Full text data of STAT6
STAT6
[Confidence: low (only semi-automatic identification from reviews)]
Signal transducer and activator of transcription 6 (IL-4 Stat)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Signal transducer and activator of transcription 6 (IL-4 Stat)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P42226
ID STAT6_HUMAN Reviewed; 847 AA.
AC P42226; A8K316; B7ZA27; F5GXI9; Q5FBW5; Q71UP4;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1995, sequence version 1.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Signal transducer and activator of transcription 6;
DE AltName: Full=IL-4 Stat;
GN Name=STAT6;
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).
RX PubMed=8085155; DOI=10.1126/science.8085155;
RA Hou J., Schindler U., Henzel W.J., Ho T., Brasseur M., McKnight S.L.;
RT "An interleukin-4-induced transcription factor: IL-4 Stat.";
RL Science 265:1701-1706(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9782085; DOI=10.1006/geno.1998.5436;
RA Patel B.K., Keck C.L., O'Leary R.S., Popescu N.C., LaRochelle W.J.;
RT "Localization of the human stat6 gene to chromosome 12q13.3-q14.1, a
RT region implicated in multiple solid tumors.";
RL Genomics 52:192-200(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Tabata Y., Sameshima E., Hayashi A., Iida K., Mitsuyama M., Kanai S.,
RA Furuya T., Saito T.;
RT "STAT6 mRNA, nirs splice variant 2.";
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ARG-181.
RG SeattleSNPs variation discovery resource;
RL Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Uterus;
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 [8]
RP INTERACTION WITH NCOA1, AND MUTAGENESIS OF LEU-802 AND LEU-805.
RX PubMed=12138096; DOI=10.1074/jbc.M203556200;
RA Litterst C.M., Pfitzner E.;
RT "An LXXLL motif in the transactivation domain of STAT6 mediates
RT recruitment of NCoA-1/SRC-1.";
RL J. Biol. Chem. 277:36052-36060(2002).
RN [9]
RP FUNCTION IN IL4 SIGNALING, PHOSPHORYLATION, AND DEPHOSPHORYLATION BY
RP PTPN2.
RX PubMed=17210636; DOI=10.1128/MCB.01234-06;
RA Lu X., Chen J., Sasmono R.T., Hsi E.D., Sarosiek K.A., Tiganis T.,
RA Lossos I.S.;
RT "T-cell protein tyrosine phosphatase, distinctively expressed in
RT activated-B-cell-like diffuse large B-cell lymphomas, is the nuclear
RT phosphatase of STAT6.";
RL Mol. Cell. Biol. 27:2166-2179(2007).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 795-808 IN COMPLEX WITH
RP 257-385 OF NCOA1.
RX PubMed=14757047; DOI=10.1016/j.jmb.2003.12.057;
RA Razeto A., Ramakrishnan V., Litterst C.M., Giller K., Griesinger C.,
RA Carlomagno T., Lakomek N., Heimburg T., Lodrini M., Pfitzner E.,
RA Becker S.;
RT "Structure of the NCoA-1/SRC-1 PAS-B domain bound to the LXXLL motif
RT of the STAT6 transactivation domain.";
RL J. Mol. Biol. 336:319-329(2004).
CC -!- FUNCTION: Carries out a dual function: signal transduction and
CC activation of transcription. Involved in IL4/interleukin-4- and
CC IL3/interleukin-3-mediated signaling.
CC -!- SUBUNIT: Forms a homodimer or a heterodimer with a related family
CC member (By similarity). Interacts with NCOA1 via its C-terminal
CC LXXLL motif.
CC -!- INTERACTION:
CC Self; NbExp=2; IntAct=EBI-1186478, EBI-1186478;
CC Q09472:EP300; NbExp=2; IntAct=EBI-1186478, EBI-447295;
CC P24394:IL4R; NbExp=4; IntAct=EBI-1186478, EBI-367009;
CC Q9UHD2:TBK1; NbExp=7; IntAct=EBI-1186478, EBI-356402;
CC Q86WV6:TMEM173; NbExp=12; IntAct=EBI-1186478, EBI-2800345;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Translocated into
CC the nucleus in response to phosphorylation.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P42226-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P42226-2; Sequence=VSP_031871, VSP_031872;
CC Name=3;
CC IsoId=P42226-3; Sequence=VSP_045282;
CC Note=No experimental confirmation available;
CC -!- PTM: Tyrosine phosphorylated following stimulation by
CC IL4/interleukin-4 and IL3/interleukin-3 (By similarity).
CC Dephosphorylation on tyrosine residues by PTPN2 negatively
CC regulates the IL4/interleukin-4 mediated signaling.
CC -!- SIMILARITY: Belongs to the transcription factor STAT family.
CC -!- SIMILARITY: Contains 1 SH2 domain.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/stat6/";
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DR EMBL; U16031; AAA57193.1; -; mRNA.
DR EMBL; AF067575; AAC67525.1; -; Genomic_DNA.
DR EMBL; AF067572; AAC67525.1; JOINED; Genomic_DNA.
