Full text data of IL6ST
IL6ST
[Confidence: high (a blood group or CD marker)]
Interleukin-6 receptor subunit beta; IL-6 receptor subunit beta; IL-6R subunit beta; IL-6R-beta; IL-6RB (CDw130; Interleukin-6 signal transducer; Membrane glycoprotein 130; gp130; Oncostatin-M receptor subunit alpha; CD130; Flags: Precursor)
Interleukin-6 receptor subunit beta; IL-6 receptor subunit beta; IL-6R subunit beta; IL-6R-beta; IL-6RB (CDw130; Interleukin-6 signal transducer; Membrane glycoprotein 130; gp130; Oncostatin-M receptor subunit alpha; CD130; Flags: Precursor)
UniProt
P40189
ID IL6RB_HUMAN Reviewed; 918 AA.
AC P40189; A0N0L4; Q5FC04; Q9UQ41;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 25-NOV-2008, sequence version 2.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Interleukin-6 receptor subunit beta;
DE Short=IL-6 receptor subunit beta;
DE Short=IL-6R subunit beta;
DE Short=IL-6R-beta;
DE Short=IL-6RB;
DE AltName: Full=CDw130;
DE AltName: Full=Interleukin-6 signal transducer;
DE AltName: Full=Membrane glycoprotein 130;
DE Short=gp130;
DE AltName: Full=Oncostatin-M receptor subunit alpha;
DE AltName: CD_antigen=CD130;
DE Flags: Precursor;
GN Name=IL6ST;
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] (ISOFORM 1), AND VARIANT VAL-8.
RC TISSUE=Myeloma, and Placenta;
RX PubMed=2261637; DOI=10.1016/0092-8674(90)90411-7;
RA Hibi M., Murakami M., Saito M., Hirano T., Taga T., Kishimoto T.;
RT "Molecular cloning and expression of an IL-6 signal transducer,
RT gp130.";
RL Cell 63:1149-1157(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANT VAL-8.
RC TISSUE=Synovium;
RX PubMed=10880057; DOI=10.1172/JCI7479;
RA Tanaka M., Kishimura M., Ozaki S., Osakada F., Hashimoto H., Okubo M.,
RA Murakami M., Nakao K.;
RT "Cloning of novel soluble gp130 and detection of its neutralizing
RT autoantibodies in rheumatoid arthritis.";
RL J. Clin. Invest. 106:137-144(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RA Hayashi A., Sameshima E., Tabata Y., Iida K., Mitsuyama M., Kanai S.,
RA Furuya T., Saito T.;
RT "IL6ST mRNA, nirs splice variant 4.";
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Livingston R.J., Shaffer T., McFarland I., Nguyen C.P., Stanaway I.B.,
RA Rajkumar N., Johnson E.J., da Ponte S.H., Willa H., Ahearn M.O.,
RA Bertucci C., Acklestad J., Carroll A., Swanson J., Gildersleeve H.I.,
RA Nickerson D.A.;
RL Submitted (OCT-2006) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [6]
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 [7]
RP PARTIAL PROTEIN SEQUENCE, DISULFIDE BONDS, AND GLYCOSYLATION AT
RP ASN-43; ASN-83; ASN-131; ASN-157; ASN-227; ASN-379; ASN-383; ASN-553
RP AND ASN-564.
RX PubMed=11098061; DOI=10.1074/jbc.M009979200;
RA Moritz R.L., Hall N.E., Connolly L.M., Simpson R.J.;
RT "Determination of the disulfide structure and N-glycosylation sites of
RT the extracellular domain of the human signal transducer gp130.";
RL J. Biol. Chem. 276:8244-8253(2001).
RN [8]
RP SUBUNIT, AND INDUCTION.
RX PubMed=8999038; DOI=10.1074/jbc.271.51.32635;
RA Mosley B., De Imus C., Friend D., Boiani N., Thoma B., Park L.S.,
RA Cosman D.;
RT "Dual oncostatin M (OSM) receptors. Cloning and characterization of an
RT alternative signaling subunit conferring OSM-specific receptor
RT activation.";
RL J. Biol. Chem. 271:32635-32643(1996).
RN [9]
RP INTERACTION WITH HCK.
RX PubMed=9406996;
RA Hallek M., Neumann C., Schaffer M., Danhauser-Riedl S.,
RA von Bubnoff N., de Vos G., Druker B.J., Yasukawa K., Griffin J.D.,
RA Emmerich B.;
RT "Signal transduction of interleukin-6 involves tyrosine
RT phosphorylation of multiple cytosolic proteins and activation of Src-
RT family kinases Fyn, Hck, and Lyn in multiple myeloma cell lines.";
RL Exp. Hematol. 25:1367-1377(1997).
RN [10]
RP PHOSPHORYLATION AT SER-782, MUTAGENESIS OF SER-782, AND MASS
RP SPECTROMETRY.
RX PubMed=10811661; DOI=10.1074/jbc.M907658199;
RA Gibson R.M., Schiemann W.P., Prichard L.B., Reno J.M., Ericsson L.H.,
RA Nathanson N.M.;
RT "Phosphorylation of human gp130 at Ser-782 adjacent to the di-leucine
RT internalization motif. Effects on expression and signaling.";
RL J. Biol. Chem. 275:22574-22582(2000).
RN [11]
RP INTERACTION WITH HHV-8 PROTEIN VIL6.
RX PubMed=11238858; DOI=10.1128/JVI.75.7.3325-3334.2001;
RA Li H., Wang H., Nicholas J.;
RT "Detection of direct binding of human herpesvirus 8-encoded
RT interleukin-6 (vIL-6) to both gp130 and IL-6 receptor (IL-6R) and
RT identification of amino acid residues of vIL-6 important for IL-6R-
RT dependent and -independent signaling.";
RL J. Virol. 75:3325-3334(2001).
RN [12]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-379 AND ASN-383, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-829, AND MASS
RP SPECTROMETRY.
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 [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-667, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-227 AND ASN-390, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [17]
RP GLYCOSYLATION AT ASN-390.
RX PubMed=19139490; DOI=10.1074/mcp.M800504-MCP200;
RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-667, AND MASS
RP 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 [19]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 122-325.
RX PubMed=9501088; DOI=10.1093/emboj/17.6.1665;
RA Bravo J., Staunton D., Heath J.K., Jones E.Y.;
RT "Crystal structure of a cytokine-binding region of gp130.";
RL EMBO J. 17:1665-1674(1998).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 23-325 IN COMPLEX WITH HERPES
RP VIRUS IL6, SUBUNIT, AND GLYCOSYLATION.
RX PubMed=11251120; DOI=10.1126/science.1058308;
RA Chow D.-C., He X.-L., Snow A.L., Rose-John S., Garcia K.C.;
RT "Structure of an extracellular gp130 cytokine receptor signaling
RT complex.";
RL Science 291:2150-2155(2001).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 123-323 IN COMPLEX WITH LIF.
RX PubMed=14527405; DOI=10.1016/S1097-2765(03)00365-4;
RA Boulanger M.J., Bankovich A.J., Kortemme T., Baker D., Garcia K.C.;
RT "Convergent mechanisms for recognition of divergent cytokines by the
RT shared signaling receptor gp130.";
RL Mol. Cell 12:577-589(2003).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (3.65 ANGSTROMS) OF 23-321 IN COMPLEX WITH IL6
RP AND IL6R, AND SUBUNIT.
RX PubMed=12829785; DOI=10.1126/science.1083901;
RA Boulanger M.J., Chow D.-C., Brevnova E.E., Garcia K.C.;
RT "Hexameric structure and assembly of the interleukin-6/IL-6 alpha-
RT receptor/gp130 complex.";
RL Science 300:2101-2104(2003).
RN [23]
RP VARIANT [LARGE SCALE ANALYSIS] ILE-415.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Signal-transducing molecule. The receptor systems for
CC IL6, LIF, OSM, CNTF, IL11, CTF1 and BSF3 can utilize gp130 for
CC initiating signal transmission. Binds to IL6/IL6R (alpha chain)
CC complex, resulting in the formation of high-affinity IL6 binding
CC sites, and transduces the signal. Does not bind IL6. May have a
CC role in embryonic development (By similarity). The type I OSM
CC receptor is capable of transducing OSM-specific signaling events.
CC -!- SUBUNIT: Interacts with INPP5D/SHIP1 (By similarity). Forms
CC heterodimers composed of LIPR and IL6ST (type I OSM receptor).
CC Also forms heterodimers composed of OSMR and IL6ST (type II OSM
CC receptor). Homodimer. The homodimer binds two molecules of herpes
CC virus 8/HHV-8 protein vIL-6. Component of a hexamer of two
CC molecules each of IL6, IL6R and IL6ST. Interacts with HCK.
CC -!- INTERACTION:
CC P42227:Stat3 (xeno); NbExp=6; IntAct=EBI-1030834, EBI-602878;
CC -!- SUBCELLULAR LOCATION: Isoform 1: Cell membrane; Single-pass type I
CC membrane protein.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P40189-1; Sequence=Displayed;
CC Name=2; Synonyms=GP130-RAPS;
CC IsoId=P40189-2; Sequence=VSP_001684, VSP_001685;
CC Name=3;
CC IsoId=P40189-3; Sequence=VSP_043716;
CC -!- TISSUE SPECIFICITY: Found in all the tissues and cell lines
CC examined. Expression not restricted to IL6 responsive cells.
CC -!- INDUCTION: LIF and OSM activate the type I OSM receptor while only
CC OSM can activate the type II OSM receptor.
CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein
CC folding and thereby efficient intracellular transport and cell-
CC surface receptor binding.
CC -!- DOMAIN: The box 1 motif is required for JAK interaction and/or
CC activation.
CC -!- PTM: Phosphorylation of Ser-782 down-regulates cell surface
CC expression.
CC -!- PTM: Heavily N-glycosylated.
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 2
CC subfamily.
CC -!- SIMILARITY: Contains 5 fibronectin type-III domains.
CC -!- SIMILARITY: Contains 1 Ig-like C2-type (immunoglobulin-like)
CC domain.
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DR EMBL; M57230; AAA59155.1; -; mRNA.
DR EMBL; AB015706; BAA78112.1; -; mRNA.
DR EMBL; AB102802; BAD89393.1; -; mRNA.
DR EMBL; EF064722; ABK41905.1; -; Genomic_DNA.
DR EMBL; AC008914; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC016596; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471123; EAW54936.1; -; Genomic_DNA.
DR PIR; A36337; A36337.
DR RefSeq; NP_001177910.1; NM_001190981.1.
DR RefSeq; NP_002175.2; NM_002184.3.
DR RefSeq; NP_786943.1; NM_175767.2.
DR UniGene; Hs.532082; -.
DR UniGene; Hs.706627; -.
DR PDB; 1BJ8; NMR; -; A=219-325.
DR PDB; 1BQU; X-ray; 2.00 A; A/B=122-333.
DR PDB; 1I1R; X-ray; 2.40 A; A=23-325.
DR PDB; 1N2Q; Model; -; A/B=23-324.
DR PDB; 1P9M; X-ray; 3.65 A; A=23-321.
DR PDB; 1PVH; X-ray; 2.50 A; A/C=123-323.
DR PDB; 3L5H; X-ray; 3.60 A; A=24-612.
DR PDB; 3L5I; X-ray; 1.90 A; A=323-612.
DR PDB; 3L5J; X-ray; 3.04 A; A/B=323-610.
DR PDBsum; 1BJ8; -.
DR PDBsum; 1BQU; -.
DR PDBsum; 1I1R; -.
DR PDBsum; 1N2Q; -.
DR PDBsum; 1P9M; -.
DR PDBsum; 1PVH; -.
