catalyzed
phosphorylation of 4EBP1 and mediates TOR action in vivo.

Vellai et al. (2003) demonstrated that TOR deficiency in C. elegans more
than doubles its natural life span. The absence of Let363/TOR activity
caused developmental arrest at the L3 larval stage. At 25.5 degrees C,
the mean life span of Let363 mutants was 25 days compared with a life
span of 10 days in wildtype worms.

By immunoprecipitation analysis, Kim et al. (2003) identified GBL
(612190) as an additional subunit of the MTOR signaling complex in human
embryonic kidney cells. GBL bound the kinase domain of MTOR and
stabilized the interaction of raptor with MTOR. Loss-of-function
experiments using small interfering RNA showed that, like MTOR and
raptor, GBL participated in nutrient- and growth factor-mediated
signaling to S6K1 and in control of cell size. Binding of GBL to MTOR
strongly stimulated MTOR kinase activity toward S6K1 and 4EBP1, and this
effect was reversed by stable interaction of raptor with MTOR. Nutrients
and rapamycin regulated the association of MTOR with raptor only in
complexes that also contained GBL. Kim et al. (2003) proposed that GBL
and raptor function together to modulate MTOR kinase activity.

Huntington disease (HD; 143100) is an inherited neurodegenerative
disorder caused by a polyglutamine tract expansion in which expanded
polyglutamine proteins accumulate abnormally in intracellular
aggregates. Ravikumar et al. (2004) showed that mammalian target of
rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell
models, transgenic mice, and human brains. Sequestration of mTOR impairs
its kinase activity and induces autophagy, a key clearance pathway for
mutant huntingtin (613004) fragments. This protects against
polyglutamine toxicity, as the specific mTOR inhibitor rapamycin
attenuates huntingtin accumulation and cell death in cell models of HD,
and inhibition of autophagy has converse effects. Furthermore, rapamycin
protects against neurodegeneration in a fly model of HD, and the
rapamycin analog CCI-779 improved performance on 4 different behavioral
tasks and decreased aggregate formation in a mouse model of HD. The data
provided proof of principle for the potential of inducing autophagy to
treat HD.

Scott et al. (2004) found that signaling through Tor and its upstream
regulators, Pi3k and Rheb (601293), was necessary and sufficient to
suppress starvation-induced autophagy in the Drosophila fat body. In
contrast, a downstream Tor effector, S6k, promoted rather than
suppressed autophagy, suggesting S6K downregulation may limit autophagy
during extended starvation.

Hay and Sonenberg (2004) reviewed the roles of MTOR in protein
synthesis, cell growth and proliferation, synaptic plasticity, and
cancer.

Brugarolas et al. (2004) showed that downregulation of Mtor by hypoxia
in mice required de novo transcription and expression of Redd1 (607729)
and an intact Tsc1 (605284)/Tsc2 (191092) complex.

Beuvink et al. (2005) showed that the drug RAD001 (everolimus), a
rapamycin derivative, dramatically enhanced cisplatin-induced apoptosis
in wildtype p53 but not mutant p53 tumor cells. The use of isogenic
tumor cell lines expressing either wildtype MTOR cDNA or an MTOR mutant
unable to bind RAD001 demonstrated that the effects of RAD001 resulted
from inhibition of MTOR function. Beuvink et al. (2005) showed that
RAD001 sensitized cells to cisplatin by inhibiting p53-induced p21
(116899) expression. This effect was attributed to a small but
significant inhibition of p21 translation, combined with the short
half-life of p21.

Kwon et al. (2003) found that inhibition of Mtor decreased the seizure
frequency and death rate in mice with conditional Pten (601728)
deficiency, prevented the increase in Pten-deficient neuronal soma size
in young mice, and reversed neuronal soma enlargement in adult mice.
Mtor inhibition did not decrease the size of wildtype adult neurons.
Kwon et al. (2003) concluded that MTOR is required for neuronal
hypertrophy downstream of PTEN deficiency, but it is not required for
maintenance of normal neuronal soma size. They proposed that MTOR
inhibitors may be useful therapeutic agents for the treatment of brain
diseases resulting from PTEN deficiency, such as Lhermitte-Duclos
disease (see 158350) or glioblastoma multiforme (137800).

Akt/PKB (164730) activation requires the phosphorylation of ser473.
Sarbassov et al. (2005) showed that in Drosophila and in human cells TOR
and its associated protein rictor are necessary for ser473
phosphorylation, and that a reduction in rictor or mTOR expression
inhibited an AKT/PKB effector. The rictor-mTOR complex directly
phosphorylated Akt/PKB on ser473 in vitro and facilitated thr308
phosphorylation by PDK1 (605213).

Holz et al. (2005) showed that MTOR and S6K1 maneuvered on and off the
EIF3 (see 602039) translation initiation complex in HEK293 cells in a
signal-dependent, choreographed fashion. When inactive, S6K1 associated
with the EIF3 complex, while the S6K1 activator MTOR, in association
with RAPTOR, did not. Hormone- or mitogen-mediated cell stimulation
promoted MTOR/RAPTOR binding to the EIF3 complex and phosphorylation of
S6K1. Phosphorylation resulted in S6K1 dissociation and activation,
followed by phosphorylation of S6K1 targets, including EIF4B (603928),
which, upon phosphorylation, was recruited into the EIF3 complex. Holz
et al. (2005) concluded that the EIF3 preinitiation complex acts as a
scaffold to coordinate responses to stimuli that promote efficient
protein synthesis.

Cota et al. (2006) demonstrated that mTOR signaling plays a role in the
brain mechanisms that respond to nutrient availability, regulating
energy balance. In the rat, mTOR signaling is controlled by energy
status in specific regions of the hypothalamus and colocalizes with
neuropeptide Y (162640) and proopiomelanocortin (POMC; 176830) neurons
in the arcuate nucleus. Central administration of leucine increases
hypothalamic mTOR signaling and decreases food intake and body weight.
The hormone leptin (164160) increases hypothalamic mTOR activity, and
the inhibition of mTOR signaling blunts leptin's anorectic effect. Thus,
Cota et al. (2006) concluded that mTOR is a cellular fuel sensor whose
hypothalamic activity is directly tied to the regulation of energy
intake.

