Full text data of RPTOR
RPTOR
(KIAA1303, RAPTOR)
[Confidence: low (only semi-automatic identification from reviews)]
Regulatory-associated protein of mTOR; Raptor (p150 target of rapamycin (TOR)-scaffold protein)
Regulatory-associated protein of mTOR; Raptor (p150 target of rapamycin (TOR)-scaffold protein)
UniProt
Q8N122
ID RPTOR_HUMAN Reviewed; 1335 AA.
AC Q8N122; B2RN36; Q8N4V9; Q8TB32; Q9P2P3;
DT 26-APR-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2002, sequence version 1.
DT 22-JAN-2014, entry version 116.
DE RecName: Full=Regulatory-associated protein of mTOR;
DE Short=Raptor;
DE AltName: Full=p150 target of rapamycin (TOR)-scaffold protein;
GN Name=RPTOR; Synonyms=KIAA1303, RAPTOR;
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], FUNCTION, TISSUE SPECIFICITY, AND
RP INTERACTION WITH 4EBP1 AND RPS6KB1.
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 [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND INTERACTION WITH 4EBP1 AND
RP RPS6KB1.
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 995-1135 (ISOFORM 1).
RC TISSUE=Brain, Placenta, and Testis;
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 [LARGE SCALE MRNA] OF 217-1335.
RC TISSUE=Brain;
RX PubMed=10718198; DOI=10.1093/dnares/7.1.65;
RA Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XVI.
RT The complete sequences of 150 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 7:65-73(2000).
RN [7]
RP INTERACTION WITH MTOR AND MLST8, IDENTIFICATION IN THE TORC1 COMPLEX,
RP 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 [8]
RP INTERACTION WITH EIF4EBP1.
RX PubMed=12747827; DOI=10.1016/S0960-9822(03)00329-4;
RA Schalm S.S., Fingar D.C., Sabatini D.M., Blenis J.;
RT "TOS motif-mediated raptor binding regulates 4E-BP1 multisite
RT phosphorylation and function.";
RL Curr. Biol. 13:797-806(2003).
RN [9]
RP DISSOCIATION OF COMPLEX BY RAPAMYCIN.
RX PubMed=15066126; DOI=10.1111/j.1356-9597.2004.00727.x;
RA Oshiro N., Yoshino K., Hidayat S., Tokunaga C., Hara K., Eguchi S.,
RA Avruch J., Yonezawa K.;
RT "Dissociation of raptor from mTOR is a mechanism of rapamycin-induced
RT inhibition of mTOR function.";
RL Genes Cells 9:359-366(2004).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-863, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [12]
RP INTERACTION WITH AKT1S1.
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 [13]
RP PHOSPHORYLATION AT SER-719; SER-721 AND SER-722.
RX PubMed=18722121; DOI=10.1016/j.cub.2008.07.078;
RA Carriere A., Cargnello M., Julien L.A., Gao H., Bonneil E.,
RA Thibault P., Roux P.P.;
RT "Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-
RT mediated raptor phosphorylation.";
RL Curr. Biol. 18:1269-1277(2008).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [15]
RP PHOSPHORYLATION AT SER-722 AND SER-792, MUTAGENESIS OF SER-722 AND
RP SER-792, AND INTERACTION WITH 14-3-3.
RX PubMed=18439900; DOI=10.1016/j.molcel.2008.03.003;
RA Gwinn D.M., Shackelford D.B., Egan D.F., Mihaylova M.M., Mery A.,
RA Vasquez D.S., Turk B.E., Shaw R.J.;
RT "AMPK phosphorylation of raptor mediates a metabolic checkpoint.";
RL Mol. Cell 30:214-226(2008).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-877, 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 [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-719; SER-859; SER-863
RP AND SER-877, AND 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 [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [19]
RP INTERACTION WITH ULK1.
RX PubMed=19211835; DOI=10.1091/mbc.E08-12-1248;
RA Hosokawa N., Hara T., Kaizuka T., Kishi C., Takamura A., Miura Y.,
RA Iemura S., Natsume T., Takehana K., Yamada N., Guan J.L., Oshiro N.,
RA Mizushima N.;
RT "Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200
RT complex required for autophagy.";
RL Mol. Biol. Cell 20:1981-1991(2009).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-877, 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 [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-859; SER-863 AND
RP SER-877, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [22]
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 [23]
RP PHOSPHORYLATION AT SER-696; THR-706; SER-855; SER-859; SER-863 AND
RP SER-877.
RX PubMed=19864431; DOI=10.1074/jbc.M109.029637;
RA Foster K.G., Acosta-Jaquez H.A., Romeo Y., Ekim B., Soliman G.A.,
RA Carriere A., Roux P.P., Ballif B.A., Fingar D.C.;
RT "Regulation of mTOR complex 1 (mTORC1) by raptor Ser863 and multisite
RT phosphorylation.";
RL J. Biol. Chem. 285:80-94(2010).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-859; SER-863 AND
RP SER-877, AND 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 [25]
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 [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-863 AND SER-877, AND
RP MASS SPECTROMETRY.
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 [27]
RP PHOSPHORYLATION AT SER-696; THR-706 AND SER-863.
RX PubMed=22493283; DOI=10.1074/jbc.M111.326538;
RA Kwak D., Choi S., Jeong H., Jang J.H., Lee Y., Jeon H., Lee M.N.,
RA Noh J., Cho K., Yoo J.S., Hwang D., Suh P.G., Ryu S.H.;
RT "Osmotic stress regulates mammalian target of rapamycin (mTOR) complex
RT 1 via c-Jun N-terminal Kinase (JNK)-mediated Raptor protein
RT phosphorylation.";
RL J. Biol. Chem. 287:18398-18407(2012).
RN [28]
RP FUNCTION IN CILIOGENESIS.
RX PubMed=23727834; DOI=10.1093/hmg/ddt253;
RA Cardenas-Rodriguez M., Irigoin F., Osborn D.P., Gascue C.,
RA Katsanis N., Beales P.L., Badano J.L.;
RT "The Bardet-Biedl syndrome-related protein CCDC28B modulates mTORC2
RT function and interacts with SIN1 to control cilia length independently
RT of the mTOR complex.";
RL Hum. Mol. Genet. 22:4031-4042(2013).
CC -!- FUNCTION: Involved in the control of the mammalian target of
CC rapamycin complex 1 (mTORC1) activity which regulates cell growth
CC and survival, and autophagy in response to nutrient and hormonal
CC signals; functions as a scaffold for recruiting mTORC1 substrates.