DR EMBL; AF067573; AAC67525.1; JOINED; Genomic_DNA.
DR EMBL; AB103089; BAD89432.1; -; mRNA.
DR EMBL; AK290431; BAF83120.1; -; mRNA.
DR EMBL; AK316142; BAH14513.1; -; mRNA.
DR EMBL; AF417842; AAL06595.1; -; Genomic_DNA.
DR EMBL; AC023237; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC075852; AAH75852.1; -; mRNA.
DR PIR; A54740; A54740.
DR RefSeq; NP_001171549.1; NM_001178078.1.
DR RefSeq; NP_001171550.1; NM_001178079.1.
DR RefSeq; NP_001171551.1; NM_001178080.1.
DR RefSeq; NP_003144.3; NM_003153.4.
DR UniGene; Hs.524518; -.
DR PDB; 1OJ5; X-ray; 2.20 A; B=795-808.
DR PDBsum; 1OJ5; -.
DR ProteinModelPortal; P42226; -.
DR SMR; P42226; 13-631.
DR IntAct; P42226; 31.
DR MINT; MINT-8020389; -.
DR STRING; 9606.ENSP00000300134; -.
DR BindingDB; P42226; -.
DR ChEMBL; CHEMBL5401; -.
DR PhosphoSite; P42226; -.
DR DMDM; 1174459; -.
DR PaxDb; P42226; -.
DR PRIDE; P42226; -.
DR DNASU; 6778; -.
DR Ensembl; ENST00000300134; ENSP00000300134; ENSG00000166888.
DR Ensembl; ENST00000454075; ENSP00000401486; ENSG00000166888.
DR Ensembl; ENST00000537215; ENSP00000444530; ENSG00000166888.
DR Ensembl; ENST00000538913; ENSP00000445409; ENSG00000166888.
DR Ensembl; ENST00000543873; ENSP00000438451; ENSG00000166888.
DR Ensembl; ENST00000556155; ENSP00000451742; ENSG00000166888.
DR GeneID; 6778; -.
DR KEGG; hsa:6778; -.
DR UCSC; uc001sna.3; human.
DR CTD; 6778; -.
DR GeneCards; GC12M057489; -.
DR HGNC; HGNC:11368; STAT6.
DR HPA; HPA001861; -.
DR MIM; 601512; gene.
DR neXtProt; NX_P42226; -.
DR Orphanet; 2126; Solitary fibrous tumor.
DR PharmGKB; PA339; -.
DR eggNOG; NOG278979; -.
DR HOGENOM; HOG000230988; -.
DR HOVERGEN; HBG107486; -.
DR InParanoid; P42226; -.
DR KO; K11225; -.
DR OMA; KFQAGVR; -.
DR OrthoDB; EOG73JKTT; -.
DR PhylomeDB; P42226; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P42226; -.
DR ChiTaRS; STAT6; human.
DR EvolutionaryTrace; P42226; -.
DR GeneWiki; STAT6; -.
DR GenomeRNAi; 6778; -.
DR NextBio; 26458; -.
DR PRO; PR:P42226; -.
DR ArrayExpress; P42226; -.
DR Bgee; P42226; -.
DR CleanEx; HS_STAT6; -.
DR Genevestigator; P42226; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0000790; C:nuclear chromatin; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0000979; F:RNA polymerase II core promoter sequence-specific DNA binding; IEA:Ensembl.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; TAS:ProtInc.
DR GO; GO:0004871; F:signal transducer activity; IEA:InterPro.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0035771; P:interleukin-4-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0033598; P:mammary gland epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0060443; P:mammary gland morphogenesis; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0002829; P:negative regulation of type 2 immune response; IEA:Ensembl.
DR GO; GO:0048295; P:positive regulation of isotype switching to IgE isotypes; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0032481; P:positive regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0042127; P:regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0006357; P:regulation of transcription from RNA polymerase II promoter; TAS:ProtInc.
DR GO; GO:0002296; P:T-helper 1 cell lineage commitment; IEA:Ensembl.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR Gene3D; 1.10.238.10; -; 1.
DR Gene3D; 1.10.532.10; -; 1.
DR Gene3D; 1.20.1050.20; -; 1.
DR Gene3D; 2.60.40.630; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR008967; p53-like_TF_DNA-bd.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR001217; STAT.
DR InterPro; IPR028187; STAT6_C.
DR InterPro; IPR013800; STAT_TF_alpha.
DR InterPro; IPR015988; STAT_TF_coiled-coil.
DR InterPro; IPR013801; STAT_TF_DNA-bd.
DR InterPro; IPR012345; STAT_TF_DNA-bd_sub.
DR InterPro; IPR013799; STAT_TF_prot_interaction.
DR PANTHER; PTHR11801; PTHR11801; 1.
DR Pfam; PF00017; SH2; 1.
DR Pfam; PF14596; STAT6_C; 1.
DR Pfam; PF01017; STAT_alpha; 1.
DR Pfam; PF02864; STAT_bind; 1.
DR Pfam; PF02865; STAT_int; 1.
DR SMART; SM00252; SH2; 1.