Laviano et al. (2006) questioned the clinical validity of the
experiments performed by Cota et al. (2006) given that in human
conditions such as hepatic encephalopathy and cancer, and in
malnourished uremic patients undergoing hemodialysis, supplementation
with 7 grams per day of leucine, which comprises 50% of a branched-chain
amino acid mix, improves appetite and muscle protein synthesis. Cota et
al. (2006) responded that their experiments were done in healthy rats of
normal weight to investigate the physiologic role of hypothalamic mTOR
in the regulation of food intake.

Bernardi et al. (2006) identified PML (102578) as a critical inhibitor
of neoangiogenesis (the formation of new blood vessels) in vivo, in both
ischemic and neoplastic conditions, through the control of protein
translation. Bernardi et al. (2006) demonstrated that in hypoxic
conditions PML acts as a negative regulator of the synthesis rate of
hypoxia-inducible factor 1-alpha (HIF1A; 603348) by repressing mTOR. PML
physically interacts with mTOR and negatively regulates its association
with the small GTPase RHEB (601293) by favoring mTOR nuclear
accumulation. Notably, PML-null cells and tumors displayed higher
sensitivity both in vitro and in vivo to growth inhibition by rapamycin,
and lack of PML inversely correlated with phosphorylation of ribosomal
protein S6 (180460) and tumor angiogenesis in mouse and human tumors.
Thus, Bernardi et al. (2006) concluded that their findings identified
PML as a novel suppressor of mTOR and neoangiogenesis.

Li et al. (2006) demonstrated that Tor1 is dynamically distributed in
the cytoplasm and nucleus in yeast. Tor1 nuclear localization is
nutrient-dependent and rapamycin-sensitive: starvation or treatment with
rapamycin causes Tor1 to exit from the nucleus. Tor1 nuclear
localization is critical for 35S rRNA synthesis, but not for the
expression of amino acid transporters and ribosomal protein genes. Li et
al. (2006) further showed that Tor1 is associated with 35S ribosomal DNA
(rDNA) promoter chromatin in a rapamycin- and starvation-sensitive
manner; this association is necessary for 35S rRNA synthesis and cell
growth. Li et al. (2006) concluded that the spatial regulation of Tor1
complex 1 (TORC1; see later) might be involved in differential control
of its target genes.

Raab-Graham et al. (2006) found that the mTOR inhibitor rapamycin
increased the Kv1.1 (KCNA1; 176260) voltage-gated potassium channel
protein in hippocampal neurons and promoted Kv1.1 surface expression on
dendrites without altering its axonal expression. Moreover, endogenous
Kv1.1 mRNA was detected in dendrites. Using Kv1.1 fused to the
photoconvertible fluorescence protein Kaede as a reporter for local
synthesis, Raab-Graham et al. (2006) observed Kv1.1 synthesis in
dendrites upon inhibition of mTOR or the N-methyl-D-aspartate (NMDA)
glutamate receptor (see 138251). Thus, Raab-Graham et al. (2006)
concluded that synaptic excitation may cause local suppression of
dendritic Kv1 channels by reducing their local synthesis.

Hoyer-Hansen et al. (2007) showed that Ca(2+)-induced autophagy in
mammalian cells utilized a signaling pathway that included CAMKK2, AMPK
(PRKAA2; 600497), and mTOR. Ca(2+)-induced autophagy was inhibited by
BCL2 (151430) but only when BCL2 was localized to the endoplasmic
reticulum.

The activity of mTOR is regulated by RHEB, a Ras-like small GTPase, in
response to growth factor stimulation and nutrient availability. Bai et
al. (2007) showed that RHEB regulates mTOR through FKBP38 (604840), a
member of the FK506-binding protein (FKBP) family that is structurally
related to FKBP12 (186945). FKBP38 binds to mTOR and inhibits its
activity in a manner similar to that of the FKBP12-rapamycin complex.
RHEB interacts directly with FKBP38 and prevents its association with
mTOR in a GTP-dependent manner. Bai et al. (2007) concluded that their
findings suggested that FKBP38 is an endogenous inhibitor of mTOR, whose
inhibitory activity is antagonized by RHEB in response to growth factor
stimulation and nutrient availability.

Cunningham et al. (2007) showed that mTOR is necessary for the
maintenance of mitochondrial oxidative function. In skeletal muscle
tissues and cells, the mTOR inhibitor rapamycin decreased the gene
expression of the mitochondrial transcriptional regulators PGC1-alpha
(604517), estrogen-related receptor alpha (ESRRA; 601998), and nuclear
respiratory factors, resulting in a decrease in mitochondrial gene
expression and oxygen consumption. Using computational genomics,
Cunningham et al. (2007) identified the transcription factor yin-yang 1
(YY1; 600013) as a common target of mTOR and PGC1-alpha. Knockdown of
YY1 caused a significant decrease in mitochondrial gene expression and
in respiration, and YY1 was required for rapamycin-dependent repression
of those genes. Moreover, inhibition of mTOR resulted in a failure of
YY1 to interact with and be coactivated by PGC1-alpha. Cunningham et al.
(2007) concluded that they identified a mechanism by which a nutrient
sensor (mTOR) balances energy metabolism by means of the transcriptional
control of mitochondrial oxidative function.

Mao et al. (2008) demonstrated that mTOR is targeted for ubiquitination
and consequent degradation by binding to the tumor suppressor protein
FBXW7 (606278). Human breast cancer cell lines and primary tumors showed
a reciprocal relation between loss of FBXW7 and deletion or mutation of
PTEN (601728), which also activates mTOR. Tumor cell lines harboring
deletions or mutations in FBXW7 are particularly sensitive to rapamycin
treatment, suggesting to Mao et al. (2008) that loss of FBXW7 may be a
biomarker for human cancers susceptible to treatment with inhibitors of
the mTOR pathway.

To test for the role of intrinsic impediments to axon regrowth, Park et
al. (2008) analyzed cell growth control genes using a virus-assisted in
vivo conditional knockout approach. Deletion of PTEN, a negative
regulator of the mTOR pathway, in adult retinal ganglion cells promoted
robust axon regeneration after optic nerve injury. In wildtype adult
mice, the mTOR activity was suppressed and new protein synthesis was
impaired in axotomized retinal ganglion cells, which may have
contributed to the regeneration failure. Reactivating this pathway by
conditional knockout of the TSC1 gene (605284), another negative
regulator of the mTOR pathway, also led to axon regeneration.