CC mTORC1 is activated in response to growth factors or amino acids.
CC Growth factor-stimulated mTORC1 activation involves a AKT1-
CC mediated phosphorylation of TSC1-TSC2, which leads to the
CC activation of the RHEB GTPase that potently activates the protein
CC kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires
CC its relocalization to the lysosomes mediated by the Ragulator
CC complex and the Rag GTPases. Activated mTORC1 up-regulates protein
CC synthesis by phosphorylating key regulators of mRNA translation
CC and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and
CC releases it from inhibiting the elongation initiation factor 4E
CC (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389',
CC which then promotes protein synthesis by phosphorylating PDCD4 and
CC targeting it for degradation. Involved in ciliogenesis.
CC -!- SUBUNIT: Part of the mammalian target of rapamycin complex 1
CC (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and
CC DEPTOR. mTORC1 binds to and is inhibited by FKBP12-rapamycin.
CC Binds directly to 4EBP1 and RPS6KB1 independently of its
CC association with MTOR. Binds preferentially to poorly or non-
CC phosphorylated forms of EIF4EBP1, and this binding is critical to
CC the ability of MTOR to catalyze phosphorylation. Forms a complex
CC with MTOR under both leucine-rich and -poor conditions. Interacts
CC with ULK1 in a nutrient-dependent manner; the interaction is
CC reduced during starvation. Interacts (when phosphorylated by AMPK)
CC with 14-3-3 protein, leading to inhibit its activity.
CC -!- INTERACTION:
CC Q13541:EIF4EBP1; NbExp=5; IntAct=EBI-1567928, EBI-74090;
CC Q9P2J5:LARS; NbExp=3; IntAct=EBI-1567928, EBI-356077;
CC Q9BVC4:MLST8; NbExp=3; IntAct=EBI-1567928, EBI-1387471;
CC P42345:MTOR; NbExp=18; IntAct=EBI-1567928, EBI-359260;
CC Q9JLN9:Mtor (xeno); NbExp=5; IntAct=EBI-1567928, EBI-1571628;
CC Q8TCU6:PREX1; NbExp=2; IntAct=EBI-1567928, EBI-1046542;
CC P67999:Rps6kb1 (xeno); NbExp=2; IntAct=EBI-1567928, EBI-2639458;
CC Q96EB6:SIRT1; NbExp=3; IntAct=EBI-1567928, EBI-1802965;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Lysosome. Note=Targeting to
CC lysosomes depends on amino acid availability.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8N122-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8N122-2; Sequence=VSP_010174;
CC -!- TISSUE SPECIFICITY: Highly expressed in skeletal muscle, and in a
CC lesser extent in brain, lung, small intestine, kidney and
CC placenta.
CC -!- PTM: Insulin-stimulated phosphorylation at Ser-863 by MTOR and
CC MAPK8 up-regulates mTORC1 activity. Osmotic stress also induces
CC phosphorylation at Ser-696, Thr-706 and Ser-863 by MAPK8. Ser-863
CC phosphorylation is required for phosphorylation at Ser-855 and
CC Ser-859. In response to nutrient limitation, phosphorylated by
CC AMPK; phosphorylation promotes interaction with 14-3-3 proteins,
CC leading to negative regulation of the mTORC1 complex. In response
CC to growth factors, phosphorylated at Ser-719, Ser-721 and Ser-722
CC by RPS6KA1, which stimulates mTORC1 activity.
CC -!- SIMILARITY: Belongs to the WD repeat RAPTOR family.
CC -!- SIMILARITY: Contains 7 WD repeats.
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DR EMBL; AY090663; AAM09075.1; -; mRNA.
DR EMBL; AB082951; BAC06490.1; -; mRNA.
DR EMBL; AC016245; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC109327; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC127496; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC133012; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471099; EAW89618.1; -; Genomic_DNA.
DR EMBL; BC025180; AAH25180.1; -; mRNA.
DR EMBL; BC033258; AAH33258.1; -; mRNA.
DR EMBL; BC064515; AAH64515.1; -; mRNA.
DR EMBL; BC136652; AAI36653.1; -; mRNA.
DR EMBL; BC136654; AAI36655.1; -; mRNA.
DR EMBL; AB037724; BAA92541.1; -; mRNA.
DR RefSeq; NP_065812.1; NM_020761.2.
DR UniGene; Hs.133044; -.
DR ProteinModelPortal; Q8N122; -.
DR DIP; DIP-39482N; -.
DR IntAct; Q8N122; 22.
DR MINT; MINT-3038940; -.
DR STRING; 9606.ENSP00000307272; -.
DR PhosphoSite; Q8N122; -.
DR DMDM; 46577501; -.
DR PaxDb; Q8N122; -.
DR PRIDE; Q8N122; -.
DR DNASU; 57521; -.
DR Ensembl; ENST00000306801; ENSP00000307272; ENSG00000141564.
DR Ensembl; ENST00000570891; ENSP00000460136; ENSG00000141564.
DR GeneID; 57521; -.
DR KEGG; hsa:57521; -.
DR UCSC; uc002jyt.1; human.
DR CTD; 57521; -.
DR GeneCards; GC17P078518; -.
DR HGNC; HGNC:30287; RPTOR.
DR HPA; CAB013514; -.
DR HPA; HPA029821; -.
DR MIM; 607130; gene.
DR neXtProt; NX_Q8N122; -.
DR PharmGKB; PA165432629; -.
DR eggNOG; NOG269318; -.
DR HOGENOM; HOG000184479; -.
DR HOVERGEN; HBG059496; -.
DR InParanoid; Q8N122; -.
DR KO; K07204; -.
DR OMA; TEVCTND; -.
DR PhylomeDB; Q8N122; -.
DR Reactome; REACT_111102; Signal Transduction.
DR SignaLink; Q8N122; -.
DR GeneWiki; RPTOR; -.
DR GenomeRNAi; 57521; -.
DR NextBio; 63899; -.
DR PRO; PR:Q8N122; -.
DR ArrayExpress; Q8N122; -.
DR Bgee; Q8N122; -.
DR Genevestigator; Q8N122; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0031931; C:TORC1 complex; IDA:UniProtKB.
DR GO; GO:0071889; F:14-3-3 protein binding; IDA:UniProtKB.
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:0007050; P:cell cycle arrest; TAS:Reactome.
DR GO; GO:0016049; P:cell growth; IMP:UniProtKB.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IMP:UniProtKB.
DR GO; GO:0031669; P:cellular response to nutrient levels; IMP:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0032008; P:positive regulation of TOR signaling cascade; IDA:UniProtKB.