DR PDBsum; 3L5H; -.
DR PDBsum; 3L5I; -.
DR PDBsum; 3L5J; -.
DR ProteinModelPortal; P40189; -.
DR SMR; P40189; 24-612.
DR DIP; DIP-95N; -.
DR IntAct; P40189; 7.
DR MINT; MINT-130473; -.
DR STRING; 9606.ENSP00000338799; -.
DR PhosphoSite; P40189; -.
DR DMDM; 215273999; -.
DR PaxDb; P40189; -.
DR PRIDE; P40189; -.
DR DNASU; 3572; -.
DR Ensembl; ENST00000336909; ENSP00000338799; ENSG00000134352.
DR Ensembl; ENST00000381287; ENSP00000370687; ENSG00000134352.
DR Ensembl; ENST00000381294; ENSP00000370694; ENSG00000134352.
DR Ensembl; ENST00000381298; ENSP00000370698; ENSG00000134352.
DR Ensembl; ENST00000502326; ENSP00000462158; ENSG00000134352.
DR Ensembl; ENST00000522633; ENSP00000435399; ENSG00000134352.
DR Ensembl; ENST00000536319; ENSP00000444456; ENSG00000134352.
DR GeneID; 3572; -.
DR KEGG; hsa:3572; -.
DR UCSC; uc003jqq.3; human.
DR CTD; 3572; -.
DR GeneCards; GC05M055230; -.
DR HGNC; HGNC:6021; IL6ST.
DR HPA; CAB025784; -.
DR HPA; HPA010558; -.
DR MIM; 600694; gene.
DR neXtProt; NX_P40189; -.
DR PharmGKB; PA29837; -.
DR eggNOG; NOG145009; -.
DR HOGENOM; HOG000015771; -.
DR HOVERGEN; HBG052119; -.
DR InParanoid; P40189; -.
DR KO; K05060; -.
DR OMA; FKQNCSQ; -.
DR OrthoDB; EOG7FXZXN; -.
DR PhylomeDB; P40189; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P40189; -.
DR ChiTaRS; IL6ST; human.
DR EvolutionaryTrace; P40189; -.
DR GeneWiki; Glycoprotein_130; -.
DR GenomeRNAi; 3572; -.
DR NextBio; 13960; -.
DR PRO; PR:P40189; -.
DR ArrayExpress; P40189; -.
DR Bgee; P40189; -.
DR CleanEx; HS_IL6ST; -.
DR Genevestigator; P40189; -.
DR GO; GO:0070110; C:ciliary neurotrophic factor receptor complex; IDA:BHF-UCL.
DR GO; GO:0030425; C:dendrite; IEA:Ensembl.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005896; C:interleukin-6 receptor complex; IDA:BHF-UCL.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0005900; C:oncostatin-M receptor complex; IDA:BHF-UCL.
DR GO; GO:0004897; F:ciliary neurotrophic factor receptor activity; IDA:BHF-UCL.
DR GO; GO:0004921; F:interleukin-11 receptor activity; IEA:Ensembl.
DR GO; GO:0045509; F:interleukin-27 receptor activity; IC:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; TAS:BHF-UCL.
DR GO; GO:0005977; P:glycogen metabolic process; IEA:Ensembl.
DR GO; GO:0070102; P:interleukin-6-mediated signaling pathway; IMP:BHF-UCL.
DR GO; GO:0048861; P:leukemia inhibitory factor signaling pathway; IGI:BHF-UCL.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:BHF-UCL.
DR GO; GO:0070104; P:negative regulation of interleukin-6-mediated signaling pathway; IDA:BHF-UCL.
DR GO; GO:0038165; P:oncostatin-M-mediated signaling pathway; IMP:BHF-UCL.
DR GO; GO:0002675; P:positive regulation of acute inflammatory response; IC:BHF-UCL.
DR GO; GO:0002821; P:positive regulation of adaptive immune response; IC:BHF-UCL.
DR GO; GO:0048711; P:positive regulation of astrocyte differentiation; IEA:Ensembl.
DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; TAS:BHF-UCL.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; IMP:BHF-UCL.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IMP:BHF-UCL.
DR GO; GO:0042511; P:positive regulation of tyrosine phosphorylation of Stat1 protein; IMP:BHF-UCL.
DR GO; GO:0042517; P:positive regulation of tyrosine phosphorylation of Stat3 protein; IMP:BHF-UCL.
DR GO; GO:0010575; P:positive regulation vascular endothelial growth factor production; TAS:BHF-UCL.
DR GO; GO:0008593; P:regulation of Notch signaling pathway; IEA:Ensembl.
DR Gene3D; 2.60.40.10; -; 5.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR003529; Hematopoietin_rcpt_Gp130_CS.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR010457; IgC2-like_lig-bd.
DR InterPro; IPR015321; IL-6_rcpt_alpha-bd.
DR Pfam; PF00041; fn3; 2.
DR Pfam; PF09240; IL6Ra-bind; 1.
DR Pfam; PF06328; Lep_receptor_Ig; 1.
DR SMART; SM00060; FN3; 5.
DR SUPFAM; SSF49265; SSF49265; 5.
DR PROSITE; PS50853; FN3; 4.
DR PROSITE; PS01353; HEMATOPO_REC_L_F2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Host-virus interaction; Immunoglobulin domain; Membrane;
KW Phosphoprotein; Polymorphism; Receptor; Reference proteome; Repeat;
KW Secreted; Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1 22
FT CHAIN 23 918 Interleukin-6 receptor subunit beta.
FT /FTId=PRO_0000010899.
FT TOPO_DOM 23 619 Extracellular (Potential).
FT TRANSMEM 620 641 Helical; (Potential).
FT TOPO_DOM 642 918 Cytoplasmic (Potential).
FT DOMAIN 26 120 Ig-like C2-type.
FT DOMAIN 125 216 Fibronectin type-III 1.
FT DOMAIN 224 324 Fibronectin type-III 2.
FT DOMAIN 329 424 Fibronectin type-III 3.
FT DOMAIN 426 517 Fibronectin type-III 4.
FT DOMAIN 518 613 Fibronectin type-III 5.
FT MOTIF 310 314 WSXWS motif.
FT MOTIF 651 659 Box 1 motif.
FT COMPBIAS 725 755 Ser-rich.
FT MOD_RES 667 667 Phosphoserine.
FT MOD_RES 782 782 Phosphoserine.
FT MOD_RES 829 829 Phosphoserine.
FT CARBOHYD 43 43 N-linked (GlcNAc...).
FT CARBOHYD 83 83 N-linked (GlcNAc...).
FT CARBOHYD 131 131 N-linked (GlcNAc...).
FT CARBOHYD 157 157 N-linked (GlcNAc...).
FT CARBOHYD 227 227 N-linked (GlcNAc...).
FT CARBOHYD 379 379 N-linked (GlcNAc...).
FT CARBOHYD 383 383 N-linked (GlcNAc...).
FT CARBOHYD 390 390 N-linked (GlcNAc...) (complex).
FT CARBOHYD 553 553 N-linked (GlcNAc...).
FT CARBOHYD 564 564 N-linked (GlcNAc...).
FT DISULFID 28 54
FT DISULFID 48 103
FT DISULFID 134 144
FT DISULFID 172 182
FT DISULFID 458 466
FT VAR_SEQ 325 329 RPSKA -> NIASF (in isoform 2).
FT /FTId=VSP_001684.
FT VAR_SEQ 330 918 Missing (in isoform 2).
FT /FTId=VSP_001685.
FT VAR_SEQ 423 483 Missing (in isoform 3).
FT /FTId=VSP_043716.
FT VARIANT 8 8 L -> V (in dbSNP:rs1063560).
FT /FTId=VAR_047782.
FT VARIANT 148 148 G -> R (in dbSNP:rs2228044).
FT /FTId=VAR_047783.
FT VARIANT 397 397 L -> V (in dbSNP:rs2228043).
FT /FTId=VAR_047784.
FT VARIANT 415 415 T -> I (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036165.
FT VARIANT 454 454 I -> T (in dbSNP:rs2228046).
FT /FTId=VAR_047785.
FT VARIANT 499 499 V -> I (in dbSNP:rs34417936).
FT /FTId=VAR_047786.
FT MUTAGEN 782 782 S->A: Increases cell surface expression.
FT STRAND 28 35
FT STRAND 37 39
FT STRAND 44 50
FT HELIX 52 58
FT HELIX 62 64
FT STRAND 65 69
FT HELIX 76 78
FT STRAND 80 83
FT STRAND 86 91
FT STRAND 97 107
FT TURN 108 110
FT STRAND 111 123
FT STRAND 130 137
FT STRAND 143 147
FT STRAND 157 164
FT STRAND 176 178
FT STRAND 181 183
FT STRAND 194 202
FT STRAND 205 208
FT STRAND 212 214
FT HELIX 216 218
FT STRAND 219 221
FT STRAND 226 231
FT STRAND 234 238
FT STRAND 240 245
FT HELIX 248 251
FT STRAND 255 263
FT HELIX 274 277
FT STRAND 282 286
FT STRAND 291 303
FT STRAND 317 321
FT HELIX 325 331
FT STRAND 332 338
FT STRAND 345 351
FT HELIX 356 359
FT STRAND 363 372
FT STRAND 378 391
FT STRAND 396 406
FT STRAND 412 416
FT STRAND 428 435
FT STRAND 438 444
FT STRAND 452 460
FT STRAND 462 464
FT STRAND 469 474
FT STRAND 478 481
FT STRAND 491 500
FT STRAND 508 515
FT STRAND 525 530
FT STRAND 535 539
FT HELIX 544 547
FT STRAND 553 560
FT STRAND 566 571
FT STRAND 575 579
FT STRAND 587 596
FT STRAND 599 602
FT STRAND 606 609
SQ SEQUENCE 918 AA; 103537 MW; 6510A4409FFCF08C CRC64;
MLTLQTWLVQ ALFIFLTTES TGELLDPCGY ISPESPVVQL HSNFTAVCVL KEKCMDYFHV
NANYIVWKTN HFTIPKEQYT IINRTASSVT FTDIASLNIQ LTCNILTFGQ LEQNVYGITI
ISGLPPEKPK NLSCIVNEGK KMRCEWDGGR ETHLETNFTL KSEWATHKFA DCKAKRDTPT
SCTVDYSTVY FVNIEVWVEA ENALGKVTSD HINFDPVYKV KPNPPHNLSV INSEELSSIL
KLTWTNPSIK SVIILKYNIQ YRTKDASTWS QIPPEDTAST RSSFTVQDLK PFTEYVFRIR
CMKEDGKGYW SDWSEEASGI TYEDRPSKAP SFWYKIDPSH TQGYRTVQLV WKTLPPFEAN
GKILDYEVTL TRWKSHLQNY TVNATKLTVN LTNDRYLATL TVRNLVGKSD AAVLTIPACD
FQATHPVMDL KAFPKDNMLW VEWTTPRESV KKYILEWCVL SDKAPCITDW QQEDGTVHRT
YLRGNLAESK CYLITVTPVY ADGPGSPESI KAYLKQAPPS KGPTVRTKKV GKNEAVLEWD
QLPVDVQNGF IRNYTIFYRT IIGNETAVNV DSSHTEYTLS SLTSDTLYMV RMAAYTDEGG
KDGPEFTFTT PKFAQGEIEA IVVPVCLAFL LTTLLGVLFC FNKRDLIKKH IWPNVPDPSK
SHIAQWSPHT PPRHNFNSKD QMYSDGNFTD VSVVEIEAND KKPFPEDLKS LDLFKKEKIN
TEGHSSGIGG SSCMSSSRPS ISSSDENESS QNTSSTVQYS TVVHSGYRHQ VPSVQVFSRS
ESTQPLLDSE ERPEDLQLVD HVDGGDGILP RQQYFKQNCS QHESSPDISH FERSKQVSSV
NEEDFVRLKQ QISDHISQSC GSGQMKMFQE VSAADAFGPG TEGQVERFET VGMEAATDEG
MPKSYLPQTV RQGGYMPQ
//
ID IL6RB_HUMAN Reviewed; 918 AA.