Genomewide copy number analyses of human cancers identified a frequent
5p13 amplification in several solid tumor types, including lung (56%),
ovarian (38%), breast (32%), prostate (37%), and melanoma (32%). Using
integrative analysis of a genomic profile of the region, Scott et al.
(2009) identified a Golgi protein, GOLPH3 (612207), as a candidate
targeted for amplification. Gain- and loss-of-function studies in vitro
and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3
localizes to the trans-Golgi network and interacts with components of
the retromer complex, which in yeast has been linked to TOR signaling.
Mechanistically, GOLPH3 regulates cell size, enhances growth
factor-induced mTOR signaling in human cancer cells, and alters the
response of an mTOR inhibitor in vivo. Thus, Scott et al. (2009)
concluded that genomic and genetic, biologic, functional, and
biochemical data in yeast and humans established GOLPH3 as a novel
oncogene that is commonly targeted for amplification in human cancer,
and is capable of modulating the response to rapamycin, a cancer drug in
clinical use.

Mutations in the TSC1 (605284) and TSC2 (191092) genes cause tuberous
sclerosis (191100 and 613254, respectively); the protein products of
these genes form a complex in the TOR pathway that integrates
environmental signals to regulate cell growth, proliferation, and
survival. DiBella et al. (2009) showed that morpholino knockdown of
zebrafish Tsc1a led to a ciliary phenotype including kidney cyst
formation and left-right asymmetry defects. Tsc1a localized to the
Golgi, but morpholinos against it, nonetheless, acted synthetically with
ciliary genes in producing kidney cysts. Consistent with a role of the
cilium in the same pathway as Tsc genes, the TOR pathway was found to be
aberrantly activated in ciliary mutants, resembling the effect of Tsc1a
knockdown, and kidney cyst formation in ciliary mutants was blocked by
rapamycin. DiBella et al. (2009) suggested a signaling network between
the cilium and the TOR pathway wherein ciliary signals can feed into the
TOR pathway and where Tsc1a may regulate the length of the cilium
itself.

Araki et al. (2009) demonstrated that mTOR is a major regulator of
memory CD8 T-cell differentiation and that the immunosuppressive drug
rapamycin has immunostimulatory effects on the generation of memory CD8
T cells. Treatment of mice with rapamycin following acute lymphocytic
choriomeningitis virus infection enhanced not only the quantity but also
the quality of virus-specific CD8 T cells. Similar effects were seen
after immunization of mice with a vaccine based on nonreplicating
virus-like particles. In addition, rapamycin treatment also enhanced
memory T-cell responses in nonhuman primates following vaccination with
modified vaccinia virus Ankara. Rapamycin was effective during both the
expansion and contraction phases of the T cell response; during the
expansion phase it increased the number of memory precursors, and during
the contraction phase (effector to memory transition) it accelerated the
memory T cell differentiation program. Experiments using RNA
interference to inhibit expression of mTOR, raptor (607130) or FKBP12
(186945) in antigen-specific CD8 T cells showed that mTOR acts
intrinsically through the mTORC1 (mTOR complex 1; see later) pathway to
regulate memory T-cell differentiation. Araki et al. (2009) concluded
that their studies identified a molecular pathway to regulate memory
T-cell differentiation and provided a strategy for improving the
functional qualities of vaccine- or infection-induced memory T cells.

Sestrins (see 606103) are conserved proteins that accumulate in cells
exposed to stress, potentiate adenosine monophosphate-activated protein
kinase (AMPK; 602739), and inhibit activation of TOR (mTOR). Lee et al.
(2010) showed that the abundance of Drosophila sestrin is increased upon
chronic TOR activation through accumulation of reactive oxygen species
that cause activation of c-Jun N-terminal kinase (see 601158) and
transcription factor Forkhead box O (Foxo; see 136533). Loss of
Drosophila Sesn resulted in age-associated pathologies including
triglyceride accumulation, mitochondrial dysfunction, muscle
degeneration, and cardiac malfunction, which were prevented by
pharmacologic activation of AMPK or inhibition of TOR. Hence, Lee et al.
(2010) concluded that Drosophila Sesn appears to be a negative feedback
regulator of TOR that integrates metabolic and stress inputs and
prevents pathologies caused by chronic TOR activation that may result
from diminished autophagic clearance of damaged mitochondria, protein
aggregates, or lipids.

Using naive CD8 T (OT-I) cells from Rag2 (179616) -/- mice, Rao et al.
(2010) showed that IL12 (161560) enhanced and sustained antigen and B7.1
(CD80; 112203) costimulatory molecule-induced mTor kinase activity via
Pi3k and Stat4 (600558) pathways. Blocking mTor activity with rapamycin
reversed IL12-induced effector functions through loss of Tbet (TBX21;
604895) expression. Rapamycin treatment of IL12-conditioned OT-I cells
also induced Eomes (604615) expression and memory T cell precursors with
greater antitumor efficacy. Rao et al. (2010) concluded that mTOR is the
central regulator of transcriptional programs determining effector
and/or memory cell fates of CD8+ T cells.

Yu et al. (2010) showed that mTOR signaling in rat kidney cells is
inhibited during initiation of autophagy, but reactivated by prolonged
starvation. Reactivation of mTOR is autophagy-dependent and requires the
degradation of autolysosomal products. Increased mTOR activity
attenuates autophagy and generates protolysosomal tubules and vesicles
that extrude from autolysosomes and ultimately mature into functional
lysosomes, thereby restoring the full complement of lysosomes in the
cell--a process Yu et al. (2010) identified in multiple animal species.
Thus, Yu et al. (2010) concluded that an evolutionarily conserved cycle
in autophagy governs nutrient sensing and lysosome homeostasis during
starvation.

Ketamine results in a rapid antidepressant response after administration
in treatment-resistant depressed patients. Li et al. (2010) observed
that ketamine rapidly activated the mTOR pathway, leading to increased
synaptic signaling proteins and increased number and function of new
spine synapses in the prefrontal cortex of rats. Moreover, blockade of
mTOR signaling completely blocked ketamine induction of synaptogenesis
and behavioral responses in models of depression. Li et al. (2010)
concluded that these effects of ketamine are opposite to the synaptic
deficits that result from exposure to stress and could contribute to the
fast antidepressant actions of ketamine. Furthermore, Li et al. (2010)
demonstrated that another compound, which selectively acts on NR2B
(138252), had similar effects to ketamine, suggesting that this effect
is mediated through NMDA receptors.