DR GO; GO:0045945; P:positive regulation of transcription from RNA polymerase III promoter; IMP:UniProtKB.
DR GO; GO:0008361; P:regulation of cell size; IMP:UniProtKB.
DR GO; GO:0031929; P:TOR signaling cascade; IDA:UniProtKB.
DR Gene3D; 1.25.10.10; -; 2.
DR Gene3D; 2.130.10.10; -; 1.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR000357; HEAT.
DR InterPro; IPR004083; Raptor.
DR InterPro; IPR027466; Raptor_metazoan.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom.
DR InterPro; IPR001680; WD40_repeat.
DR InterPro; IPR017986; WD40_repeat_dom.
DR PANTHER; PTHR12848; PTHR12848; 1.
DR PANTHER; PTHR12848:SF6; PTHR12848:SF6; 1.
DR Pfam; PF02985; HEAT; 1.
DR Pfam; PF00400; WD40; 2.
DR PRINTS; PR01547; YEAST176DUF.
DR SMART; SM00320; WD40; 7.
DR SUPFAM; SSF48371; SSF48371; 2.
DR SUPFAM; SSF50978; SSF50978; 1.
DR PROSITE; PS00678; WD_REPEATS_1; FALSE_NEG.
DR PROSITE; PS50082; WD_REPEATS_2; FALSE_NEG.
DR PROSITE; PS50294; WD_REPEATS_REGION; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Cytoplasm; Lysosome;
KW Phosphoprotein; Reference proteome; Repeat; WD repeat.
FT CHAIN 1 1335 Regulatory-associated protein of mTOR.
FT /FTId=PRO_0000051200.
FT REPEAT 1020 1061 WD 1.
FT REPEAT 1065 1106 WD 2.
FT REPEAT 1121 1160 WD 3.
FT REPEAT 1164 1203 WD 4.
FT REPEAT 1209 1249 WD 5.
FT REPEAT 1251 1291 WD 6.
FT REPEAT 1299 1335 WD 7.
FT COMPBIAS 881 887 Poly-Ser.
FT MOD_RES 696 696 Phosphoserine; by MAPK8.
FT MOD_RES 706 706 Phosphothreonine; by MAPK8.
FT MOD_RES 719 719 Phosphoserine; by RPS6KA1.
FT MOD_RES 721 721 Phosphoserine; by RPS6KA1.
FT MOD_RES 722 722 Phosphoserine; by AMPK and RPS6KA1.
FT MOD_RES 792 792 Phosphoserine; by AMPK.
FT MOD_RES 855 855 Phosphoserine.
FT MOD_RES 859 859 Phosphoserine; by MTOR.
FT MOD_RES 863 863 Phosphoserine; by MAPK8 and MTOR.
FT MOD_RES 877 877 Phosphoserine.
FT VAR_SEQ 380 1335 Missing (in isoform 2).
FT /FTId=VSP_010174.
FT MUTAGEN 722 722 S->A: Abolishes AMPK-mediated
FT phosphorylation; when associated with A-
FT 792.
FT MUTAGEN 792 792 S->A: Abolishes AMPK-mediated
FT phosphorylation; when associated with A-
FT 722.
FT CONFLICT 217 218 LE -> RQ (in Ref. 6; BAA92541).
SQ SEQUENCE 1335 AA; 149038 MW; 688ED1943F45045A CRC64;
MESEMLQSPL LGLGEEDEAD LTDWNLPLAF MKKRHCEKIE GSKSLAQSWR MKDRMKTVSV
ALVLCLNVGV DPPDVVKTTP CARLECWIDP LSMGPQKALE TIGANLQKQY ENWQPRARYK
QSLDPTVDEV KKLCTSLRRN AKEERVLFHY NGHGVPRPTV NGEVWVFNKN YTQYIPLSIY
DLQTWMGSPS IFVYDCSNAG LIVKSFKQFA LQREQELEVA AINPNHPLAQ MPLPPSMKNC
IQLAACEATE LLPMIPDLPA DLFTSCLTTP IKIALRWFCM QKCVSLVPGV TLDLIEKIPG
RLNDRRTPLG ELNWIFTAIT DTIAWNVLPR DLFQKLFRQD LLVASLFRNF LLAERIMRSY
NCTPVSSPRL PPTYMHAMWQ AWDLAVDICL SQLPTIIEEG TAFRHSPFFA EQLTAFQVWL
TMGVENRNPP EQLPIVLQVL LSQVHRLRAL DLLGRFLDLG PWAVSLALSV GIFPYVLKLL
QSSARELRPL LVFIWAKILA VDSSCQADLV KDNGHKYFLS VLADPYMPAE HRTMTAFILA
VIVNSYHTGQ EACLQGNLIA ICLEQLNDPH PLLRQWVAIC LGRIWQNFDS ARWCGVRDSA
HEKLYSLLSD PIPEVRCAAV FALGTFVGNS AERTDHSTTI DHNVAMMLAQ LVSDGSPMVR
KELVVALSHL VVQYESNFCT VALQFIEEEK NYALPSPATT EGGSLTPVRD SPCTPRLRSV
SSYGNIRAVA TARSLNKSLQ NLSLTEESGG AVAFSPGNLS TSSSASSTLG SPENEEHILS
FETIDKMRRA SSYSSLNSLI GVSFNSVYTQ IWRVLLHLAA DPYPEVSDVA MKVLNSIAYK
ATVNARPQRV LDTSSLTQSA PASPTNKGVH IHQAGGSPPA SSTSSSSLTN DVAKQPVSRD
LPSGRPGTTG PAGAQYTPHS HQFPRTRKMF DKGPEQTADD ADDAAGHKSF ISATVQTGFC
DWSARYFAQP VMKIPEEHDL ESQIRKEREW RFLRNSRVRR QAQQVIQKGI TRLDDQIFLN
RNPGVPSVVK FHPFTPCIAV ADKDSICFWD WEKGEKLDYF HNGNPRYTRV TAMEYLNGQD
CSLLLTATDD GAIRVWKNFA DLEKNPEMVT AWQGLSDMLP TTRGAGMVVD WEQETGLLMS
SGDVRIVRIW DTDREMKVQD IPTGADSCVT SLSCDSHRSL IVAGLGDGSI RVYDRRMALS
ECRVMTYREH TAWVVKASLQ KRPDGHIVSV SVNGDVRIFD PRMPESVNVL QIVKGLTALD
IHPQADLIAC GSVNQFTAIY NSSGELINNI KYYDGFMGQR VGAISCLAFH PHWPHLAVGS
NDYYISVYSV EKRVR
//
ID RPTOR_HUMAN Reviewed; 1335 AA.