AC P40189; A0N0L4; Q5FC04; Q9UQ41;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 25-NOV-2008, sequence version 2.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Interleukin-6 receptor subunit beta;
DE Short=IL-6 receptor subunit beta;
DE Short=IL-6R subunit beta;
DE Short=IL-6R-beta;
DE Short=IL-6RB;
DE AltName: Full=CDw130;
DE AltName: Full=Interleukin-6 signal transducer;
DE AltName: Full=Membrane glycoprotein 130;
DE Short=gp130;
DE AltName: Full=Oncostatin-M receptor subunit alpha;
DE AltName: CD_antigen=CD130;
DE Flags: Precursor;
GN Name=IL6ST;
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] (ISOFORM 1), AND VARIANT VAL-8.
RC TISSUE=Myeloma, and Placenta;
RX PubMed=2261637; DOI=10.1016/0092-8674(90)90411-7;
RA Hibi M., Murakami M., Saito M., Hirano T., Taga T., Kishimoto T.;
RT "Molecular cloning and expression of an IL-6 signal transducer,
RT gp130.";
RL Cell 63:1149-1157(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANT VAL-8.
RC TISSUE=Synovium;
RX PubMed=10880057; DOI=10.1172/JCI7479;
RA Tanaka M., Kishimura M., Ozaki S., Osakada F., Hashimoto H., Okubo M.,
RA Murakami M., Nakao K.;
RT "Cloning of novel soluble gp130 and detection of its neutralizing
RT autoantibodies in rheumatoid arthritis.";
RL J. Clin. Invest. 106:137-144(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RA Hayashi A., Sameshima E., Tabata Y., Iida K., Mitsuyama M., Kanai S.,
RA Furuya T., Saito T.;
RT "IL6ST mRNA, nirs splice variant 4.";
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Livingston R.J., Shaffer T., McFarland I., Nguyen C.P., Stanaway I.B.,
RA Rajkumar N., Johnson E.J., da Ponte S.H., Willa H., Ahearn M.O.,
RA Bertucci C., Acklestad J., Carroll A., Swanson J., Gildersleeve H.I.,
RA Nickerson D.A.;
RL Submitted (OCT-2006) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [6]
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 [7]
RP PARTIAL PROTEIN SEQUENCE, DISULFIDE BONDS, AND GLYCOSYLATION AT
RP ASN-43; ASN-83; ASN-131; ASN-157; ASN-227; ASN-379; ASN-383; ASN-553
RP AND ASN-564.
RX PubMed=11098061; DOI=10.1074/jbc.M009979200;
RA Moritz R.L., Hall N.E., Connolly L.M., Simpson R.J.;
RT "Determination of the disulfide structure and N-glycosylation sites of
RT the extracellular domain of the human signal transducer gp130.";
RL J. Biol. Chem. 276:8244-8253(2001).
RN [8]
RP SUBUNIT, AND INDUCTION.
RX PubMed=8999038; DOI=10.1074/jbc.271.51.32635;
RA Mosley B., De Imus C., Friend D., Boiani N., Thoma B., Park L.S.,
RA Cosman D.;
RT "Dual oncostatin M (OSM) receptors. Cloning and characterization of an
RT alternative signaling subunit conferring OSM-specific receptor
RT activation.";
RL J. Biol. Chem. 271:32635-32643(1996).
RN [9]
RP INTERACTION WITH HCK.
RX PubMed=9406996;
RA Hallek M., Neumann C., Schaffer M., Danhauser-Riedl S.,
RA von Bubnoff N., de Vos G., Druker B.J., Yasukawa K., Griffin J.D.,
RA Emmerich B.;
RT "Signal transduction of interleukin-6 involves tyrosine
RT phosphorylation of multiple cytosolic proteins and activation of Src-
RT family kinases Fyn, Hck, and Lyn in multiple myeloma cell lines.";
RL Exp. Hematol. 25:1367-1377(1997).
RN [10]
RP PHOSPHORYLATION AT SER-782, MUTAGENESIS OF SER-782, AND MASS
RP SPECTROMETRY.
RX PubMed=10811661; DOI=10.1074/jbc.M907658199;
RA Gibson R.M., Schiemann W.P., Prichard L.B., Reno J.M., Ericsson L.H.,
RA Nathanson N.M.;
RT "Phosphorylation of human gp130 at Ser-782 adjacent to the di-leucine
RT internalization motif. Effects on expression and signaling.";
RL J. Biol. Chem. 275:22574-22582(2000).
RN [11]
RP INTERACTION WITH HHV-8 PROTEIN VIL6.
RX PubMed=11238858; DOI=10.1128/JVI.75.7.3325-3334.2001;
RA Li H., Wang H., Nicholas J.;
RT "Detection of direct binding of human herpesvirus 8-encoded
RT interleukin-6 (vIL-6) to both gp130 and IL-6 receptor (IL-6R) and
RT identification of amino acid residues of vIL-6 important for IL-6R-
RT dependent and -independent signaling.";
RL J. Virol. 75:3325-3334(2001).
RN [12]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-379 AND ASN-383, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-829, AND MASS
RP SPECTROMETRY.
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 [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-667, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-227 AND ASN-390, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [17]
RP GLYCOSYLATION AT ASN-390.
RX PubMed=19139490; DOI=10.1074/mcp.M800504-MCP200;
RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-667, AND MASS
RP 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 [19]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 122-325.
RX PubMed=9501088; DOI=10.1093/emboj/17.6.1665;
RA Bravo J., Staunton D., Heath J.K., Jones E.Y.;
RT "Crystal structure of a cytokine-binding region of gp130.";
RL EMBO J. 17:1665-1674(1998).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 23-325 IN COMPLEX WITH HERPES
RP VIRUS IL6, SUBUNIT, AND GLYCOSYLATION.
RX PubMed=11251120; DOI=10.1126/science.1058308;
RA Chow D.-C., He X.-L., Snow A.L., Rose-John S., Garcia K.C.;
RT "Structure of an extracellular gp130 cytokine receptor signaling
RT complex.";
RL Science 291:2150-2155(2001).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 123-323 IN COMPLEX WITH LIF.
RX PubMed=14527405; DOI=10.1016/S1097-2765(03)00365-4;
RA Boulanger M.J., Bankovich A.J., Kortemme T., Baker D., Garcia K.C.;
RT "Convergent mechanisms for recognition of divergent cytokines by the
RT shared signaling receptor gp130.";
RL Mol. Cell 12:577-589(2003).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (3.65 ANGSTROMS) OF 23-321 IN COMPLEX WITH IL6
RP AND IL6R, AND SUBUNIT.
RX PubMed=12829785; DOI=10.1126/science.1083901;
RA Boulanger M.J., Chow D.-C., Brevnova E.E., Garcia K.C.;
RT "Hexameric structure and assembly of the interleukin-6/IL-6 alpha-
RT receptor/gp130 complex.";
RL Science 300:2101-2104(2003).
RN [23]
RP VARIANT [LARGE SCALE ANALYSIS] ILE-415.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Signal-transducing molecule. The receptor systems for
CC IL6, LIF, OSM, CNTF, IL11, CTF1 and BSF3 can utilize gp130 for
CC initiating signal transmission. Binds to IL6/IL6R (alpha chain)
CC complex, resulting in the formation of high-affinity IL6 binding
CC sites, and transduces the signal. Does not bind IL6. May have a
CC role in embryonic development (By similarity). The type I OSM
CC receptor is capable of transducing OSM-specific signaling events.
CC -!- SUBUNIT: Interacts with INPP5D/SHIP1 (By similarity). Forms
CC heterodimers composed of LIPR and IL6ST (type I OSM receptor).
CC Also forms heterodimers composed of OSMR and IL6ST (type II OSM
CC receptor). Homodimer. The homodimer binds two molecules of herpes
CC virus 8/HHV-8 protein vIL-6. Component of a hexamer of two
CC molecules each of IL6, IL6R and IL6ST. Interacts with HCK.
CC -!- INTERACTION:
CC P42227:Stat3 (xeno); NbExp=6; IntAct=EBI-1030834, EBI-602878;
CC -!- SUBCELLULAR LOCATION: Isoform 1: Cell membrane; Single-pass type I
CC membrane protein.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P40189-1; Sequence=Displayed;
CC Name=2; Synonyms=GP130-RAPS;
CC IsoId=P40189-2; Sequence=VSP_001684, VSP_001685;
CC Name=3;
CC IsoId=P40189-3; Sequence=VSP_043716;
CC -!- TISSUE SPECIFICITY: Found in all the tissues and cell lines
CC examined. Expression not restricted to IL6 responsive cells.
CC -!- INDUCTION: LIF and OSM activate the type I OSM receptor while only
CC OSM can activate the type II OSM receptor.
CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein
CC folding and thereby efficient intracellular transport and cell-
CC surface receptor binding.
CC -!- DOMAIN: The box 1 motif is required for JAK interaction and/or
CC activation.
CC -!- PTM: Phosphorylation of Ser-782 down-regulates cell surface
CC expression.
CC -!- PTM: Heavily N-glycosylated.
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 2
CC subfamily.
CC -!- SIMILARITY: Contains 5 fibronectin type-III domains.
CC -!- SIMILARITY: Contains 1 Ig-like C2-type (immunoglobulin-like)
CC domain.
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DR EMBL; M57230; AAA59155.1; -; mRNA.
DR EMBL; AB015706; BAA78112.1; -; mRNA.
DR EMBL; AB102802; BAD89393.1; -; mRNA.
DR EMBL; EF064722; ABK41905.1; -; Genomic_DNA.
DR EMBL; AC008914; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC016596; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471123; EAW54936.1; -; Genomic_DNA.
DR PIR; A36337; A36337.
DR RefSeq; NP_001177910.1; NM_001190981.1.
DR RefSeq; NP_002175.2; NM_002184.3.
DR RefSeq; NP_786943.1; NM_175767.2.
DR UniGene; Hs.532082; -.
DR UniGene; Hs.706627; -.
DR PDB; 1BJ8; NMR; -; A=219-325.
DR PDB; 1BQU; X-ray; 2.00 A; A/B=122-333.
DR PDB; 1I1R; X-ray; 2.40 A; A=23-325.
DR PDB; 1N2Q; Model; -; A/B=23-324.
DR PDB; 1P9M; X-ray; 3.65 A; A=23-321.
DR PDB; 1PVH; X-ray; 2.50 A; A/C=123-323.
DR PDB; 3L5H; X-ray; 3.60 A; A=24-612.
DR PDB; 3L5I; X-ray; 1.90 A; A=323-612.
DR PDB; 3L5J; X-ray; 3.04 A; A/B=323-610.
DR PDBsum; 1BJ8; -.
DR PDBsum; 1BQU; -.
DR PDBsum; 1I1R; -.
DR PDBsum; 1N2Q; -.
DR PDBsum; 1P9M; -.
DR PDBsum; 1PVH; -.
DR PDBsum; 3L5H; -.
DR PDBsum; 3L5I; -.
DR PDBsum; 3L5J; -.
DR ProteinModelPortal; P40189; -.
DR SMR; P40189; 24-612.
DR DIP; DIP-95N; -.
DR IntAct; P40189; 7.
DR MINT; MINT-130473; -.
DR STRING; 9606.ENSP00000338799; -.
DR PhosphoSite; P40189; -.