Sathaliyawala et al. (2010) found that the Mtor inhibitor rapamycin
impaired mouse Flt3l (FLT3LG; 600007)-driven dendritic cell (DC)
development in vitro, with plasmacytoid DCs and classical DCs most
profoundly affected. Depletion of the Pi3k-Mtor negative regulator Pten
facilitated Flt3l-driven DC development in culture. Targeting Pten in
DCs in vivo caused expansion of Cd8-positive and Cd103 (ITGAE;
604682)-positive classical DCs, which could be reversed by rapamycin.
Increased Cd8-positive classical DC numbers caused by Pten deletion
correlated with increased susceptibility to Listeria infection.
Sathaliyawala et al. (2010) concluded that PI3K-MTOR signaling
downstream of FLT3L controls DC development, and that restriction by
PTEN ensures optimal DC numbers and subset composition.

Protein synthesis and autophagic degradation are regulated in an
opposite manner by mTOR, whereas under certain conditions it would be
beneficial if they occurred in unison to handle rapid protein turnover.
Narita et al. (2011) observed a distinct cellular compartment at the
trans side of the Golgi apparatus, the TOR-autophagy spatial coupling
compartment (TASCC), where (auto)lysosomes and mTOR accumulated during
Ras-induced senescence. mTOR recruitment to the TASCC was amino acid-
and Rag guanosine triphosphatase (e.g., 612194)-dependent, and
disruption of mTOR localization to the TASCC suppressed interleukin-6/8
(147620/146930) synthesis. TASCC formation was observed during
macrophage differentiation and in glomerular podocytes; both displayed
increased protein secretion. Narita et al. (2011) concluded that the
spatial coupling of cells' catabolic and anabolic machinery could
augment their respective functions and facilitate the mass synthesis of
secretory proteins.

Using ribosome profiling, Hsieh et al. (2012) uncovered specialized
translation of the prostate cancer genome by oncogenic mTOR signaling,
revealing a remarkably specific repertoire of genes involved in cell
proliferation, metabolism, and invasion. Hsieh et al. (2012) extended
these findings by functionally characterizing a class of translationally
controlled proinvasion mRNAs that direct prostate cancer invasion and
metastatis downstream of oncogenic mTOR signaling. Hsieh et al. (2012)
developed a clinically relevant ATP site inhibitor of mTOR, called
INK128, which reprograms this gene expression signature with therapeutic
benefit for prostate cancer metastasis.

- MTOR Complexes 1 and 2

Jacinto et al. (2004) identified 2 distinct mammalian TOR complexes:
TORC1, which contains TOR, LST8 (612190), and RAPTOR (607130), and
TORC2, which contains TOR, LST8, and RICTOR (609022), which they called
AVO3. Like yeast TORC2, mammalian TORC2 was rapamycin-insensitive and
functioned upstream of Rho GTPases to regulate the actin cytoskeleton.
TORC2 did not regulate S6K (see 608938) activity. Knockdown of TORC2,
but not TORC1, prevented paxillin (602505) phosphorylation, actin
polymerization, and cell spreading.

Sarbassov et al. (2004) identified a RICTOR (609022)-containing MTOR
complex that contains GBL (LST8) but not RAPTOR. The RICTOR-MTOR complex
did not regulate the MTOR effector S6K1 and was not bound by FKBP12
(186945)-rapamycin. Rapamycin treatment of human embryonic kidney cells
eliminated the binding of MTOR to RAPTOR, but did not affect the
interaction of MTOR with RICTOR. Knockdown of RICTOR caused accumulation
of thick actin fibers throughout much of the cytoplasm in HeLa cells,
loss of actin at the cell cortex, altered distribution of cytoskeletal
proteins, and reduced protein kinase C (PKC)-alpha (see 176960)
activity. Sarbassov et al. (2004) concluded that the RICTOR-MTOR complex
modulates the phosphorylation of PKC-alpha and the actin cytoskeleton,
similar to TOR signaling in yeast.

The multiprotein mTORC1 protein kinase complex is the central component
of a pathway that promotes growth in response to insulin, energy levels,
and amino acids and is deregulated in common cancers. Sancak et al.
(2008) found that the Rag proteins, a family of 4 related small
guanosine triphosphatases (GTPases) (RAGA, 612194; RAGB, 300725; RAGC,
608267; and RAGD, 608268), interact with mTORC1 in an amino
acid-sensitive manner and are necessary for the activation of the mTORC1
pathway by amino acids. A Rag mutant that was constitutively bound to
guanosine triphosphate interacted strongly with mTORC1, and its
expression within cells made the mTORC1 pathway resistant to amino acid
deprivation. Conversely, expression of a guanosine diphosphate-bound Rag
mutant prevented stimulation of mTORC1 by amino acids. Sancak et al.
(2008) concluded that the Rag proteins do not directly stimulate the
kinase activity of mTORC1, but, like amino acids, promote the
intracellular localization of mTOR to a compartment that also contains
its activator RHEB (601293).

Dowling et al. (2010) inhibited the mTORC1 pathway in cells lacking the
eukaryotic translation initiation factor 4E binding proteins EIF4EBP1
(602223), EIF4EBP2 (602224), and EIF4EBP3 (603483) and analyzed the
effects on cell size, cell proliferation, and cell cycle progression.
Although the EIF4EBPs had no effect on cell size, they inhibited cell
proliferation by selectively inhibiting the translation of mRNAs that
encode proliferation-promoting proteins and proteins involved in cell
cycle progression. Thus, Dowling et al. (2010) concluded that control of
cell size and cell cycle progression appear to be independent in
mammalian cells, whereas in lower eukaryotes, EIF4E binding proteins
influence both cell growth and proliferation.

Rosner et al. (2009) reported that the mTORC1-mediated consequences on
cell cycle and cell size were separable and did not involve effects on
mTORC2 activity. However, mTORC2 itself was a potent regulator of
mammalian cell size and cell cycle via a mechanism involving the Akt
(see 164730)/TSC2 (191092)/Rheb (601293) cascade.

Heublein et al. (2010) stated that path, a Drosophila amino acid
transporter, functions in nutrient-dependent growth via MTORC1. They
showed that the human orthologs of path, PAT1 (SLC36A1; 606561) and PAT4
(SLC36A4; 613760), had similar growth regulatory functions when
expressed in flies. Knockdown of PAT1 or PAT4 in human MCF-7 breast
cancer cells or HEK293 cells via small interfering RNA inhibited cell
proliferation without affecting cell survival, similar to the effect of
MTOR knockdown. Knockdown of PAT1, PAT4, or MTOR reduced phosphorylation
of the MTORC1 targets S6K1, S6, and 4EBP1, but had a much smaller effect
on signaling through PI3K and AKT and had no effect on MTORC2. Knockdown
of PAT1, PAT4, or MTOR in serum- and nutrient-starved cells reduced
amino acid-dependent MTORC1 signaling following refeeding. Conversely,
overexpression of PAT1 in starved cells enhanced the sensitivity of the
MTORC1 response to amino acids during refeeding. Heublein et al. (2010)
hypothesized that PAT1 and PAT4 participate in amino acid sensing and
contribute to the MTORC1 response to amino acids.