AC Q8N122; B2RN36; Q8N4V9; Q8TB32; Q9P2P3;
DT 26-APR-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2002, sequence version 1.
DT 22-JAN-2014, entry version 116.
DE RecName: Full=Regulatory-associated protein of mTOR;
DE Short=Raptor;
DE AltName: Full=p150 target of rapamycin (TOR)-scaffold protein;
GN Name=RPTOR; Synonyms=KIAA1303, RAPTOR;
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], FUNCTION, TISSUE SPECIFICITY, AND
RP INTERACTION WITH 4EBP1 AND RPS6KB1.
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 [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND INTERACTION WITH 4EBP1 AND
RP RPS6KB1.
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 995-1135 (ISOFORM 1).
RC TISSUE=Brain, Placenta, and Testis;
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 [LARGE SCALE MRNA] OF 217-1335.
RC TISSUE=Brain;
RX PubMed=10718198; DOI=10.1093/dnares/7.1.65;
RA Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XVI.
RT The complete sequences of 150 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 7:65-73(2000).
RN [7]
RP INTERACTION WITH MTOR AND MLST8, IDENTIFICATION IN THE TORC1 COMPLEX,
RP 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 [8]
RP INTERACTION WITH EIF4EBP1.
RX PubMed=12747827; DOI=10.1016/S0960-9822(03)00329-4;
RA Schalm S.S., Fingar D.C., Sabatini D.M., Blenis J.;
RT "TOS motif-mediated raptor binding regulates 4E-BP1 multisite
RT phosphorylation and function.";
RL Curr. Biol. 13:797-806(2003).
RN [9]
RP DISSOCIATION OF COMPLEX BY RAPAMYCIN.
RX PubMed=15066126; DOI=10.1111/j.1356-9597.2004.00727.x;
RA Oshiro N., Yoshino K., Hidayat S., Tokunaga C., Hara K., Eguchi S.,
RA Avruch J., Yonezawa K.;
RT "Dissociation of raptor from mTOR is a mechanism of rapamycin-induced
RT inhibition of mTOR function.";
RL Genes Cells 9:359-366(2004).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-863, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [12]
RP INTERACTION WITH AKT1S1.
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 [13]
RP PHOSPHORYLATION AT SER-719; SER-721 AND SER-722.
RX PubMed=18722121; DOI=10.1016/j.cub.2008.07.078;
RA Carriere A., Cargnello M., Julien L.A., Gao H., Bonneil E.,
RA Thibault P., Roux P.P.;
RT "Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-
RT mediated raptor phosphorylation.";
RL Curr. Biol. 18:1269-1277(2008).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [15]
RP PHOSPHORYLATION AT SER-722 AND SER-792, MUTAGENESIS OF SER-722 AND
RP SER-792, AND INTERACTION WITH 14-3-3.
RX PubMed=18439900; DOI=10.1016/j.molcel.2008.03.003;
RA Gwinn D.M., Shackelford D.B., Egan D.F., Mihaylova M.M., Mery A.,
RA Vasquez D.S., Turk B.E., Shaw R.J.;
RT "AMPK phosphorylation of raptor mediates a metabolic checkpoint.";
RL Mol. Cell 30:214-226(2008).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-877, 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 [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-719; SER-859; SER-863
RP AND SER-877, AND 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 [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [19]
RP INTERACTION WITH ULK1.
RX PubMed=19211835; DOI=10.1091/mbc.E08-12-1248;
RA Hosokawa N., Hara T., Kaizuka T., Kishi C., Takamura A., Miura Y.,
RA Iemura S., Natsume T., Takehana K., Yamada N., Guan J.L., Oshiro N.,
RA Mizushima N.;
RT "Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200
RT complex required for autophagy.";
RL Mol. Biol. Cell 20:1981-1991(2009).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-877, 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 [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-859; SER-863 AND
RP SER-877, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [22]
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 [23]
RP PHOSPHORYLATION AT SER-696; THR-706; SER-855; SER-859; SER-863 AND
RP SER-877.
RX PubMed=19864431; DOI=10.1074/jbc.M109.029637;
RA Foster K.G., Acosta-Jaquez H.A., Romeo Y., Ekim B., Soliman G.A.,
RA Carriere A., Roux P.P., Ballif B.A., Fingar D.C.;
RT "Regulation of mTOR complex 1 (mTORC1) by raptor Ser863 and multisite
RT phosphorylation.";
RL J. Biol. Chem. 285:80-94(2010).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-859; SER-863 AND
RP SER-877, AND 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 [25]
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 [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-863 AND SER-877, AND
RP MASS SPECTROMETRY.
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 [27]
RP PHOSPHORYLATION AT SER-696; THR-706 AND SER-863.
RX PubMed=22493283; DOI=10.1074/jbc.M111.326538;
RA Kwak D., Choi S., Jeong H., Jang J.H., Lee Y., Jeon H., Lee M.N.,
RA Noh J., Cho K., Yoo J.S., Hwang D., Suh P.G., Ryu S.H.;
RT "Osmotic stress regulates mammalian target of rapamycin (mTOR) complex
RT 1 via c-Jun N-terminal Kinase (JNK)-mediated Raptor protein
RT phosphorylation.";
RL J. Biol. Chem. 287:18398-18407(2012).
RN [28]
RP FUNCTION IN CILIOGENESIS.
RX PubMed=23727834; DOI=10.1093/hmg/ddt253;
RA Cardenas-Rodriguez M., Irigoin F., Osborn D.P., Gascue C.,
RA Katsanis N., Beales P.L., Badano J.L.;
RT "The Bardet-Biedl syndrome-related protein CCDC28B modulates mTORC2
RT function and interacts with SIN1 to control cilia length independently
RT of the mTOR complex.";
RL Hum. Mol. Genet. 22:4031-4042(2013).
CC -!- FUNCTION: Involved in the control of the mammalian target of
CC rapamycin complex 1 (mTORC1) activity which regulates cell growth
CC and survival, and autophagy in response to nutrient and hormonal
CC signals; functions as a scaffold for recruiting mTORC1 substrates.
CC mTORC1 is activated in response to growth factors or amino acids.