DR DMDM; 215273999; -.
DR PaxDb; P40189; -.
DR PRIDE; P40189; -.
DR DNASU; 3572; -.
DR Ensembl; ENST00000336909; ENSP00000338799; ENSG00000134352.
DR Ensembl; ENST00000381287; ENSP00000370687; ENSG00000134352.
DR Ensembl; ENST00000381294; ENSP00000370694; ENSG00000134352.
DR Ensembl; ENST00000381298; ENSP00000370698; ENSG00000134352.
DR Ensembl; ENST00000502326; ENSP00000462158; ENSG00000134352.
DR Ensembl; ENST00000522633; ENSP00000435399; ENSG00000134352.
DR Ensembl; ENST00000536319; ENSP00000444456; ENSG00000134352.
DR GeneID; 3572; -.
DR KEGG; hsa:3572; -.
DR UCSC; uc003jqq.3; human.
DR CTD; 3572; -.
DR GeneCards; GC05M055230; -.
DR HGNC; HGNC:6021; IL6ST.
DR HPA; CAB025784; -.
DR HPA; HPA010558; -.
DR MIM; 600694; gene.
DR neXtProt; NX_P40189; -.
DR PharmGKB; PA29837; -.
DR eggNOG; NOG145009; -.
DR HOGENOM; HOG000015771; -.
DR HOVERGEN; HBG052119; -.
DR InParanoid; P40189; -.
DR KO; K05060; -.
DR OMA; FKQNCSQ; -.
DR OrthoDB; EOG7FXZXN; -.
DR PhylomeDB; P40189; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P40189; -.
DR ChiTaRS; IL6ST; human.
DR EvolutionaryTrace; P40189; -.
DR GeneWiki; Glycoprotein_130; -.
DR GenomeRNAi; 3572; -.
DR NextBio; 13960; -.
DR PRO; PR:P40189; -.
DR ArrayExpress; P40189; -.
DR Bgee; P40189; -.
DR CleanEx; HS_IL6ST; -.
DR Genevestigator; P40189; -.
DR GO; GO:0070110; C:ciliary neurotrophic factor receptor complex; IDA:BHF-UCL.
DR GO; GO:0030425; C:dendrite; IEA:Ensembl.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005896; C:interleukin-6 receptor complex; IDA:BHF-UCL.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0005900; C:oncostatin-M receptor complex; IDA:BHF-UCL.
DR GO; GO:0004897; F:ciliary neurotrophic factor receptor activity; IDA:BHF-UCL.
DR GO; GO:0004921; F:interleukin-11 receptor activity; IEA:Ensembl.
DR GO; GO:0045509; F:interleukin-27 receptor activity; IC:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; TAS:BHF-UCL.
DR GO; GO:0005977; P:glycogen metabolic process; IEA:Ensembl.
DR GO; GO:0070102; P:interleukin-6-mediated signaling pathway; IMP:BHF-UCL.
DR GO; GO:0048861; P:leukemia inhibitory factor signaling pathway; IGI:BHF-UCL.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:BHF-UCL.
DR GO; GO:0070104; P:negative regulation of interleukin-6-mediated signaling pathway; IDA:BHF-UCL.
DR GO; GO:0038165; P:oncostatin-M-mediated signaling pathway; IMP:BHF-UCL.
DR GO; GO:0002675; P:positive regulation of acute inflammatory response; IC:BHF-UCL.
DR GO; GO:0002821; P:positive regulation of adaptive immune response; IC:BHF-UCL.
DR GO; GO:0048711; P:positive regulation of astrocyte differentiation; IEA:Ensembl.
DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; TAS:BHF-UCL.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; IMP:BHF-UCL.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IMP:BHF-UCL.
DR GO; GO:0042511; P:positive regulation of tyrosine phosphorylation of Stat1 protein; IMP:BHF-UCL.
DR GO; GO:0042517; P:positive regulation of tyrosine phosphorylation of Stat3 protein; IMP:BHF-UCL.
DR GO; GO:0010575; P:positive regulation vascular endothelial growth factor production; TAS:BHF-UCL.
DR GO; GO:0008593; P:regulation of Notch signaling pathway; IEA:Ensembl.
DR Gene3D; 2.60.40.10; -; 5.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR003529; Hematopoietin_rcpt_Gp130_CS.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR010457; IgC2-like_lig-bd.
DR InterPro; IPR015321; IL-6_rcpt_alpha-bd.
DR Pfam; PF00041; fn3; 2.
DR Pfam; PF09240; IL6Ra-bind; 1.
DR Pfam; PF06328; Lep_receptor_Ig; 1.
DR SMART; SM00060; FN3; 5.
DR SUPFAM; SSF49265; SSF49265; 5.
DR PROSITE; PS50853; FN3; 4.
DR PROSITE; PS01353; HEMATOPO_REC_L_F2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Host-virus interaction; Immunoglobulin domain; Membrane;
KW Phosphoprotein; Polymorphism; Receptor; Reference proteome; Repeat;
KW Secreted; Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1 22
FT CHAIN 23 918 Interleukin-6 receptor subunit beta.
FT /FTId=PRO_0000010899.
FT TOPO_DOM 23 619 Extracellular (Potential).
FT TRANSMEM 620 641 Helical; (Potential).
FT TOPO_DOM 642 918 Cytoplasmic (Potential).
FT DOMAIN 26 120 Ig-like C2-type.
FT DOMAIN 125 216 Fibronectin type-III 1.
FT DOMAIN 224 324 Fibronectin type-III 2.
FT DOMAIN 329 424 Fibronectin type-III 3.
FT DOMAIN 426 517 Fibronectin type-III 4.
FT DOMAIN 518 613 Fibronectin type-III 5.
FT MOTIF 310 314 WSXWS motif.
FT MOTIF 651 659 Box 1 motif.
FT COMPBIAS 725 755 Ser-rich.
FT MOD_RES 667 667 Phosphoserine.
FT MOD_RES 782 782 Phosphoserine.
FT MOD_RES 829 829 Phosphoserine.
FT CARBOHYD 43 43 N-linked (GlcNAc...).
FT CARBOHYD 83 83 N-linked (GlcNAc...).
FT CARBOHYD 131 131 N-linked (GlcNAc...).
FT CARBOHYD 157 157 N-linked (GlcNAc...).
FT CARBOHYD 227 227 N-linked (GlcNAc...).
FT CARBOHYD 379 379 N-linked (GlcNAc...).
FT CARBOHYD 383 383 N-linked (GlcNAc...).
FT CARBOHYD 390 390 N-linked (GlcNAc...) (complex).
FT CARBOHYD 553 553 N-linked (GlcNAc...).
FT CARBOHYD 564 564 N-linked (GlcNAc...).
FT DISULFID 28 54
FT DISULFID 48 103
FT DISULFID 134 144
FT DISULFID 172 182
FT DISULFID 458 466
FT VAR_SEQ 325 329 RPSKA -> NIASF (in isoform 2).
FT /FTId=VSP_001684.
FT VAR_SEQ 330 918 Missing (in isoform 2).
FT /FTId=VSP_001685.
FT VAR_SEQ 423 483 Missing (in isoform 3).
FT /FTId=VSP_043716.
FT VARIANT 8 8 L -> V (in dbSNP:rs1063560).
FT /FTId=VAR_047782.
FT VARIANT 148 148 G -> R (in dbSNP:rs2228044).
FT /FTId=VAR_047783.
FT VARIANT 397 397 L -> V (in dbSNP:rs2228043).
FT /FTId=VAR_047784.
FT VARIANT 415 415 T -> I (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036165.
FT VARIANT 454 454 I -> T (in dbSNP:rs2228046).
FT /FTId=VAR_047785.
FT VARIANT 499 499 V -> I (in dbSNP:rs34417936).
FT /FTId=VAR_047786.
FT MUTAGEN 782 782 S->A: Increases cell surface expression.
FT STRAND 28 35
FT STRAND 37 39
FT STRAND 44 50
FT HELIX 52 58
FT HELIX 62 64
FT STRAND 65 69
FT HELIX 76 78
FT STRAND 80 83
FT STRAND 86 91
FT STRAND 97 107
FT TURN 108 110
FT STRAND 111 123
FT STRAND 130 137
FT STRAND 143 147
FT STRAND 157 164
FT STRAND 176 178
FT STRAND 181 183
FT STRAND 194 202
FT STRAND 205 208
FT STRAND 212 214
FT HELIX 216 218
FT STRAND 219 221
FT STRAND 226 231
FT STRAND 234 238
FT STRAND 240 245
FT HELIX 248 251
FT STRAND 255 263
FT HELIX 274 277
FT STRAND 282 286
FT STRAND 291 303
FT STRAND 317 321
FT HELIX 325 331
FT STRAND 332 338
FT STRAND 345 351
FT HELIX 356 359
FT STRAND 363 372
FT STRAND 378 391
FT STRAND 396 406
FT STRAND 412 416
FT STRAND 428 435
FT STRAND 438 444
FT STRAND 452 460
FT STRAND 462 464
FT STRAND 469 474
FT STRAND 478 481
FT STRAND 491 500
FT STRAND 508 515
FT STRAND 525 530
FT STRAND 535 539
FT HELIX 544 547
FT STRAND 553 560
FT STRAND 566 571
FT STRAND 575 579
FT STRAND 587 596
FT STRAND 599 602
FT STRAND 606 609
SQ SEQUENCE 918 AA; 103537 MW; 6510A4409FFCF08C CRC64;
MLTLQTWLVQ ALFIFLTTES TGELLDPCGY ISPESPVVQL HSNFTAVCVL KEKCMDYFHV
NANYIVWKTN HFTIPKEQYT IINRTASSVT FTDIASLNIQ LTCNILTFGQ LEQNVYGITI
ISGLPPEKPK NLSCIVNEGK KMRCEWDGGR ETHLETNFTL KSEWATHKFA DCKAKRDTPT
SCTVDYSTVY FVNIEVWVEA ENALGKVTSD HINFDPVYKV KPNPPHNLSV INSEELSSIL
KLTWTNPSIK SVIILKYNIQ YRTKDASTWS QIPPEDTAST RSSFTVQDLK PFTEYVFRIR
CMKEDGKGYW SDWSEEASGI TYEDRPSKAP SFWYKIDPSH TQGYRTVQLV WKTLPPFEAN
GKILDYEVTL TRWKSHLQNY TVNATKLTVN LTNDRYLATL TVRNLVGKSD AAVLTIPACD
FQATHPVMDL KAFPKDNMLW VEWTTPRESV KKYILEWCVL SDKAPCITDW QQEDGTVHRT
YLRGNLAESK CYLITVTPVY ADGPGSPESI KAYLKQAPPS KGPTVRTKKV GKNEAVLEWD
QLPVDVQNGF IRNYTIFYRT IIGNETAVNV DSSHTEYTLS SLTSDTLYMV RMAAYTDEGG
KDGPEFTFTT PKFAQGEIEA IVVPVCLAFL LTTLLGVLFC FNKRDLIKKH IWPNVPDPSK
SHIAQWSPHT PPRHNFNSKD QMYSDGNFTD VSVVEIEAND KKPFPEDLKS LDLFKKEKIN
TEGHSSGIGG SSCMSSSRPS ISSSDENESS QNTSSTVQYS TVVHSGYRHQ VPSVQVFSRS
ESTQPLLDSE ERPEDLQLVD HVDGGDGILP RQQYFKQNCS QHESSPDISH FERSKQVSSV
NEEDFVRLKQ QISDHISQSC GSGQMKMFQE VSAADAFGPG TEGQVERFET VGMEAATDEG
MPKSYLPQTV RQGGYMPQ
//
MIM
600694
*RECORD*
*FIELD* NO
600694
*FIELD* TI
*600694 INTERLEUKIN 6 SIGNAL TRANSDUCER; IL6ST
;;GP130 TRANSDUCER CHAIN; GP130
*FIELD* TX
read more
DESCRIPTION
Initially described as the interleukin-6 signal transducer, gp130 is a
transducer chain shared by many cytokines, including IL6 (147620), IL11
(147681), leukemia inhibitory factor (LIF; 159540), oncostatin M (OSM;
165095), and ciliary neurotrophic factor (CNTF; 118945), as reviewed by
Kishimoto et al. (1994). All of these cytokines act via a bi- or
tripartite receptor complex in which signaling is triggered by
homodimerization (IL6) or heterodimerization with LIF-Rb/gp190 protein
(IL11, LIF, OSM, and CNTF) of gp130. These cytokines thus mediate
similar biologic activities in various tissues. See also IL6RA (147880).