Sengupta et al. (2010) showed that mTORC1 controls ketogenesis in mice
in response to fasting. The authors found that liver-specific loss of
TSC1 (605284), an mTORC1 inhibitor, led to a fasting-resistant increase
in liver size, and to a pronounced defect in ketone body production and
ketogenic gene expression on fasting. The loss of raptor (607130), an
essential mTORC1 component, had the opposite effect. In addition,
Sengupta et al. (2010) found that the inhibition of mTORC1 is required
for the fasting-induced activation of PPAR-alpha (170998) and that
suppression of NCoR1 (600849), a corepressor of PPAR-alpha, reactivates
ketogenesis in cells and livers with hyperactive mTORC1 signaling. Like
livers with activated mTORC1, livers from aged mice have a defect in
ketogenesis, which correlates with an increase in mTORC1 signaling.
Moreover, Sengupta et al. (2010) showed that suppressive effects of
mTORC1 activation and aging on PPAR-alpha activity and ketone production
are not additive, and that mTORC1 inhibition is sufficient to prevent
the aging-induced defect in ketogenesis. Thus, Sengupta et al. (2010)
concluded that their findings revealed that mTORC1 is a key regulator of
PPAR-alpha function and hepatic ketogenesis and suggested a role for
mTORC1 activity in promoting the aging of the liver.

Hsu et al. (2011) defined the mTOR-regulated phosphoproteome by
quantitative mass spectrometry and characterized the primary sequence
motif specificity of mTOR using positional scanning peptide libraries.
Hsu et al. (2011) found that the phosphorylation response to insulin is
largely mTOR-dependent and that mTOR exhibits a unique preference for
proline, hydrophobic, and aromatic residues at the +1 position. The
adaptor protein growth factor receptor-bound protein-10 (GRB10; 601523)
was identified as an mTORC1 substrate that mediates the inhibition of
phosphoinositide 3-kinase (PI3K; see 171834) typical of cells lacking
tuberous sclerosis complex-2 (TSC2; 191092), a tumor suppressor and
negative regulator of mTORC1.

Yu et al. (2011) used large-scale quantitative phosphoproteomics
experiments to define the signaling networks downstream of mTORC1 and
mTORC2. Characterization of an mTORC1 substrate, Grb10, showed that
mTORC1-mediated phosphorylation stabilized Grb10, leading to feedback
inhibition of the PI3K and extracellular
signal-regulated/mitogen-activated protein kinase (ERK/MAPK; see 176872)
pathways. Grb10 expression is frequently downregulated in various
cancers, and loss of Grb10 and loss of the well-established tumor
suppressor phosphatase PTEN (601728) appear to be mutually exclusive
events, suggesting that Grb10 might be a tumor suppressor regulated by
mTORC1.

Amino acids activate the Rag GTPases, which promote the translocation of
mTORC1 to the lysosomal surface, the site of mTORC1 activation. Zoncu et
al. (2011) found that the vacuolar hydrogen proton-adenosine
triphosphatase ATPase (v-ATPase; see 607027) is necessary for amino
acids to activate mTORC1. The v-ATPase engages in extensive amino
acid-sensitive interactions with the Ragulator, a scaffolding complex
that anchors the Rag GTPases to the lysosome. In a cell-free system, ATP
hydrolysis by the v-ATPase was necessary for amino acids to regulate the
v-ATPase-Ragulator interaction and promote mTORC1 translocation. The
results obtained in vitro and in human cells suggested that amino acid
signaling begins within the lysosomal lumen. Zoncu et al. (2011)
concluded that their results identified the v-ATPase as a component of
the mTOR pathway and delineated a lysosome-associated machinery for
amino acid sensing.

Yilmaz et al. (2012) found that Paneth cells, a key constituent of the
mammalian intestinal stem cell (ISC) niche, augment stem cell function
in response to calorie restriction. Calorie restriction acts by reducing
mTORC1 signaling in Paneth cells, and the ISC-enhancing effects of
calorie restriction can be mimicked by rapamycin. Calorie intake
regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of
mTORC1 in Paneth cells during calorie restriction abolishes the
ISC-augmenting effects of the niche. Finally, increased expression of
bone stromal antigen-1 (BST1; 600387), an ectoenzyme that produces the
paracrine factor cyclic ADP ribose, in Paneth cells mediates the effects
of calorie restriction and rapamycin on ISC function. Yilmaz et al.
(2012) concluded that their findings established that mTORC1
non-cell-autonomously regulates stem cell self-renewal, and highlighted
a significant role of the mammalian intestinal niche in coupling stem
cell function to organismal physiology.

Thoreen et al. (2012) used high-resolution transcriptome-scale ribosome
profiling to monitor translation in mouse cells acutely treated with the
mTOR inhibitor Torin-1, which, unlike rapamycin, fully inhibits mTORC1.
Their data revealed a surprisingly simple model of the mRNA features and
mechanisms that confer mTORC1-dependent translation control. The subset
of mRNAs that are specifically regulated by mTORC1 consists almost
entirely of transcripts with established 5-prime terminal
oligopyrimidine (TOP) motifs, or, like Hsp90ab1 (140572) and Ybx1
(154030), with previously unrecognized TOP or related TOP-like motifs
that were identified. Thoreen et al. (2012) found no evidence to support
proposals that mTORC1 preferentially regulates mRNAs with increased
5-prime untranslated region length or complexity. mTORC1 phosphorylates
a myriad of translational regulators, but how it controls TOP mRNA
translation was unknown. Remarkably, loss of just the E4-BP family of
translational repressors, arguably the best characterized mTORC1
substrates, is sufficient to render TOP and TOP-like mRNA translation
resistant to Torin-1. The 4E-BPs inhibit translation initiation by
interfering with the interaction between the cap-binding protein eIF4E
(133440) and eIF4G1 (600495). Loss of this interaction diminishes the
capacity of eIF4E to bind TOP and TOP-like mRNAs much more than other
mRNAs, explaining why mTOR inhibition selectively suppresses their
translation.