CC Growth factor-stimulated mTORC1 activation involves a AKT1-
CC mediated phosphorylation of TSC1-TSC2, which leads to the
CC activation of the RHEB GTPase that potently activates the protein
CC kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires
CC its relocalization to the lysosomes mediated by the Ragulator
CC complex and the Rag GTPases. Activated mTORC1 up-regulates protein
CC synthesis by phosphorylating key regulators of mRNA translation
CC and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and
CC releases it from inhibiting the elongation initiation factor 4E
CC (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389',
CC which then promotes protein synthesis by phosphorylating PDCD4 and
CC targeting it for degradation. Involved in ciliogenesis.
CC -!- SUBUNIT: Part of the mammalian target of rapamycin complex 1
CC (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and
CC DEPTOR. mTORC1 binds to and is inhibited by FKBP12-rapamycin.
CC Binds directly to 4EBP1 and RPS6KB1 independently of its
CC association with MTOR. Binds preferentially to poorly or non-
CC phosphorylated forms of EIF4EBP1, and this binding is critical to
CC the ability of MTOR to catalyze phosphorylation. Forms a complex
CC with MTOR under both leucine-rich and -poor conditions. Interacts
CC with ULK1 in a nutrient-dependent manner; the interaction is
CC reduced during starvation. Interacts (when phosphorylated by AMPK)
CC with 14-3-3 protein, leading to inhibit its activity.
CC -!- INTERACTION:
CC Q13541:EIF4EBP1; NbExp=5; IntAct=EBI-1567928, EBI-74090;
CC Q9P2J5:LARS; NbExp=3; IntAct=EBI-1567928, EBI-356077;
CC Q9BVC4:MLST8; NbExp=3; IntAct=EBI-1567928, EBI-1387471;
CC P42345:MTOR; NbExp=18; IntAct=EBI-1567928, EBI-359260;
CC Q9JLN9:Mtor (xeno); NbExp=5; IntAct=EBI-1567928, EBI-1571628;
CC Q8TCU6:PREX1; NbExp=2; IntAct=EBI-1567928, EBI-1046542;
CC P67999:Rps6kb1 (xeno); NbExp=2; IntAct=EBI-1567928, EBI-2639458;
CC Q96EB6:SIRT1; NbExp=3; IntAct=EBI-1567928, EBI-1802965;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Lysosome. Note=Targeting to
CC lysosomes depends on amino acid availability.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8N122-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8N122-2; Sequence=VSP_010174;
CC -!- TISSUE SPECIFICITY: Highly expressed in skeletal muscle, and in a
CC lesser extent in brain, lung, small intestine, kidney and
CC placenta.
CC -!- PTM: Insulin-stimulated phosphorylation at Ser-863 by MTOR and
CC MAPK8 up-regulates mTORC1 activity. Osmotic stress also induces
CC phosphorylation at Ser-696, Thr-706 and Ser-863 by MAPK8. Ser-863
CC phosphorylation is required for phosphorylation at Ser-855 and
CC Ser-859. In response to nutrient limitation, phosphorylated by
CC AMPK; phosphorylation promotes interaction with 14-3-3 proteins,
CC leading to negative regulation of the mTORC1 complex. In response
CC to growth factors, phosphorylated at Ser-719, Ser-721 and Ser-722
CC by RPS6KA1, which stimulates mTORC1 activity.
CC -!- SIMILARITY: Belongs to the WD repeat RAPTOR family.
CC -!- SIMILARITY: Contains 7 WD repeats.
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DR EMBL; AY090663; AAM09075.1; -; mRNA.
DR EMBL; AB082951; BAC06490.1; -; mRNA.
DR EMBL; AC016245; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC109327; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC127496; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC133012; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471099; EAW89618.1; -; Genomic_DNA.
DR EMBL; BC025180; AAH25180.1; -; mRNA.
DR EMBL; BC033258; AAH33258.1; -; mRNA.
DR EMBL; BC064515; AAH64515.1; -; mRNA.
DR EMBL; BC136652; AAI36653.1; -; mRNA.
DR EMBL; BC136654; AAI36655.1; -; mRNA.
DR EMBL; AB037724; BAA92541.1; -; mRNA.
DR RefSeq; NP_065812.1; NM_020761.2.
DR UniGene; Hs.133044; -.
DR ProteinModelPortal; Q8N122; -.
DR DIP; DIP-39482N; -.
DR IntAct; Q8N122; 22.
DR MINT; MINT-3038940; -.
DR STRING; 9606.ENSP00000307272; -.
DR PhosphoSite; Q8N122; -.
DR DMDM; 46577501; -.
DR PaxDb; Q8N122; -.
DR PRIDE; Q8N122; -.
DR DNASU; 57521; -.
DR Ensembl; ENST00000306801; ENSP00000307272; ENSG00000141564.
DR Ensembl; ENST00000570891; ENSP00000460136; ENSG00000141564.
DR GeneID; 57521; -.
DR KEGG; hsa:57521; -.
DR UCSC; uc002jyt.1; human.
DR CTD; 57521; -.
DR GeneCards; GC17P078518; -.
DR HGNC; HGNC:30287; RPTOR.
DR HPA; CAB013514; -.
DR HPA; HPA029821; -.
DR MIM; 607130; gene.
DR neXtProt; NX_Q8N122; -.
DR PharmGKB; PA165432629; -.
DR eggNOG; NOG269318; -.
DR HOGENOM; HOG000184479; -.
DR HOVERGEN; HBG059496; -.
DR InParanoid; Q8N122; -.
DR KO; K07204; -.
DR OMA; TEVCTND; -.
DR PhylomeDB; Q8N122; -.
DR Reactome; REACT_111102; Signal Transduction.
DR SignaLink; Q8N122; -.
DR GeneWiki; RPTOR; -.
DR GenomeRNAi; 57521; -.
DR NextBio; 63899; -.
DR PRO; PR:Q8N122; -.
DR ArrayExpress; Q8N122; -.
DR Bgee; Q8N122; -.
DR Genevestigator; Q8N122; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0031931; C:TORC1 complex; IDA:UniProtKB.
DR GO; GO:0071889; F:14-3-3 protein binding; IDA:UniProtKB.
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:0007050; P:cell cycle arrest; TAS:Reactome.
DR GO; GO:0016049; P:cell growth; IMP:UniProtKB.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IMP:UniProtKB.
DR GO; GO:0031669; P:cellular response to nutrient levels; IMP:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0032008; P:positive regulation of TOR signaling cascade; IDA:UniProtKB.
DR GO; GO:0045945; P:positive regulation of transcription from RNA polymerase III promoter; IMP:UniProtKB.
DR GO; GO:0008361; P:regulation of cell size; IMP:UniProtKB.
DR GO; GO:0031929; P:TOR signaling cascade; IDA:UniProtKB.