CLONING
By immunoscreening a placenta cDNA expression library with antibodies to
human gp130, followed by screening a myeloma cell line cDNA library,
Hibi et al. (1990) cloned gp130. The deduced 918-amino acid protein has
an N-terminal signal peptide, followed by a 597-amino acid extracellular
region, a transmembrane domain, and a 277-amino acid cytoplasmic domain.
It also contains 14 potential N-glycosylation sites. The mature
896-amino acid protein has a calculated molecular mass of 101 kD. Part
of the extracellular region, including 4 conserved cysteines and a WSxWS
motif, shows significant homology with cytokine receptors. Gp130 is most
closely related to GCSFR (CSF3R; 138971). Both receptors contain 6
fibronectin (135600) type III modules in the extracellular region. The
intracellular domain has a consensus nucleotide-binding domain, but it
has no protein kinase catalytic domain. Four sequences in the
intracellular domain are similar to GTP-binding motifs of RAS
(190020)-related proteins. Northern blot analysis detected a 7.0-kb
transcript in all cell lines examined. Gp130 showed an apparent
molecular mass of 130 kD by SDS-PAGE.
Saito et al. (1992) cloned mouse gp130. The deduced 917-amino acid
protein has a domain structure equivalent to that of human gp130,
including 4 conserved cysteines and the 4 GTP-binding motif-like
sequences. Mouse and human gp130 share 76.8% amino acid homology,
including 100% identity in a 116-amino acid stretch that spans the
transmembrane domain. Northern blot analysis detected 7.0- and 10.0-kb
transcripts expressed in varying ratios in all tissues examined. Lowest
expression was in spleen. During mouse embryonic development, robust
expression of both gp130 transcripts was detected on day 6, and
expression peaked on day 8.
Narazaki et al. (1993) purified 2 soluble forms of gp130 (sgp130) from
human serum. These proteins had apparent molecular masses of 90 and 110
kD.
Diamant et al. (1997) cloned sgp130 from a peripheral blood mononuclear
cell cDNA library. The deduced protein contains 624 amino acids. Diamant
et al. (1997) determined that the sgp130 transcript results from
alternative splicing and includes an 85-bp exon just before the
transmembrane-coding exon. This insertion results in a frameshift, and
the sequence following the insertion encodes 4 amino acids not found in
full-length membrane-bound gp130, followed by a stop codon 1 bp from the
transmembrane-coding region. PCR analysis detected expression of sgp130
in all myeloma cell lines tested except 1 line growing independent of
IL6 stimulation. Chinese hamster ovary (CHO) cells transfected with
sgp130 secreted the protein into the medium. Some sgp130 was also
secreted by CHO cells transfected with cDNA encoding full-length gp130,
but at a much lower concentration. Diamant et al. (1997) concluded that
sgp130 could be generated both by shedding and by expressing an
alternatively spliced transcript.
GENE FUNCTION
Hibi et al. (1990) determined that cells transfected with IL6RA
expressed mainly low-affinity IL6-binding sites. Cotransfection of gp130
cDNA increased the number of high-affinity binding sites, but gp130 did
not directly bind IL6 or several other cytokines. Mouse IL3
(147740)-dependent pre-B cells proliferated when cultured with IL6 plus
soluble IL6RA only following transfection with human gp130. Hibi et al.
(1990) concluded that gp130 is involved in the formation of
high-affinity IL6-binding sites and in IL6 signal transduction.
Murakami et al. (1991) analyzed C-terminal truncation mutants of gp130.
Mutants retaining only the last 10 amino acids of the 277-amino acid
C-terminal region proximal to the transmembrane domain were capable of
binding the IL6/IL6R complex; however, these mutants were unable to
transduce the growth signal following IL6/IL6R complex binding. Signal
transduction required a 61-amino acid region containing 2 short segments
that share homology with other cytokine receptor family members. Gp130
molecules with mutations in either of these segments could not transduce
a growth signal. Loss of signal-transducing ability coincided with loss
of IL6-induced tyrosine phosphorylation of gp130.
Saito et al. (1992) determined that administration of IL6 in mice caused
upregulation of gp130 mRNA in several tissues. In liver, both gp130 and
Il6ra mRNA were upregulated by IL6.
Narazaki et al. (1993) determined that sgp130 within human serum or
exogenous recombinant sgp130 inhibited growth of transfected mouse pre-B
cells induced by the IL6/IL6R complex. Recombinant sgp130 also inhibited
growth in erythroleukemia cells stimulated by OSM or the CNTF/CNTFR
(118946) complex in a dose-dependent manner. Recombinant sgp130 was less
inhibitory to growth induced by LIF or the IL6/IL6R complex. Narazaki et
al. (1993) concluded that sgp130 has a role in modulating signals
transduced by membrane-bound gp130.
Chow et al. (2001) noted that cytokines that activate gp130 share a
common 4-helix bundle fold and that gp130 recognition of ligands occurs
through its cytokine-binding homology region, located at domains 2 and
3. In addition, activation occurs through a separate N-terminal, Ig-like
domain (domain 1). Kaposi sarcoma-associated herpesvirus (KSHV, or
HHV-8) encodes a functional homolog of IL6 (termed vIL6; 25% sequence
homology) that is expressed in KSHV-infected cells and is able to induce
angiogenesis and hematopoiesis in IL6-dependent cell lines. In contrast
to IL6, which binds to gp130 only after it forms a complex with IL6RA,
vIL6 directly activates gp130. By crystal structure analysis, Chow et
al. (2001) demonstrated that in the extracellular signaling assembly
between vIL6 and gp130, 2 complexes are cross-linked into a tetramer
through direct interactions between the Ig domain of gp130 and site III
of vIL6, which is necessary for gp130 activation. Unlike IL6, vIL6 uses
mainly hydrophobic residues to contact gp130, enhancing the
complementarity of the vIL6-gp130 binding interfaces. Identical
positions of 2 disulfide bonds in IL6 and vIL6 and the high conservation
of the hydrophobic core residues account for the reproduction of the
helical scaffold by vIL6, enabling gp130 contact.
Pflanz et al. (2004) found that transfection of WSX1 (605350) into a
cell line expressing gp130 but only low levels of WSX1 resulted in IL27
(see 605816)-dependent phosphorylation of STAT1 (600555) and STAT3
(102582). In addition, they showed that anti-gp130 blocked IL27-mediated
cellular effects. Quantitative PCR analysis indicated that, in addition
to naive CD4 (186940)-positive T cells, numerous cell types expressed
both gp130 and WSX1, including mast cells. IL27 stimulation of mast
cells resulted in upregulation of proinflammatory cytokine expression.
Pflanz et al. (2004) concluded that IL27 not only contributes to the
development of an adaptive immune response through its action on
CD4-positive T cells, but also directly acts on cells of the innate
immune system.
BIOCHEMICAL FEATURES
- Crystal Structure
IL6 is an immunoregulatory cytokine that activates a cell-surface
signaling assembly composed of IL6, IL6RA, and the shared signaling
receptor gp130. Boulanger et al. (2003) solved the crystal structure of
the extracellular signaling complex to 3.65-angstrom resolution, which
revealed a hexameric, interlocking assembly mediated by a total of 10
symmetry-related, thermodynamically coupled interfaces. Assembly of the
hexameric complex occurs sequentially: IL6 is first engaged by
IL6R-alpha and then presented to gp130 in the proper geometry to
facilitate a cooperative transition into the high affinity,
signaling-competent hexamer. The quaternary structures of other IL6/IL12
family signaling complexes are likely constructed by means of a similar
topologic blueprint.
GENE STRUCTURE
Szalai et al. (2000) determined that the IL6ST gene contains 17 exons
and spans about 51 kb.
MAPPING
By fluorescence in situ hybridization, Rodriguez et al. (1995) assigned
the functional IL6ST gene to chromosome 5q11 and its nontranscribed
pseudogene to 17p11.
Hartz (2010) mapped the IL6ST gene to chromosome 5q11.2 based on an
alignment of the IL6ST sequence (GenBank GENBANK AB015706) with the
genomic sequence (GRCh37).
- Pseudogenes
Kidd et al. (1992) concluded that there are 2 functional genes for
IL6ST. Rodriguez et al. (1995) showed, however, that the 2 localizations
correspond to a pseudogene (on chromosome 17) and the functional gene on
chromosome 5.
MOLECULAR GENETICS
Rebouissou et al. (2009) demonstrated a marked activation of the IL6
(147620) signaling pathway in inflammatory hepatocellular adenomas.
Sequencing candidate genes pinpointed the response to somatic
gain-of-function mutations in the IL6ST gene, which encodes the
signaling coreceptor gp130. Rebouissou et al. (2009) found that 60% of
inflammatory hepatocellular adenomas harbor small in-frame deletions
that target the binding sites of gp130 for IL6, and expression of 4
different gp130 mutants in hepatocellular cells activated STAT3 (102582)
in the absence of ligand. Furthermore, analysis of hepatocellular
carcinomas revealed that rare gp130 alterations are always accompanied
by beta-catenin (116806)-activating mutations, suggesting a cooperative
effect of these signaling pathways in the malignant conversion of
hepatocytes. The recurrent gain-of-function gp130 mutations in these
human hepatocellular adenomas fully explains activation of the acute
inflammatory phase observed in tumorous hepatocytes, and suggests that
similar alterations may occur in other inflammatory epithelial tumors
with STAT activation.
ANIMAL MODEL
Using Cre-loxP-mediated recombination to generate mice harboring a
ventricular-restricted knockout of the gp130 cytokine receptor, Hirota
et al. (1999) demonstrated a critical role for a gp130-dependent myocyte
survival pathway in the transition to heart failure. Such conditional
mutant mice have normal cardiac structure and function, but during
aortic pressure overload, these mice displayed rapid onset of dilated
cardiomyopathy and massive induction of myocyte apoptosis compared with
the control mice, which exhibited compensatory hypertrophy. Thus,
cardiac myocyte apoptosis is a critical point in the transition between
compensatory cardiac hypertrophy and heart failure. Hirota et al. (1999)
suggested that gp130-dependent cytokines may represent a novel
therapeutic strategy for preventing in vivo heart failure.
Tebbutt et al. (2002) noted that gp130 contains at least 2
cell-signaling modules. One encompasses 4 phosphotyrosine-binding sites
for the SH2 domains of STAT1 and STAT3, whereas the other includes a
phosphotyrosine that activates SHP2 (176876) upstream of the RAS
(190020)-ERK (see 601795) pathway. Tebbutt et al. (2002) generated mice
carrying targeted mutations in each of these modules. Mice homozygous
for a truncated version of gp130 lacking all Stat-binding sites
spontaneously developed intestinal ulceration at sites associated with
repeated mechanical trauma (gastric pylorus and rectum). Unlike wildtype
mice, those with the Stat-binding domain mutation were unable to recover
from trauma induced by ingestion of sodium dextran sulfate. Tebbutt et
al. (2002) noted that impaired wound healing occurs in Tff3
(600633)-null mice, and biochemical analysis confirmed reduced levels of
Tff3 in the mice with the Stat-binding domain mutation. Mice homozygous
for a tyr757-to-phe (Y757F) mutation, which inactivated the Shp2-binding
domain of gp130, developed normally into superficially healthy adults,
but they showed age-dependent enlargement of the stomach, proximal small
intestine, and spleen. Histologic examination revealed
hyperproliferative lesions within the antropyloric mucosa, often
circumferential, resulting in gastric outlet obstruction. Tebbutt et al.