Efeyan et al. (2013) generated knock-in mice that express a
constitutively active form of RagA (612194), RagA(GTP), from its
endogenous promoter. RagA(GTP/GTP) homozygous mice developed normally
but failed to survive postnatal day 1. When delivered by cesarean
section, fasted RagA(GTP/GTP) neonates die almost twice as rapidly as
wildtype littermates. Within an hour of birth wildtype neonates strongly
inhibit mTORC1, which coincides with profound hypoglycemia and a
decrease in plasma amino acid concentrations. In contrast, mTORC1
inhibition does not occur in RagA(GTP/GTP) neonates, despite identical
reductions in blood nutrient amounts. With prolonged fasting, wildtype
neonates recover their plasma glucose concentrations, but RagA(GTP/GTP)
mice remain hypoglycemic until death, despite using glycogen at a faster
rate. The glucose homeostasis defect correlates with the inability of
fasted RagA(GTP/GTP) neonates to trigger autophagy and produce amino
acids for de novo glucose production. Because profound hypoglycemia does
not inhibit mTORC1 in RagA(GTP/GTP) neonates, Efeyan et al. (2013)
considered the possibility that the Rag pathway signals glucose as well
as amino acid sufficiency to mTORC1. Indeed, mTORC1 is resistant to
glucose deprivation in RagA(GTP/GTP) fibroblasts, and glucose, like
amino acids, controls its recruitment to the lysosomal surface, the site
of mTORC1 activation. Thus, the Rag GTPases signal glucose and amino
acid concentrations to mTORC1, and have an unexpectedly key role in
neonates in autophagy induction and thus nutrient homeostasis and
viability.

Robitaille et al. (2013) used quantitative phosphoproteomics to identify
substrates or downstream effectors of the 2 mTOR complexes. mTOR
controlled the phosphorylation of 335 proteins, including CAD (carbamoyl
phosphate synthetase-2/aspartate transcarbamoylase/ dihydroorotase;
114010). The trifunctional CAD protein catalyzes the first 3 steps in de
novo pyrimidine synthesis. mTORC1 indirectly phosphorylated CAD-S1859
through S6 kinase (S6K; see RPSKB1, 608938). CAD-S1859 phosphorylation
promoted CAD oligomerization and thereby stimulated de novo synthesis of
pyrimidines and progression through S phase of the cell cycle in
mammalian cells. Ben-Sahra et al. (2013) independently showed that
activation of mTORC1 led to the acute stimulation of metabolic flux
through the de novo pyrimidine synthesis pathway. mTORC1 signaling
posttranslationally regulated this metabolic pathway via its downstream
target S6K1, which directly phosphorylates S1859 on CAD. Growth
signaling through mTORC1 thus stimulates the production of new
nucleotides to accommodate an increase in RNA and DNA synthesis needed
for ribosome biogenesis and anabolic growth.

Zeng et al. (2013) demonstrated that mTORC1 signaling is a pivotal
positive determinant of regulatory T cell (Treg) function in mice. Tregs
have elevated steady-state mTORC1 activity compared to naive T cells.
Signals through the T cell antigen receptor (TCR; see 186880) and
interleukin-2 (IL2; 147680) provide major inputs for mTORC1 activation,
which in turn programs the suppressive function of Tregs. Disruption of
mTORC1 through Treg-specific deletion of the essential component raptor
(607130) leads to a profound loss of Treg-suppressive activity in vivo
and the development of a fatal early-onset inflammatory disorder.
Mechanistically, raptor/mTORC1 signaling in Tregs promotes cholesterol
and lipid metabolism, with the mevalonate pathway particularly important
for coordinating Treg proliferation and upregulation of the suppressive
molecules CTLA4 (123890) and ICOS (604558) to establish Treg functional
competency. By contrast, mTORC1 does not directly affect the expression
of Foxp3 (300292) or anti- and proinflammatory cytokines in Treg cells,
suggesting a nonconventional mechanism for Treg functional regulation.
Finally, Zeng et al. (2013) provided evidence that mTORC1 maintains Treg
function partly through inhibiting the mTORC2 pathway. Zeng et al.
(2013) concluded that their results showed that mTORC1 acts as a
fundamental rheostat in Tregs to link immunologic signals from TCR and
IL2 to lipogenic pathways and functional fitness, and highlighted a
central role of metabolic programming of Treg suppressive activity in
immune homeostasis and tolerance.

Loss of MTM1 (300415), a phosphatase that can dephosphorylate
PtdIns(3)P, causes X-linked myotubular myopathy (310400) in humans and
in the Mtm1 -/- mouse model. Fetalvero et al. (2013) found that mTORC1
activity was inhibited in Mtm1 -/- mouse skeletal muscle, concomitant
with increased content of PtdIns(3)P, ubiquitinated proteins, and
lipidated proteins normally degraded via autophagy. Mtm1 -/- muscle also
showed accumulation of defective mitochondria with decreased COX enzyme
activity. No change in mTORC1, mitochondria, or content of nondegraded
proteins was observed in liver, heart, or brain of Mtm1 -/- mice.
Overnight fasting activated mTORC1-dependent inhibition of autophagy in
wildtype, but not Mtm1 -/-, skeletal muscle. Inhibition of
hyperactivated mTORC1 normalized autophagy and rescued muscle mass in
Mtm1 -/- mice. Fetalvero et al. (2013) concluded that MTM1 is involved
in the regulation of mTORC1 and autophagy specifically in skeletal
muscle.

Thedieck et al. (2013) showed that astrin (SPAG5; 615562) functioned as
a negative regulator of MTORC1 following exposure of HeLa cells to cell
stresses, such as arsenite, hydrogen peroxide, or excessive heat. Astrin
localized to centrosomes in unstressed cells, but localized to stress
granules following induction of stress granules by cell stress. Astrin
competed with MTOR in binding RAPTOR and sequestered RAPTOR to stress
granules, inhibiting the MTORC1 apoptotic response to stress. Knockdown
of astrin via small interfering RNA resulted in MTORC1 assembly and
activation in both stressed and unstressed cells. Thedieck et al. (2013)
concluded that astrin-mediated inhibition of apoptosis may be beneficial
in preventing healthy cells from undergoing apoptosis upon transient
stresses or metabolic challenge.