DR Gene3D; 1.25.10.10; -; 2.
DR Gene3D; 2.130.10.10; -; 1.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR000357; HEAT.
DR InterPro; IPR004083; Raptor.
DR InterPro; IPR027466; Raptor_metazoan.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom.
DR InterPro; IPR001680; WD40_repeat.
DR InterPro; IPR017986; WD40_repeat_dom.
DR PANTHER; PTHR12848; PTHR12848; 1.
DR PANTHER; PTHR12848:SF6; PTHR12848:SF6; 1.
DR Pfam; PF02985; HEAT; 1.
DR Pfam; PF00400; WD40; 2.
DR PRINTS; PR01547; YEAST176DUF.
DR SMART; SM00320; WD40; 7.
DR SUPFAM; SSF48371; SSF48371; 2.
DR SUPFAM; SSF50978; SSF50978; 1.
DR PROSITE; PS00678; WD_REPEATS_1; FALSE_NEG.
DR PROSITE; PS50082; WD_REPEATS_2; FALSE_NEG.
DR PROSITE; PS50294; WD_REPEATS_REGION; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Cytoplasm; Lysosome;
KW Phosphoprotein; Reference proteome; Repeat; WD repeat.
FT CHAIN 1 1335 Regulatory-associated protein of mTOR.
FT /FTId=PRO_0000051200.
FT REPEAT 1020 1061 WD 1.
FT REPEAT 1065 1106 WD 2.
FT REPEAT 1121 1160 WD 3.
FT REPEAT 1164 1203 WD 4.
FT REPEAT 1209 1249 WD 5.
FT REPEAT 1251 1291 WD 6.
FT REPEAT 1299 1335 WD 7.
FT COMPBIAS 881 887 Poly-Ser.
FT MOD_RES 696 696 Phosphoserine; by MAPK8.
FT MOD_RES 706 706 Phosphothreonine; by MAPK8.
FT MOD_RES 719 719 Phosphoserine; by RPS6KA1.
FT MOD_RES 721 721 Phosphoserine; by RPS6KA1.
FT MOD_RES 722 722 Phosphoserine; by AMPK and RPS6KA1.
FT MOD_RES 792 792 Phosphoserine; by AMPK.
FT MOD_RES 855 855 Phosphoserine.
FT MOD_RES 859 859 Phosphoserine; by MTOR.
FT MOD_RES 863 863 Phosphoserine; by MAPK8 and MTOR.
FT MOD_RES 877 877 Phosphoserine.
FT VAR_SEQ 380 1335 Missing (in isoform 2).
FT /FTId=VSP_010174.
FT MUTAGEN 722 722 S->A: Abolishes AMPK-mediated
FT phosphorylation; when associated with A-
FT 792.
FT MUTAGEN 792 792 S->A: Abolishes AMPK-mediated
FT phosphorylation; when associated with A-
FT 722.
FT CONFLICT 217 218 LE -> RQ (in Ref. 6; BAA92541).
SQ SEQUENCE 1335 AA; 149038 MW; 688ED1943F45045A CRC64;
MESEMLQSPL LGLGEEDEAD LTDWNLPLAF MKKRHCEKIE GSKSLAQSWR MKDRMKTVSV
ALVLCLNVGV DPPDVVKTTP CARLECWIDP LSMGPQKALE TIGANLQKQY ENWQPRARYK
QSLDPTVDEV KKLCTSLRRN AKEERVLFHY NGHGVPRPTV NGEVWVFNKN YTQYIPLSIY
DLQTWMGSPS IFVYDCSNAG LIVKSFKQFA LQREQELEVA AINPNHPLAQ MPLPPSMKNC
IQLAACEATE LLPMIPDLPA DLFTSCLTTP IKIALRWFCM QKCVSLVPGV TLDLIEKIPG
RLNDRRTPLG ELNWIFTAIT DTIAWNVLPR DLFQKLFRQD LLVASLFRNF LLAERIMRSY
NCTPVSSPRL PPTYMHAMWQ AWDLAVDICL SQLPTIIEEG TAFRHSPFFA EQLTAFQVWL
TMGVENRNPP EQLPIVLQVL LSQVHRLRAL DLLGRFLDLG PWAVSLALSV GIFPYVLKLL
QSSARELRPL LVFIWAKILA VDSSCQADLV KDNGHKYFLS VLADPYMPAE HRTMTAFILA
VIVNSYHTGQ EACLQGNLIA ICLEQLNDPH PLLRQWVAIC LGRIWQNFDS ARWCGVRDSA
HEKLYSLLSD PIPEVRCAAV FALGTFVGNS AERTDHSTTI DHNVAMMLAQ LVSDGSPMVR
KELVVALSHL VVQYESNFCT VALQFIEEEK NYALPSPATT EGGSLTPVRD SPCTPRLRSV
SSYGNIRAVA TARSLNKSLQ NLSLTEESGG AVAFSPGNLS TSSSASSTLG SPENEEHILS
FETIDKMRRA SSYSSLNSLI GVSFNSVYTQ IWRVLLHLAA DPYPEVSDVA MKVLNSIAYK
ATVNARPQRV LDTSSLTQSA PASPTNKGVH IHQAGGSPPA SSTSSSSLTN DVAKQPVSRD
LPSGRPGTTG PAGAQYTPHS HQFPRTRKMF DKGPEQTADD ADDAAGHKSF ISATVQTGFC
DWSARYFAQP VMKIPEEHDL ESQIRKEREW RFLRNSRVRR QAQQVIQKGI TRLDDQIFLN
RNPGVPSVVK FHPFTPCIAV ADKDSICFWD WEKGEKLDYF HNGNPRYTRV TAMEYLNGQD
CSLLLTATDD GAIRVWKNFA DLEKNPEMVT AWQGLSDMLP TTRGAGMVVD WEQETGLLMS
SGDVRIVRIW DTDREMKVQD IPTGADSCVT SLSCDSHRSL IVAGLGDGSI RVYDRRMALS
ECRVMTYREH TAWVVKASLQ KRPDGHIVSV SVNGDVRIFD PRMPESVNVL QIVKGLTALD
IHPQADLIAC GSVNQFTAIY NSSGELINNI KYYDGFMGQR VGAISCLAFH PHWPHLAVGS
NDYYISVYSV EKRVR
//
MIM
607130
*RECORD*
*FIELD* NO
607130
*FIELD* TI
*607130 REGULATORY ASSOCIATED PROTEIN OF MTOR; RPTOR
;;RAPTOR;;
KIAA1303
*FIELD* TX
read more
CLONING
MTOR (FRAP1; 601231), the target of the immunosuppressive drug
rapamycin, is the central component of a nutrient- and hormone-sensitive
signaling pathway that regulates cell growth. Kim et al. (2002) reported
that MTOR forms a stoichiometric complex with RAPTOR, an evolutionarily
conserved protein with at least 2 roles in the MTOR pathway. They cloned
the full-length cDNA for RAPTOR, which contains an open reading frame
encoding a protein with 1,335 amino acids and a predicted molecular mass
of 149 kD. A previously identified partial cDNA, KIAA1303 (Nagase et
al., 2000), is contained within the RAPTOR cDNA. All RAPTOR homologs
have a novel N-terminal domain the authors called RNC (RAPTOR N-terminal
conserved) that consists of 3 blocks with at least 67 to 79% sequence
similarity and is predicted to have a high propensity to form alpha
helices. Following the RNC domain, all RAPTOR homologs have 3 HEAT
repeats, which are followed by 7 WD40 repeats in the C-terminal third of
the protein. Northern blot analysis showed that RAPTOR is expressed in
all tissues in a pattern similar to that of MTOR, with the highest
levels of both mRNAs in skeletal muscle, brain, kidney, and placenta.