(2002) noted that the gastric pathology was essentially phenocopied in
Tff1 (113710) null mice, and biochemical analysis of gastric Tff1 levels
in mice with the Shp2-binding domain mutation confirmed a 75% reduction
in comparison with wildtype mice; levels of Tff3 were elevated in the
mutant mice. Using a luciferase reporter assay with cells transiently
transfected with gp130 carrying the Stat- and Shp2-binding domain
mutations, Tebbutt et al. (2002) confirmed simultaneous activation of
the Stat1/Stat3 and Shp2-Ras-Erk pathways in response to IL6 activation,
resulting in enhanced luciferase activity of Tff1-luc and Tff3-luc
reporter constructs. Tebbutt et al. (2002) concluded that the
pathologies observed in the gp130 mutant mice resulted from disruption
of the normally simultaneous and coordinated activation of the
Stat1/Stat3 and Shp2-Ras-Erk signaling cascades.
Atsumi et al. (2002) generated mice with a tyr759-to-phe mutation in the
Shp2-binding site of gp130. These mice developed a rheumatoid arthritis
(RA; 180300)-like joint disease at about 1 year of age, accompanied by
autoantibody production and accumulation of memory/activated T cells and
myeloid cells. Before disease onset, T cells were hyperresponsive in
vitro. Mutant mice that were also Rag2 (179616) deficient did not
develop disease, indicating the importance of lymphocytes in this model.
Atsumi et al. (2002) concluded that point mutation in the gp130 cytokine
receptor can induce autoimmune disease.
Jenkins et al. (2005) assessed the contribution of exaggerated Stat3
activation to the phenotype of mice homozygous for Y757F, which disrupts
the negative feedback mechanism on gp130-dependent Stat signaling
(Tebbutt et al., 2002). They found that development of abnormalities
associated with gp130(Y757F) homozygosity, including reduced life span,
splenomegaly, exaggerated hepatic acute-phase response, and spontaneous
gastric adenomas while young, was attenuated when gp130(Y757F)
homozygosity was expressed on a Stat3 +/- background.
Both bone formation and resorption are altered significantly in gp130
-/- mice. Although the mutation results in neonatal lethality, reduced
trabecular bone mass, associated with an increase in osteoclastogenesis,
is a feature of the neonatal skeleton (Kawasaki et al., 1997; Shin et
al., 2004). Sims et al. (2004) found that mouse strains homozygous for
gp130 mutations in the Stat activation sites had normal trabecular bone
volume and bone turnover, but reduced bone length and premature growth
plate closure, suggesting a role for gp130-STAT1/3 signaling in
chondrocyte differentiation. In contrast, mice with mutations in the
gp130 Shp2-Ras-Mapk (see 176948) activation sites showed normal bone
size, but reduced trabecular bone volume and high bone turnover,
associated with increased osteoclastogenesis. Sims et al. (2004)
concluded that gp130 controls balanced regulation of bone growth and
mass depending on selective activation of distinct downstream signaling
pathways.
*FIELD* RF
1. Atsumi, T.; Ishihara, K.; Kamimura, D.; Ikushima, H.; Ohtani, T.;
Hirota, S.; Kobayashi, H.; Park, S.-J.; Saeki, Y.; Kitamura, Y.; Hirano,
T.: A point mutation of tyr-759 in interleukin 6 family cytokine
receptor gp130 causes autoimmune arthritis. J. Exp. Med. 196: 979-990,
2002.
2. Boulanger, M. J.; Chow, D.; Brevnova, E. E.; Garcia, K. C.: Hexameric
structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130
complex. Science 300: 2101-2104, 2003. Note: Erratum: Science 301:
918 only, 2003.
3. Chow, D.; He, X.; Snow, A. L.; Rose-John, S.; Garcia, K. C.: Structure
of an extracellular gp130 cytokine receptor signaling complex. Science 291:
2150-2155, 2001.
4. Diamant, M.; Rieneck, K.; Mechti, N.; Zhang, X.-G.; Svenson, M.;
Bendtzen, K.; Klein, B.: Cloning and expression of an alternatively
spliced mRNA encoding a soluble form of the human interleukin-6 signal
transducer gp130. FEBS Lett. 412: 379-384, 1997.
5. Hartz, P. A.: Personal Communiation. Baltimore, Md. , 11/22/2010.
6. Hibi, M.; Murakami, M.; Saito, M.; Hirano, T.; Taga, T.; Kishimoto,
T.: Molecular cloning and expression of an IL-6 signal transducer,
gp130. Cell 63: 1149-1157, 1990.
7. Hirota, H.; Chen, J.; Betz, U. A. K.; Rajewsky, K.; Gu, Y.; Ross,
J., Jr.; Muller, W.; Chien, K. R.: Loss of a gp130 cardiac muscle
cell survival pathway is a critical event in the onset of heart failure
during biochemical stress. Cell 97: 189-198, 1999.
8. Jenkins, B. J.; Grail, D.; Nheu, T.; Najkovska, M.; Wang, B.; Waring,
P.; Inglese, M.; McLoughlin, R. M.; Jones, S. A.; Topley, N.; Baumann,
H.; Judd, L. M.; Giraud, A. S.; Boussioutas, A.; Zhu, H.-J.; Ernst,
M.: Hyperactivation of Stat3 in gp130 mutant mice promotes gastric
hyperproliferation and desensitizes TGF-beta signaling. Nature Med. 11:
845-852, 2005.
9. Kawasaki, K.; Gao, Y.-H.; Yokose, S.; Kaji, Y.; Nakamura, T.; Suda,
T.; Yoshida, K.; Taga, T.; Kishimoto, T.; Kataoka, H.; Yuasa, T.;
Norimatsu, H.; Yamaguchi, A.: Osteoclasts are present in gp130-deficient
mice. Endocrinology 138: 4959-4965, 1997.
10. Kidd, V. J.; Nesbitt, J. E.; Fuller, G. M.: Chromosomal localization
of the IL-6 receptor signal transducing subunit, gp130 (IL6ST). Somat.
Cell Molec. Genet. 18: 477-483, 1992.
11. Kishimoto, T.; Taga, T.; Akira, S.: Cytokine signal transduction. Cell 76:
253-262, 1994.
12. Murakami, M.; Narazaki, M.; Hibi, M.; Yawata, H.; Yasukawa, K.;
Hamaguchi, M.; Taga, T.; Kishimoto, T.: Critical cytoplasmic region
of the interleukin 6 signal transducer gp130 is conserved in the cytokine
receptor family. Proc. Nat. Acad. Sci. 88: 11349-11353, 1991.
13. Narazaki, M.; Yasukawa, K.; Saito, T.; Ohsugi, Y.; Fukui, H.;
Koishihara, Y.; Yancopoulos, G. D.; Taga, T.; Kishimoto, T.: Soluble
forms of the interleukin-6 signal-transducing receptor component gp130
in human serum possessing a potential to inhibit signals through membrane-anchored
gp130. Blood 82: 1120-1126, 1993.
14. Pflanz, S.; Hibbert, L.; Mattson, J.; Rosales, R.; Vaisberg, E.;
Bazan, J. F.; Phillips, J. H.; McClanahan, T. K.; de Waal Malefyt,
R.; Kastelein, R. A.: WSX-1 and glycoprotein 130 constitute a signal-transducing
receptor for IL-27. J. Immun. 172: 2225-2231, 2004.
15. Rebouissou, S.; Amessou, M.; Couchy, G.; Poussin, K.; Imbeaud,
S.; Pilati, C.; Izard, T.; Balabaud, C.; Bioulac-Sage, P.; Zucman-Rossi,
J.: Frequent in-frame somatic deletions activate gp130 in inflammatory
hepatocellular tumours. Nature 457: 200-204, 2009.
16. Rodriguez, C.; Grosgeorge, J.; Nguyen, V. C.; Gaudray, P.; Theillet,
C.: Human gp130 transducer chain gene (IL6ST) is localized to chromosome
band 5q11 and possesses a pseudogene on chromosome band 17p11. Cytogenet.
Cell Genet. 70: 64-67, 1995.
17. Saito, M.; Yoshida, K.; Hibi, M.; Taga, T.; Kishimoto, T.: Molecular
cloning of a murine IL-6 receptor-associated signal transducer, gp130,
and its regulated expression in vivo. J. Immun. 148: 4066-4071,
1992.
18. Shin, H.-I.; Divieti, P.; Sims, N. A.; Kobayashi, T.; Miao, D.;
Karaplis, A. C.; Baron, R.; Bringhurst, R.; Kronenberg, H. M.: gp130-mediated
signaling is necessary for normal osteoblastic function in vivo and
in vitro. Endocrinology 145: 1376-1385, 2004.
19. Sims, N. A.; Jenkins, B. J.; Quinn, J. M. W.; Nakamura, A.; Glatt,
M.; Gillespie, M. T.; Ernst, M.; Martin, T. J.: Glycoprotein 130
regulates bone turnover and bone size by distinct downstream signaling
pathways. J. Clin. Invest. 113: 379-389, 2004.
20. Szalai, C.; Toth, S.; Falus, A.: Exon-intron organization of
the human gp130 gene. Gene 243: 161-166, 2000.
21. Tebbutt, N. C.; Giraud, A. S.; Inglese, M.; Jenkins, B.; Waring,
P.; Clay, F. J.; Malki, S.; Alderman, B. M.; Grail, D.; Hollande,
F.; Heath, J. K.; Ernst, M.: Reciprocal regulation of gastrointestinal
homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130
mutant mice. Nature Med. 8: 1089-1097, 2002.
*FIELD* CN
Ada Hamosh - updated: 1/27/2009
Paul J. Converse - updated: 1/5/2006
Patricia A. Hartz - updated: 9/9/2005
Paul J. Converse - updated: 8/11/2004
Patricia A. Hartz - updated: 5/10/2004
Cassandra L. Kniffin - updated: 4/19/2004
Ada Hamosh - updated: 7/8/2003
Patricia A. Hartz - updated: 9/11/2002
Paul J. Converse - updated: 3/19/2001
Stylianos E. Antonarakis - updated: 5/11/1999
*FIELD* CD
Victor A. McKusick: 7/28/1995
*FIELD* ED
terry: 08/06/2012
mgross: 8/3/2012
terry: 8/3/2012
mgross: 11/23/2010
terry: 11/22/2010
alopez: 1/28/2009
terry: 1/27/2009
mgross: 1/5/2006
terry: 10/12/2005
mgross: 9/9/2005
mgross: 8/2/2005
mgross: 8/11/2004
terry: 6/18/2004
mgross: 5/11/2004
terry: 5/10/2004
tkritzer: 4/21/2004
ckniffin: 4/19/2004
tkritzer: 11/4/2003
alopez: 7/10/2003
terry: 7/8/2003
alopez: 10/18/2002
mgross: 9/12/2002
mgross: 9/11/2002
mgross: 3/20/2001
mgross: 3/19/2001
mgross: 5/12/1999
mgross: 5/11/1999
dkim: 7/2/1998
mark: 7/28/1995
*RECORD*
*FIELD* NO
600694
*FIELD* TI
*600694 INTERLEUKIN 6 SIGNAL TRANSDUCER; IL6ST
;;GP130 TRANSDUCER CHAIN; GP130
*FIELD* TX
read more
DESCRIPTION
Initially described as the interleukin-6 signal transducer, gp130 is a
transducer chain shared by many cytokines, including IL6 (147620), IL11
(147681), leukemia inhibitory factor (LIF; 159540), oncostatin M (OSM;
165095), and ciliary neurotrophic factor (CNTF; 118945), as reviewed by
Kishimoto et al. (1994). All of these cytokines act via a bi- or
tripartite receptor complex in which signaling is triggered by
homodimerization (IL6) or heterodimerization with LIF-Rb/gp190 protein
(IL11, LIF, OSM, and CNTF) of gp130. These cytokines thus mediate
similar biologic activities in various tissues. See also IL6RA (147880).