BIOCHEMICAL FEATURES

- Crystal Structure

Yang et al. (2013) reported cocrystal structures of a complex of
truncated mTOR and mammalian lethal with SEC13 protein-8 (mLST8; 612190)
with an ATP transition state mimic and with ATP-site inhibitors. The
structures revealed an intrinsically active kinase conformation, with
catalytic residues and a catalytic mechanism remarkably similar to
canonical protein kinases. The active site is highly recessed owing to
the FKBP12 (186945)-rapamycin-binding (FRB) domain and an inhibitory
helix protruding from the catalytic cleft. mTOR-activating mutations map
to the structural framework that holds these elements in place,
indicating that the kinase is controlled by restricted access. In vitro
biochemistry showed that the FRB domain acts as a gatekeeper, with its
rapamycin-binding site interacting with substrates to grant them access
to the restricted active site. Rapamycin-FKBP12 inhibits the kinase by
directly blocking substrate recruitment and by further restricting
active-site access. Yang et al. (2013) concluded that the structures
also revealed active-site residues and conformational changes that
underlie inhibitor potency and specificity.

PATHOGENESIS

- Pancreatic Neuroendocrine Tumors

Jiao et al. (2011) explored the genetic basis of pancreatic
neuroendocrine tumors (PanNETs) by determining the exomic sequence of 10
nonfamilial PanNETs and then screened the most commonly mutated genes in
58 additional PanNETs. Jiao et al. (2011) found mutations in genes in
the mTOR pathway in 14% of the tumors, a finding that could potentially
be used to stratify patients for treatments with mTOR inhibitors. The
most frequently mutated genes specify proteins implicated in chromatin
remodeling: 44% of the tumors had somatic inactivating mutations in MEN1
(613733), and 43% had mutations in genes encoding either of the 2
subunits of a transcription/chromatin remodeling complex consisting of
DAXX (603186) and ATRX (300032). Clinically, mutations in the MEN1 and
DAXX/ATRX genes were associated with better prognosis.

MAPPING

Moore et al. (1996) assigned the FRAP gene to chromosome 1p36 by
fluorescence in situ hybridization (FISH). Lench et al. (1997) mapped
the FRAP gene to 1p36.2 by FISH following radiation-hybrid mapping to
that general region. Chromosome 1p36.2 is the region most consistently
deleted in neuroblastomas. Given the role of PIK-related kinase proteins
in DNA repair, recombination, and cell cycle checkpoints, the authors
suggested that the possible role of FRAP in solid tumors with deletions
at 1p36 should be investigated. Onyango et al. (1998) established the
order of genes in the 1p36 region, telomere to centromere, as CDC2L1
(176873)--PTPRZ2 (604008)--ENO1 (172430)--PGD (172200)--XBX1--FRAP2
(FRAP1)--CD30 (153243).

ANIMAL MODEL

Murakami et al. (2004) generated mTor-knockout mice by disrupting the
kinase domain of mouse mTor and found that mTor +/- mice were normal and
fertile, but that mTor -/- mice exhibited embryonic lethality shortly
after implantation. Although homozygous blastocysts appeared normal,
their inner cell mass and trophoblast did not proliferate in vitro.
Mutation analysis showed that the 6 C-terminal amino acids of mTOR are
essential for kinase activity and are necessary for normal cell size and
proliferation in embryonic stem cells. Murakami et al. (2004) concluded
that mTOR controls both cell size and proliferation in early mouse
embryos and embryonic stem cells. Independently, Gangloff et al. (2004)
observed defects in mTor -/- mice but not in mTor +/- mice confirming
the findings of Murakami et al. (2004).

By generating mice with a deletion of mTor specifically in T
lymphocytes, Delgoffe et al. (2009) demonstrated that mTor activation is
not necessary for normal activation and IL2 (147680) secretion but is
necessary for Th1 (see IFNG, 147570), Th2 (see IL4, 147780), and Th17
(see IL17, 603149) differentiation. Under fully activating conditions,
mTor-null T cells differentiated into Foxp3 (300292)-positive regulatory
T cells. This differentiation was associated with hyperactive Smad3
(603109) activation in the absence of exogenous Tgfb (190180). T cells
lacking the Torc1 protein complex did not divert to a regulatory
pathway, thus implicating both Torc1 and Torc2 in preventing the
generation of regulatory T cells. Delgoffe et al. (2009) suggested that
MTOR kinase signaling regulates the commitment to effector or regulatory
T cell lineages.

Harrison et al. (2009) found that rapamycin feeding increased both
median and maximum life span in genetically heterogeneous mice, even
when started late in life. The effect was observed in both male and
female mice and occurred in the absence of diet restriction or reduction
in body weight. Rapamycin did not change the distribution of presumptive
causes of death.

N-acylethanolamines (NAEs) are lipid-derived signaling molecules, which
include the mammalian endocannabinoid arachidonoyl ethanolamide. Given
its involvement in regulating nutrient intake and energy balance, the
endocannabinoid system is an excellent candidate for a metabolic signal
that coordinates the organismal response to dietary restriction and
maintains homeostasis when nutrients are limited. Lucanic et al. (2011)
identified NAEs in C. elegans and showed that NAE abundance is reduced
under dietary restriction and that NAE deficiency is sufficient to
extend life span through a dietary restriction mechanism requiring PHA4,
a homolog of FOXA1 (602294). Conversely, dietary supplementation with
the nematode NAE eicosapentaenoyl ethanolamide not only inhibited
dietary restriction-induced life span extension in wildtype worms, but
also suppressed life span extension in a TOR pathway mutant. Lucanic et
al. (2011) concluded that their study demonstrated a role for NAE
signaling in aging and indicated that NAEs represent a signal that
coordinates nutrient status with metabolic changes that ultimately
determine life span.

Calorie restriction, which increases life span and insulin sensitivity,
is proposed to function by inhibition of mTORC1, yet paradoxically,
chronic administration of rapamycin substantially impairs glucose
tolerance and insulin action. Lamming et al. (2012) demonstrated that
rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that
mTORC2 was required for the insulin-mediated suppression of hepatic
gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to
extend life span independently from changes in glucose homeostasis, as
female mice heterozygous for both mTOR and mLST8 (612190) exhibited
decreased mTORC1 activity and extended life span but had normal glucose
tolerance and insulin sensitivity. Thus, Lamming et al. (2012) concluded
that mTORC2 disruption is an important mediator of the effects of
rapamycin in vivo.

Cina et al. (2012) targeted Mtor disruption to mouse podocytes. Mutant
mice developed proteinuria at 3 weeks and end stage renal failure by 5
weeks after birth. Podocytes from mutant mice exhibited accumulation of
autophagosomes, autophagolysosomal vesicles, and damaged mitochondria.
Similarly, human podocytes treated with rapamycin accumulated
autophagosomes and autophagolysosomes.