Independently, Hara et al. (2002) also cloned the RAPTOR gene. They
found that RAPTOR is a 150-kD MTOR-binding protein that also binds
eukaryotic initiation factor 4E-binding protein-1 (4EBP1; 602223) and
p70 S6 kinase-alpha (S6K1; 608938). They determined that mouse and human
RAPTOR share about 97% amino acid identity.
GENE FUNCTION
Kim et al. (2002) showed that RAPTOR has a positive role in
nutrient-stimulated signaling to the downstream effector S6K1,
maintenance of cell size, and MTOR protein expression. The association
of RAPTOR with MTOR also negatively regulates the 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. The authors proposed that RAPTOR is a
component of the MTOR pathway that, through its association with MTOR,
regulates cell size in response to nutrient levels.
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.
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.
The multiprotein mTORC1 protein kinase complex (see 601231) 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. Coimmunoprecipitation assays indicated
that RAPTOR is the key mediator of the Rag-mTORC1 interaction.
MAPPING
By genomic sequence analysis, Kim et al. (2002) mapped the RPTOR gene to
chromosome 17q25.3.
MOLECULAR GENETICS
In a dataset of 233 parent-offspring trios with psoriasis (see 177900),
Capon et al. (2004) analyzed 8 representative SNPs selected from 2
psoriasis susceptibility (PSORS2; 602723) association peaks previously
identified by Helms et al. (2003) encompassing the SLC9AR1 (604990)-NAT9
genes and the third intron of the RAPTOR gene, respectively. They found
evidence for association only at RAPTOR dbSNP rs2019154 (p = 0.027).
Restricting the analysis to 116 trios with a well-documented family
history of psoriasis increased the significance of the association for 3
RAPTOR SNPs, with rs2019154 yielding a p value of 0.008.
In a study of 579 pedigrees with psoriasis, Stuart et al. (2006) found
no evidence for a disease association with 3 SNPS in the RAPTOR gene.
*FIELD* RF
1. Capon, F.; Helms, C.; Veal, C. D.; Tillman, D.; Burden, A. D.;
Barker, J. N.; Bowcock, A. M.; Trembath, R. C.: Genetic analysis
of PSORS2 markers in a UK dataset supports the association between
RAPTOR SNPs and familial psoriasis. (Letter) J. Med. Genet. 41:
459-460, 2004.
2. Hara, K.; Maruki, Y.; Long, X.; Yoshino, K.; Oshiro, N.; Hidayat,
S.; Tokunaga, C.; Avruch, J.; Yonezawa, K.: Raptor, a binding partner
of target of rapamycin, mediates TOR action. Cell 110: 177-189,
2002.
3. Helms, C.; Cao, L.; Krueger, J. G.; Wijsman, E. M.; Chamian, F.;
Gordon, D.; Heffernan, M.; Daw, J. A. W.; Robarge, J.; Ott, J.; Kwok,
P.-Y.; Menter, A.; Bowcock, A. M.: A putative RUNX1 binding site
variant between SLC9A3R1 and NAT9 is associated with susceptibility
to psoriasis. Nature Genet. 35: 349-356, 2003.
4. Kim, D.-H.; Sarbassov, D. D.; Ali, S. M.; King, J. E.; Latek, R.
R.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D. M.: mTOR interacts
with raptor to form a nutrient-sensitive complex that signals to the
cell growth machinery. Cell 110: 163-175, 2002.
5. Nagase, T.; Kikuno, R.; Ishikawa, K.; Hirosawa, M.; Ohara, O.:
Prediction of the coding sequences of unidentified human genes. XVI.
The complete sequences of 150 new cDNA clones from brain which code
for large proteins in vitro. DNA Res. 7: 65-73, 2000.
6. Sancak, Y.; Peterson, T. R.; Shaul, Y. D.; Lindquist, R. A.; Thoreen,
C. C.; Bar-Peled, L.; Sabatini, D. M.: The Rag GTPases bind raptor
and mediate amino acid signaling to mTORC1. Science 320: 1496-1501,
2008.
7. Stuart, P.; Nair, R. P.; Abecasis, G. R.; Nistor, I.; Hiremagalore,
R.; Chia, N. V.; Qin, Z. S.; Thompson, R. A.; Jenisch, S.; Weichenthal,
M.; Janiga, J.; Lim, H. W.; Christophers, E.; Voorhees, J. J.; Elder,
J. T.: Analysis of RUNX1 binding site and RAPTOR polymorphisms in
psoriasis: no evidence for association despite adequate power and
evidence for linkage. J. Med. Genet. 43: 12-17, 2006.