CLONING
By immunoscreening a placenta cDNA expression library with antibodies to
human gp130, followed by screening a myeloma cell line cDNA library,
Hibi et al. (1990) cloned gp130. The deduced 918-amino acid protein has
an N-terminal signal peptide, followed by a 597-amino acid extracellular
region, a transmembrane domain, and a 277-amino acid cytoplasmic domain.
It also contains 14 potential N-glycosylation sites. The mature
896-amino acid protein has a calculated molecular mass of 101 kD. Part
of the extracellular region, including 4 conserved cysteines and a WSxWS
motif, shows significant homology with cytokine receptors. Gp130 is most
closely related to GCSFR (CSF3R; 138971). Both receptors contain 6
fibronectin (135600) type III modules in the extracellular region. The
intracellular domain has a consensus nucleotide-binding domain, but it
has no protein kinase catalytic domain. Four sequences in the
intracellular domain are similar to GTP-binding motifs of RAS
(190020)-related proteins. Northern blot analysis detected a 7.0-kb
transcript in all cell lines examined. Gp130 showed an apparent
molecular mass of 130 kD by SDS-PAGE.
Saito et al. (1992) cloned mouse gp130. The deduced 917-amino acid
protein has a domain structure equivalent to that of human gp130,
including 4 conserved cysteines and the 4 GTP-binding motif-like
sequences. Mouse and human gp130 share 76.8% amino acid homology,
including 100% identity in a 116-amino acid stretch that spans the
transmembrane domain. Northern blot analysis detected 7.0- and 10.0-kb
transcripts expressed in varying ratios in all tissues examined. Lowest
expression was in spleen. During mouse embryonic development, robust
expression of both gp130 transcripts was detected on day 6, and
expression peaked on day 8.
Narazaki et al. (1993) purified 2 soluble forms of gp130 (sgp130) from
human serum. These proteins had apparent molecular masses of 90 and 110
kD.
Diamant et al. (1997) cloned sgp130 from a peripheral blood mononuclear
cell cDNA library. The deduced protein contains 624 amino acids. Diamant
et al. (1997) determined that the sgp130 transcript results from
alternative splicing and includes an 85-bp exon just before the
transmembrane-coding exon. This insertion results in a frameshift, and
the sequence following the insertion encodes 4 amino acids not found in
full-length membrane-bound gp130, followed by a stop codon 1 bp from the
transmembrane-coding region. PCR analysis detected expression of sgp130
in all myeloma cell lines tested except 1 line growing independent of
IL6 stimulation. Chinese hamster ovary (CHO) cells transfected with
sgp130 secreted the protein into the medium. Some sgp130 was also
secreted by CHO cells transfected with cDNA encoding full-length gp130,
but at a much lower concentration. Diamant et al. (1997) concluded that
sgp130 could be generated both by shedding and by expressing an
alternatively spliced transcript.
GENE FUNCTION
Hibi et al. (1990) determined that cells transfected with IL6RA
expressed mainly low-affinity IL6-binding sites. Cotransfection of gp130
cDNA increased the number of high-affinity binding sites, but gp130 did
not directly bind IL6 or several other cytokines. Mouse IL3
(147740)-dependent pre-B cells proliferated when cultured with IL6 plus
soluble IL6RA only following transfection with human gp130. Hibi et al.
(1990) concluded that gp130 is involved in the formation of
high-affinity IL6-binding sites and in IL6 signal transduction.
Murakami et al. (1991) analyzed C-terminal truncation mutants of gp130.
Mutants retaining only the last 10 amino acids of the 277-amino acid
C-terminal region proximal to the transmembrane domain were capable of
binding the IL6/IL6R complex; however, these mutants were unable to
transduce the growth signal following IL6/IL6R complex binding. Signal
transduction required a 61-amino acid region containing 2 short segments
that share homology with other cytokine receptor family members. Gp130
molecules with mutations in either of these segments could not transduce
a growth signal. Loss of signal-transducing ability coincided with loss
of IL6-induced tyrosine phosphorylation of gp130.
Saito et al. (1992) determined that administration of IL6 in mice caused
upregulation of gp130 mRNA in several tissues. In liver, both gp130 and
Il6ra mRNA were upregulated by IL6.
Narazaki et al. (1993) determined that sgp130 within human serum or
exogenous recombinant sgp130 inhibited growth of transfected mouse pre-B
cells induced by the IL6/IL6R complex. Recombinant sgp130 also inhibited
growth in erythroleukemia cells stimulated by OSM or the CNTF/CNTFR
(118946) complex in a dose-dependent manner. Recombinant sgp130 was less
inhibitory to growth induced by LIF or the IL6/IL6R complex. Narazaki et
al. (1993) concluded that sgp130 has a role in modulating signals
transduced by membrane-bound gp130.
Chow et al. (2001) noted that cytokines that activate gp130 share a
common 4-helix bundle fold and that gp130 recognition of ligands occurs
through its cytokine-binding homology region, located at domains 2 and
3. In addition, activation occurs through a separate N-terminal, Ig-like
domain (domain 1). Kaposi sarcoma-associated herpesvirus (KSHV, or
HHV-8) encodes a functional homolog of IL6 (termed vIL6; 25% sequence
homology) that is expressed in KSHV-infected cells and is able to induce
angiogenesis and hematopoiesis in IL6-dependent cell lines. In contrast
to IL6, which binds to gp130 only after it forms a complex with IL6RA,
vIL6 directly activates gp130. By crystal structure analysis, Chow et
al. (2001) demonstrated that in the extracellular signaling assembly
between vIL6 and gp130, 2 complexes are cross-linked into a tetramer
through direct interactions between the Ig domain of gp130 and site III
of vIL6, which is necessary for gp130 activation. Unlike IL6, vIL6 uses
mainly hydrophobic residues to contact gp130, enhancing the
complementarity of the vIL6-gp130 binding interfaces. Identical
positions of 2 disulfide bonds in IL6 and vIL6 and the high conservation
of the hydrophobic core residues account for the reproduction of the
helical scaffold by vIL6, enabling gp130 contact.
Pflanz et al. (2004) found that transfection of WSX1 (605350) into a
cell line expressing gp130 but only low levels of WSX1 resulted in IL27
(see 605816)-dependent phosphorylation of STAT1 (600555) and STAT3
(102582). In addition, they showed that anti-gp130 blocked IL27-mediated
cellular effects. Quantitative PCR analysis indicated that, in addition
to naive CD4 (186940)-positive T cells, numerous cell types expressed
both gp130 and WSX1, including mast cells. IL27 stimulation of mast
cells resulted in upregulation of proinflammatory cytokine expression.
Pflanz et al. (2004) concluded that IL27 not only contributes to the
development of an adaptive immune response through its action on
CD4-positive T cells, but also directly acts on cells of the innate
immune system.
BIOCHEMICAL FEATURES
- Crystal Structure
IL6 is an immunoregulatory cytokine that activates a cell-surface
signaling assembly composed of IL6, IL6RA, and the shared signaling
receptor gp130. Boulanger et al. (2003) solved the crystal structure of
the extracellular signaling complex to 3.65-angstrom resolution, which
revealed a hexameric, interlocking assembly mediated by a total of 10
symmetry-related, thermodynamically coupled interfaces. Assembly of the
hexameric complex occurs sequentially: IL6 is first engaged by
IL6R-alpha and then presented to gp130 in the proper geometry to
facilitate a cooperative transition into the high affinity,
signaling-competent hexamer. The quaternary structures of other IL6/IL12
family signaling complexes are likely constructed by means of a similar
topologic blueprint.
GENE STRUCTURE
Szalai et al. (2000) determined that the IL6ST gene contains 17 exons
and spans about 51 kb.
MAPPING
By fluorescence in situ hybridization, Rodriguez et al. (1995) assigned
the functional IL6ST gene to chromosome 5q11 and its nontranscribed
pseudogene to 17p11.
Hartz (2010) mapped the IL6ST gene to chromosome 5q11.2 based on an
alignment of the IL6ST sequence (GenBank GENBANK AB015706) with the
genomic sequence (GRCh37).
- Pseudogenes
Kidd et al. (1992) concluded that there are 2 functional genes for
IL6ST. Rodriguez et al. (1995) showed, however, that the 2 localizations
correspond to a pseudogene (on chromosome 17) and the functional gene on
chromosome 5.
MOLECULAR GENETICS
Rebouissou et al. (2009) demonstrated a marked activation of the IL6
(147620) signaling pathway in inflammatory hepatocellular adenomas.
Sequencing candidate genes pinpointed the response to somatic
gain-of-function mutations in the IL6ST gene, which encodes the
signaling coreceptor gp130. Rebouissou et al. (2009) found that 60% of
inflammatory hepatocellular adenomas harbor small in-frame deletions
that target the binding sites of gp130 for IL6, and expression of 4
different gp130 mutants in hepatocellular cells activated STAT3 (102582)
in the absence of ligand. Furthermore, analysis of hepatocellular
carcinomas revealed that rare gp130 alterations are always accompanied
by beta-catenin (116806)-activating mutations, suggesting a cooperative
effect of these signaling pathways in the malignant conversion of
hepatocytes. The recurrent gain-of-function gp130 mutations in these
human hepatocellular adenomas fully explains activation of the acute
inflammatory phase observed in tumorous hepatocytes, and suggests that
similar alterations may occur in other inflammatory epithelial tumors
with STAT activation.
ANIMAL MODEL
Using Cre-loxP-mediated recombination to generate mice harboring a
ventricular-restricted knockout of the gp130 cytokine receptor, Hirota
et al. (1999) demonstrated a critical role for a gp130-dependent myocyte
survival pathway in the transition to heart failure. Such conditional
mutant mice have normal cardiac structure and function, but during
aortic pressure overload, these mice displayed rapid onset of dilated
cardiomyopathy and massive induction of myocyte apoptosis compared with
the control mice, which exhibited compensatory hypertrophy. Thus,
cardiac myocyte apoptosis is a critical point in the transition between
compensatory cardiac hypertrophy and heart failure. Hirota et al. (1999)
suggested that gp130-dependent cytokines may represent a novel
therapeutic strategy for preventing in vivo heart failure.