HISTORY

Crino (2008) noted that rapamycin was discovered in the 1970s as a
macrolide antibiotic and antifungal in a soil sample from Rapa Nui, also
known as Easter Island.

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*FIELD* CN
Patricia A. Hartz - updated: 12/13/2013
Patricia A. Hartz - updated: 11/1/2013
Ada Hamosh - updated: 9/30/2013
Ada Hamosh - updated: 7/8/2013
Ada Hamosh - updated: 5/22/2013
Ada Hamosh - updated: 3/21/2013
Patricia A. Hartz - updated: 11/8/2012
Ada Hamosh - updated: 9/20/2012
Ada Hamosh - updated: 7/17/2012
Ada Hamosh - updated: 4/24/2012
Ada Hamosh - updated: 11/29/2011
Ada Hamosh - updated: 7/26/2011
Ada Hamosh - updated: 6/6/2011
Ada Hamosh - updated: 5/24/2011
Ada Hamosh - updated: 3/31/2011
Patricia A. Hartz - updated: 2/21/2011
Paul J. Converse - updated: 1/24/2011
Paul J. Converse - updated: 12/3/2010
Ada Hamosh - updated: 9/29/2010
George E. Tiller - updated: 7/7/2010
Ada Hamosh - updated: 7/1/2010
Ada Hamosh - updated: 6/14/2010
Paul J. Converse - updated: 5/26/2010
Ada Hamosh - updated: 4/22/2010
Ada Hamosh - updated: 8/25/2009
Patricia A. Hartz - updated: 8/13/2009
George E. Tiller - updated: 8/10/2009
Ada Hamosh - updated: 7/9/2009
Patricia A. Hartz - updated: 5/5/2009
Cassandra L. Kniffin - updated: 4/15/2009
Ada Hamosh - updated: 12/30/2008
Ada Hamosh - updated: 9/29/2008
Ada Hamosh - updated: 7/23/2008
Matthew B. Gross - updated: 7/22/2008
Ada Hamosh - updated: 1/22/2008
Ada Hamosh - updated: 11/26/2007
Patricia A. Hartz - updated: 5/3/2007
Ada Hamosh - updated: 10/24/2006
Ada Hamosh - updated: 9/8/2006
Ada Hamosh - updated: 6/6/2006
Ada Hamosh - updated: 2/10/2006
Patricia A. Hartz - updated: 2/2/2006
Stylianos E. Antonarakis - updated: 4/6/2005
Patricia A. Hartz - updated: 2/1/2005
Patricia A. Hartz - updated: 11/10/2004
Patricia A. Hartz - updated: 9/23/2004
Patricia A. Hartz - updated: 9/9/2004
Victor A. McKusick - updated: 5/18/2004
Ada Hamosh - updated: 12/16/2003
Stylianos E. Antonarakis - updated: 7/31/2002
Ada Hamosh - updated: 1/7/2002
Paul J. Converse - updated: 12/11/2001
Ada Hamosh - updated: 11/14/2001
Jennifer P. Macke - updated: 7/13/1999
Victor A. McKusick - updated: 5/19/1997

*FIELD* CD
Mark H. Paalman: 4/29/1996

*FIELD* ED
mgross: 12/13/2013
mgross: 11/7/2013
mcolton: 11/1/2013
mgross: 10/4/2013
alopez: 10/1/2013
alopez: 9/30/2013
alopez: 7/8/2013
alopez: 5/22/2013
alopez: 3/26/2013
terry: 3/21/2013
mgross: 11/8/2012
terry: 11/8/2012
alopez: 9/24/2012
terry: 9/20/2012
alopez: 7/19/2012
terry: 7/17/2012
alopez: 4/24/2012
terry: 4/24/2012
alopez: 11/30/2011
terry: 11/29/2011
carol: 11/22/2011
alopez: 8/8/2011
terry: 7/26/2011
alopez: 6/14/2011
terry: 6/6/2011
alopez: 5/24/2011
alopez: 3/31/2011
mgross: 2/22/2011
terry: 2/21/2011
mgross: 1/26/2011
terry: 1/24/2011
wwang: 12/27/2010
terry: 12/3/2010
alopez: 10/5/2010
terry: 9/29/2010
wwang: 7/20/2010
terry: 7/7/2010
alopez: 7/2/2010
terry: 7/1/2010
alopez: 6/18/2010
terry: 6/14/2010
wwang: 5/26/2010
alopez: 4/26/2010
terry: 4/22/2010
carol: 2/18/2010
wwang: 9/15/2009
wwang: 9/1/2009
alopez: 8/27/2009
terry: 8/25/2009
mgross: 8/13/2009
terry: 8/13/2009
wwang: 8/13/2009
terry: 8/10/2009
alopez: 7/15/2009
terry: 7/9/2009
mgross: 5/5/2009
terry: 5/5/2009
wwang: 4/15/2009
alopez: 1/5/2009
terry: 12/30/2008
alopez: 9/30/2008
terry: 9/29/2008
mgross: 9/22/2008
alopez: 7/23/2008
wwang: 7/22/2008
mgross: 7/22/2008
alopez: 1/23/2008
terry: 1/22/2008
alopez: 11/29/2007
terry: 11/26/2007
wwang: 5/3/2007
alopez: 10/25/2006
terry: 10/24/2006
alopez: 9/19/2006
terry: 9/8/2006
alopez: 6/9/2006
terry: 6/6/2006
alopez: 2/21/2006
terry: 2/10/2006
mgross: 2/9/2006
terry: 2/2/2006
mgross: 11/3/2005
mgross: 4/6/2005
mgross: 2/1/2005
alopez: 12/1/2004
mgross: 11/10/2004
mgross: 9/23/2004
mgross: 9/9/2004
alopez: 5/28/2004
alopez: 5/19/2004
terry: 5/18/2004
carol: 3/5/2004
alopez: 12/17/2003
terry: 12/16/2003
mgross: 7/31/2002
alopez: 1/7/2002
mgross: 1/3/2002
terry: 12/11/2001
terry: 12/7/2001
alopez: 11/15/2001
terry: 11/14/2001
alopez: 7/20/1999
alopez: 7/13/1999
carol: 8/17/1998
jamie: 6/3/1997
mark: 5/20/1997
terry: 5/19/1997
mark: 4/29/1996
terry: 4/29/1996
mark: 4/29/1996