*FIELD* CN
Ada Hamosh - updated: 7/23/2008
Cassandra L. Kniffin - updated: 2/10/2006
Marla J. F. O'Neill - updated: 7/9/2004
*FIELD* CD
Stylianos E. Antonarakis: 7/31/2002
*FIELD* ED
alopez: 11/16/2009
alopez: 7/23/2008
terry: 7/11/2008
carol: 5/15/2007
wwang: 2/28/2006
ckniffin: 2/10/2006
wwang: 3/11/2005
mgross: 9/23/2004
carol: 7/12/2004
terry: 7/9/2004
mgross: 10/6/2003
mgross: 7/31/2002
*RECORD*
*FIELD* NO
607130
*FIELD* TI
*607130 REGULATORY ASSOCIATED PROTEIN OF MTOR; RPTOR
;;RAPTOR;;
KIAA1303
*FIELD* TX
read more
CLONING
MTOR (FRAP1; 601231), the target of the immunosuppressive drug
rapamycin, is the central component of a nutrient- and hormone-sensitive
signaling pathway that regulates cell growth. Kim et al. (2002) reported
that MTOR forms a stoichiometric complex with RAPTOR, an evolutionarily
conserved protein with at least 2 roles in the MTOR pathway. They cloned
the full-length cDNA for RAPTOR, which contains an open reading frame
encoding a protein with 1,335 amino acids and a predicted molecular mass
of 149 kD. A previously identified partial cDNA, KIAA1303 (Nagase et
al., 2000), is contained within the RAPTOR cDNA. All RAPTOR homologs
have a novel N-terminal domain the authors called RNC (RAPTOR N-terminal
conserved) that consists of 3 blocks with at least 67 to 79% sequence
similarity and is predicted to have a high propensity to form alpha
helices. Following the RNC domain, all RAPTOR homologs have 3 HEAT
repeats, which are followed by 7 WD40 repeats in the C-terminal third of
the protein. Northern blot analysis showed that RAPTOR is expressed in
all tissues in a pattern similar to that of MTOR, with the highest
levels of both mRNAs in skeletal muscle, brain, kidney, and placenta.
Independently, Hara et al. (2002) also cloned the RAPTOR gene. They
found that RAPTOR is a 150-kD MTOR-binding protein that also binds
eukaryotic initiation factor 4E-binding protein-1 (4EBP1; 602223) and
p70 S6 kinase-alpha (S6K1; 608938). They determined that mouse and human
RAPTOR share about 97% amino acid identity.
GENE FUNCTION
Kim et al. (2002) showed that RAPTOR has a positive role in
nutrient-stimulated signaling to the downstream effector S6K1,
maintenance of cell size, and MTOR protein expression. The association
of RAPTOR with MTOR also negatively regulates the 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. The authors proposed that RAPTOR is a
component of the MTOR pathway that, through its association with MTOR,
regulates cell size in response to nutrient levels.
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.
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.
The multiprotein mTORC1 protein kinase complex (see 601231) 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. Coimmunoprecipitation assays indicated
that RAPTOR is the key mediator of the Rag-mTORC1 interaction.
MAPPING
By genomic sequence analysis, Kim et al. (2002) mapped the RPTOR gene to
chromosome 17q25.3.
MOLECULAR GENETICS
In a dataset of 233 parent-offspring trios with psoriasis (see 177900),
Capon et al. (2004) analyzed 8 representative SNPs selected from 2
psoriasis susceptibility (PSORS2; 602723) association peaks previously
identified by Helms et al. (2003) encompassing the SLC9AR1 (604990)-NAT9
genes and the third intron of the RAPTOR gene, respectively. They found
evidence for association only at RAPTOR dbSNP rs2019154 (p = 0.027).
Restricting the analysis to 116 trios with a well-documented family
history of psoriasis increased the significance of the association for 3
RAPTOR SNPs, with rs2019154 yielding a p value of 0.008.
In a study of 579 pedigrees with psoriasis, Stuart et al. (2006) found
no evidence for a disease association with 3 SNPS in the RAPTOR gene.
*FIELD* RF
1. Capon, F.; Helms, C.; Veal, C. D.; Tillman, D.; Burden, A. D.;
Barker, J. N.; Bowcock, A. M.; Trembath, R. C.: Genetic analysis
of PSORS2 markers in a UK dataset supports the association between
RAPTOR SNPs and familial psoriasis. (Letter) J. Med. Genet. 41:
459-460, 2004.
2. Hara, K.; Maruki, Y.; Long, X.; Yoshino, K.; Oshiro, N.; Hidayat,
S.; Tokunaga, C.; Avruch, J.; Yonezawa, K.: Raptor, a binding partner
of target of rapamycin, mediates TOR action. Cell 110: 177-189,
2002.
3. Helms, C.; Cao, L.; Krueger, J. G.; Wijsman, E. M.; Chamian, F.;
Gordon, D.; Heffernan, M.; Daw, J. A. W.; Robarge, J.; Ott, J.; Kwok,
P.-Y.; Menter, A.; Bowcock, A. M.: A putative RUNX1 binding site
variant between SLC9A3R1 and NAT9 is associated with susceptibility
to psoriasis. Nature Genet. 35: 349-356, 2003.
4. Kim, D.-H.; Sarbassov, D. D.; Ali, S. M.; King, J. E.; Latek, R.
R.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D. M.: mTOR interacts
with raptor to form a nutrient-sensitive complex that signals to the
cell growth machinery. Cell 110: 163-175, 2002.
5. Nagase, T.; Kikuno, R.; Ishikawa, K.; Hirosawa, M.; Ohara, O.:
Prediction of the coding sequences of unidentified human genes. XVI.
The complete sequences of 150 new cDNA clones from brain which code
for large proteins in vitro. DNA Res. 7: 65-73, 2000.
6. Sancak, Y.; Peterson, T. R.; Shaul, Y. D.; Lindquist, R. A.; Thoreen,
C. C.; Bar-Peled, L.; Sabatini, D. M.: The Rag GTPases bind raptor
and mediate amino acid signaling to mTORC1. Science 320: 1496-1501,
2008.
7. Stuart, P.; Nair, R. P.; Abecasis, G. R.; Nistor, I.; Hiremagalore,
R.; Chia, N. V.; Qin, Z. S.; Thompson, R. A.; Jenisch, S.; Weichenthal,
M.; Janiga, J.; Lim, H. W.; Christophers, E.; Voorhees, J. J.; Elder,
J. T.: Analysis of RUNX1 binding site and RAPTOR polymorphisms in
psoriasis: no evidence for association despite adequate power and
evidence for linkage. J. Med. Genet. 43: 12-17, 2006.
*FIELD* CN
Ada Hamosh - updated: 7/23/2008
Cassandra L. Kniffin - updated: 2/10/2006
Marla J. F. O'Neill - updated: 7/9/2004
*FIELD* CD
Stylianos E. Antonarakis: 7/31/2002
*FIELD* ED
alopez: 11/16/2009
alopez: 7/23/2008
terry: 7/11/2008
carol: 5/15/2007
wwang: 2/28/2006
ckniffin: 2/10/2006
wwang: 3/11/2005
mgross: 9/23/2004
carol: 7/12/2004
terry: 7/9/2004
mgross: 10/6/2003
mgross: 7/31/2002