Tebbutt et al. (2002) noted that gp130 contains at least 2
cell-signaling modules. One encompasses 4 phosphotyrosine-binding sites
for the SH2 domains of STAT1 and STAT3, whereas the other includes a
phosphotyrosine that activates SHP2 (176876) upstream of the RAS
(190020)-ERK (see 601795) pathway. Tebbutt et al. (2002) generated mice
carrying targeted mutations in each of these modules. Mice homozygous
for a truncated version of gp130 lacking all Stat-binding sites
spontaneously developed intestinal ulceration at sites associated with
repeated mechanical trauma (gastric pylorus and rectum). Unlike wildtype
mice, those with the Stat-binding domain mutation were unable to recover
from trauma induced by ingestion of sodium dextran sulfate. Tebbutt et
al. (2002) noted that impaired wound healing occurs in Tff3
(600633)-null mice, and biochemical analysis confirmed reduced levels of
Tff3 in the mice with the Stat-binding domain mutation. Mice homozygous
for a tyr757-to-phe (Y757F) mutation, which inactivated the Shp2-binding
domain of gp130, developed normally into superficially healthy adults,
but they showed age-dependent enlargement of the stomach, proximal small
intestine, and spleen. Histologic examination revealed
hyperproliferative lesions within the antropyloric mucosa, often
circumferential, resulting in gastric outlet obstruction. Tebbutt et al.
(2002) noted that the gastric pathology was essentially phenocopied in
Tff1 (113710) null mice, and biochemical analysis of gastric Tff1 levels
in mice with the Shp2-binding domain mutation confirmed a 75% reduction
in comparison with wildtype mice; levels of Tff3 were elevated in the
mutant mice. Using a luciferase reporter assay with cells transiently
transfected with gp130 carrying the Stat- and Shp2-binding domain
mutations, Tebbutt et al. (2002) confirmed simultaneous activation of
the Stat1/Stat3 and Shp2-Ras-Erk pathways in response to IL6 activation,
resulting in enhanced luciferase activity of Tff1-luc and Tff3-luc
reporter constructs. Tebbutt et al. (2002) concluded that the
pathologies observed in the gp130 mutant mice resulted from disruption
of the normally simultaneous and coordinated activation of the
Stat1/Stat3 and Shp2-Ras-Erk signaling cascades.
Atsumi et al. (2002) generated mice with a tyr759-to-phe mutation in the
Shp2-binding site of gp130. These mice developed a rheumatoid arthritis
(RA; 180300)-like joint disease at about 1 year of age, accompanied by
autoantibody production and accumulation of memory/activated T cells and
myeloid cells. Before disease onset, T cells were hyperresponsive in
vitro. Mutant mice that were also Rag2 (179616) deficient did not
develop disease, indicating the importance of lymphocytes in this model.
Atsumi et al. (2002) concluded that point mutation in the gp130 cytokine
receptor can induce autoimmune disease.
Jenkins et al. (2005) assessed the contribution of exaggerated Stat3
activation to the phenotype of mice homozygous for Y757F, which disrupts
the negative feedback mechanism on gp130-dependent Stat signaling
(Tebbutt et al., 2002). They found that development of abnormalities
associated with gp130(Y757F) homozygosity, including reduced life span,
splenomegaly, exaggerated hepatic acute-phase response, and spontaneous
gastric adenomas while young, was attenuated when gp130(Y757F)
homozygosity was expressed on a Stat3 +/- background.
Both bone formation and resorption are altered significantly in gp130
-/- mice. Although the mutation results in neonatal lethality, reduced
trabecular bone mass, associated with an increase in osteoclastogenesis,
is a feature of the neonatal skeleton (Kawasaki et al., 1997; Shin et
al., 2004). Sims et al. (2004) found that mouse strains homozygous for
gp130 mutations in the Stat activation sites had normal trabecular bone
volume and bone turnover, but reduced bone length and premature growth
plate closure, suggesting a role for gp130-STAT1/3 signaling in
chondrocyte differentiation. In contrast, mice with mutations in the
gp130 Shp2-Ras-Mapk (see 176948) activation sites showed normal bone
size, but reduced trabecular bone volume and high bone turnover,
associated with increased osteoclastogenesis. Sims et al. (2004)
concluded that gp130 controls balanced regulation of bone growth and
mass depending on selective activation of distinct downstream signaling
pathways.
*FIELD* RF
1. Atsumi, T.; Ishihara, K.; Kamimura, D.; Ikushima, H.; Ohtani, T.;
Hirota, S.; Kobayashi, H.; Park, S.-J.; Saeki, Y.; Kitamura, Y.; Hirano,
T.: A point mutation of tyr-759 in interleukin 6 family cytokine
receptor gp130 causes autoimmune arthritis. J. Exp. Med. 196: 979-990,
2002.
2. Boulanger, M. J.; Chow, D.; Brevnova, E. E.; Garcia, K. C.: Hexameric
structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130
complex. Science 300: 2101-2104, 2003. Note: Erratum: Science 301:
918 only, 2003.
3. Chow, D.; He, X.; Snow, A. L.; Rose-John, S.; Garcia, K. C.: Structure
of an extracellular gp130 cytokine receptor signaling complex. Science 291:
2150-2155, 2001.
4. Diamant, M.; Rieneck, K.; Mechti, N.; Zhang, X.-G.; Svenson, M.;
Bendtzen, K.; Klein, B.: Cloning and expression of an alternatively
spliced mRNA encoding a soluble form of the human interleukin-6 signal
transducer gp130. FEBS Lett. 412: 379-384, 1997.
5. Hartz, P. A.: Personal Communiation. Baltimore, Md. , 11/22/2010.
6. Hibi, M.; Murakami, M.; Saito, M.; Hirano, T.; Taga, T.; Kishimoto,
T.: Molecular cloning and expression of an IL-6 signal transducer,
gp130. Cell 63: 1149-1157, 1990.
7. Hirota, H.; Chen, J.; Betz, U. A. K.; Rajewsky, K.; Gu, Y.; Ross,
J., Jr.; Muller, W.; Chien, K. R.: Loss of a gp130 cardiac muscle
cell survival pathway is a critical event in the onset of heart failure
during biochemical stress. Cell 97: 189-198, 1999.
8. Jenkins, B. J.; Grail, D.; Nheu, T.; Najkovska, M.; Wang, B.; Waring,
P.; Inglese, M.; McLoughlin, R. M.; Jones, S. A.; Topley, N.; Baumann,
H.; Judd, L. M.; Giraud, A. S.; Boussioutas, A.; Zhu, H.-J.; Ernst,
M.: Hyperactivation of Stat3 in gp130 mutant mice promotes gastric
hyperproliferation and desensitizes TGF-beta signaling. Nature Med. 11:
845-852, 2005.
9. Kawasaki, K.; Gao, Y.-H.; Yokose, S.; Kaji, Y.; Nakamura, T.; Suda,
T.; Yoshida, K.; Taga, T.; Kishimoto, T.; Kataoka, H.; Yuasa, T.;
Norimatsu, H.; Yamaguchi, A.: Osteoclasts are present in gp130-deficient
mice. Endocrinology 138: 4959-4965, 1997.
10. Kidd, V. J.; Nesbitt, J. E.; Fuller, G. M.: Chromosomal localization
of the IL-6 receptor signal transducing subunit, gp130 (IL6ST). Somat.
Cell Molec. Genet. 18: 477-483, 1992.
11. Kishimoto, T.; Taga, T.; Akira, S.: Cytokine signal transduction. Cell 76:
253-262, 1994.
12. Murakami, M.; Narazaki, M.; Hibi, M.; Yawata, H.; Yasukawa, K.;
Hamaguchi, M.; Taga, T.; Kishimoto, T.: Critical cytoplasmic region
of the interleukin 6 signal transducer gp130 is conserved in the cytokine
receptor family. Proc. Nat. Acad. Sci. 88: 11349-11353, 1991.
13. Narazaki, M.; Yasukawa, K.; Saito, T.; Ohsugi, Y.; Fukui, H.;
Koishihara, Y.; Yancopoulos, G. D.; Taga, T.; Kishimoto, T.: Soluble
forms of the interleukin-6 signal-transducing receptor component gp130
in human serum possessing a potential to inhibit signals through membrane-anchored
gp130. Blood 82: 1120-1126, 1993.
14. Pflanz, S.; Hibbert, L.; Mattson, J.; Rosales, R.; Vaisberg, E.;
Bazan, J. F.; Phillips, J. H.; McClanahan, T. K.; de Waal Malefyt,
R.; Kastelein, R. A.: WSX-1 and glycoprotein 130 constitute a signal-transducing
receptor for IL-27. J. Immun. 172: 2225-2231, 2004.
15. Rebouissou, S.; Amessou, M.; Couchy, G.; Poussin, K.; Imbeaud,
S.; Pilati, C.; Izard, T.; Balabaud, C.; Bioulac-Sage, P.; Zucman-Rossi,
J.: Frequent in-frame somatic deletions activate gp130 in inflammatory
hepatocellular tumours. Nature 457: 200-204, 2009.
16. Rodriguez, C.; Grosgeorge, J.; Nguyen, V. C.; Gaudray, P.; Theillet,
C.: Human gp130 transducer chain gene (IL6ST) is localized to chromosome
band 5q11 and possesses a pseudogene on chromosome band 17p11. Cytogenet.
Cell Genet. 70: 64-67, 1995.
17. Saito, M.; Yoshida, K.; Hibi, M.; Taga, T.; Kishimoto, T.: Molecular
cloning of a murine IL-6 receptor-associated signal transducer, gp130,
and its regulated expression in vivo. J. Immun. 148: 4066-4071,
1992.
18. Shin, H.-I.; Divieti, P.; Sims, N. A.; Kobayashi, T.; Miao, D.;
Karaplis, A. C.; Baron, R.; Bringhurst, R.; Kronenberg, H. M.: gp130-mediated
signaling is necessary for normal osteoblastic function in vivo and
in vitro. Endocrinology 145: 1376-1385, 2004.
19. Sims, N. A.; Jenkins, B. J.; Quinn, J. M. W.; Nakamura, A.; Glatt,
M.; Gillespie, M. T.; Ernst, M.; Martin, T. J.: Glycoprotein 130
regulates bone turnover and bone size by distinct downstream signaling
pathways. J. Clin. Invest. 113: 379-389, 2004.
20. Szalai, C.; Toth, S.; Falus, A.: Exon-intron organization of
the human gp130 gene. Gene 243: 161-166, 2000.
21. Tebbutt, N. C.; Giraud, A. S.; Inglese, M.; Jenkins, B.; Waring,
P.; Clay, F. J.; Malki, S.; Alderman, B. M.; Grail, D.; Hollande,
F.; Heath, J. K.; Ernst, M.: Reciprocal regulation of gastrointestinal
homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130
mutant mice. Nature Med. 8: 1089-1097, 2002.
*FIELD* CN
Ada Hamosh - updated: 1/27/2009
Paul J. Converse - updated: 1/5/2006
Patricia A. Hartz - updated: 9/9/2005
Paul J. Converse - updated: 8/11/2004
Patricia A. Hartz - updated: 5/10/2004
Cassandra L. Kniffin - updated: 4/19/2004
Ada Hamosh - updated: 7/8/2003
Patricia A. Hartz - updated: 9/11/2002
Paul J. Converse - updated: 3/19/2001
Stylianos E. Antonarakis - updated: 5/11/1999
*FIELD* CD
Victor A. McKusick: 7/28/1995
*FIELD* ED
terry: 08/06/2012
mgross: 8/3/2012
terry: 8/3/2012
mgross: 11/23/2010
terry: 11/22/2010
alopez: 1/28/2009
terry: 1/27/2009
mgross: 1/5/2006
terry: 10/12/2005
mgross: 9/9/2005
mgross: 8/2/2005
mgross: 8/11/2004
terry: 6/18/2004
mgross: 5/11/2004
terry: 5/10/2004
tkritzer: 4/21/2004
ckniffin: 4/19/2004
tkritzer: 11/4/2003
alopez: 7/10/2003
terry: 7/8/2003
alopez: 10/18/2002
mgross: 9/12/2002
mgross: 9/11/2002
mgross: 3/20/2001
mgross: 3/19/2001
mgross: 5/12/1999
mgross: 5/11/1999
dkim: 7/2/1998
mark: 7/28/1995