DR SMART; SM00964; STAT_int; 1.
DR SUPFAM; SSF47655; SSF47655; 1.
DR SUPFAM; SSF48092; SSF48092; 1.
DR SUPFAM; SSF49417; SSF49417; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Complete proteome;
KW Cytoplasm; DNA-binding; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; SH2 domain; Transcription;
KW Transcription regulation.
FT CHAIN 1 847 Signal transducer and activator of
FT transcription 6.
FT /FTId=PRO_0000182433.
FT DOMAIN 517 632 SH2.
FT MOTIF 802 806 LXXLL motif.
FT MOD_RES 641 641 Phosphotyrosine; by JAK (By similarity).
FT VAR_SEQ 1 174 Missing (in isoform 2).
FT /FTId=VSP_031871.
FT VAR_SEQ 1 110 Missing (in isoform 3).
FT /FTId=VSP_045282.
FT VAR_SEQ 175 177 PSE -> MEQ (in isoform 2).
FT /FTId=VSP_031872.
FT VARIANT 181 181 M -> R (in dbSNP:rs3024952).
FT /FTId=VAR_013094.
FT VARIANT 419 419 D -> N (in dbSNP:rs11172102).
FT /FTId=VAR_059812.
FT MUTAGEN 802 802 L->A: Abolishes the interaction with
FT NCOA1; when associated with A-805.
FT MUTAGEN 805 805 L->A: Abolishes the interaction with
FT NCOA1; when associated with A-802.
FT CONFLICT 149 149 E -> Q (in Ref. 2; AAC67525).
FT CONFLICT 246 246 G -> D (in Ref. 4; BAH14513).
FT CONFLICT 733 733 S -> N (in Ref. 2; AAC67525).
FT HELIX 799 807
SQ SEQUENCE 847 AA; 94135 MW; F35075F1C1F2A677 CRC64;
MSLWGLVSKM PPEKVQRLYV DFPQHLRHLL GDWLESQPWE FLVGSDAFCC NLASALLSDT
VQHLQASVGE QGEGSTILQH ISTLESIYQR DPLKLVATFR QILQGEKKAV MEQFRHLPMP
FHWKQEELKF KTGLRRLQHR VGEIHLLREA LQKGAEAGQV SLHSLIETPA NGTGPSEALA
MLLQETTGEL EAAKALVLKR IQIWKRQQQL AGNGAPFEES LAPLQERCES LVDIYSQLQQ
EVGAAGGELE PKTRASLTGR LDEVLRTLVT SCFLVEKQPP QVLKTQTKFQ AGVRFLLGLR
FLGAPAKPPL VRADMVTEKQ ARELSVPQGP GAGAESTGEI INNTVPLENS IPGNCCSALF
KNLLLKKIKR CERKGTESVT EEKCAVLFSA SFTLGPGKLP IQLQALSLPL VVIVHGNQDN
NAKATILWDN AFSEMDRVPF VVAERVPWEK MCETLNLKFM AEVGTNRGLL PEHFLFLAQK
IFNDNSLSME AFQHRSVSWS QFNKEILLGR GFTFWQWFDG VLDLTKRCLR SYWSDRLIIG
FISKQYVTSL LLNEPDGTFL LRFSDSEIGG ITIAHVIRGQ DGSPQIENIQ PFSAKDLSIR
SLGDRIRDLA QLKNLYPKKP KDEAFRSHYK PEQMGKDGRG YVPATIKMTV ERDQPLPTPE
LQMPTMVPSY DLGMAPDSSM SMQLGPDMVP QVYPPHSHSI PPYQGLSPEE SVNVLSAFQE
PHLQMPPSLG QMSLPFDQPH PQGLLPCQPQ EHAVSSPDPL LCSDVTMVED SCLSQPVTAF
PQGTWIGEDI FPPLLPPTEQ DLTKLLLEGQ GESGGGSLGA QPLLQPSHYG QSGISMSHMD
LRANPSW
//
ID STAT6_HUMAN Reviewed; 847 AA.
AC P42226; A8K316; B7ZA27; F5GXI9; Q5FBW5; Q71UP4;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1995, sequence version 1.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Signal transducer and activator of transcription 6;
DE AltName: Full=IL-4 Stat;
GN Name=STAT6;
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).
RX PubMed=8085155; DOI=10.1126/science.8085155;
RA Hou J., Schindler U., Henzel W.J., Ho T., Brasseur M., McKnight S.L.;
RT "An interleukin-4-induced transcription factor: IL-4 Stat.";
RL Science 265:1701-1706(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9782085; DOI=10.1006/geno.1998.5436;
RA Patel B.K., Keck C.L., O'Leary R.S., Popescu N.C., LaRochelle W.J.;
RT "Localization of the human stat6 gene to chromosome 12q13.3-q14.1, a
RT region implicated in multiple solid tumors.";
RL Genomics 52:192-200(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Tabata Y., Sameshima E., Hayashi A., Iida K., Mitsuyama M., Kanai S.,
RA Furuya T., Saito T.;
RT "STAT6 mRNA, nirs splice variant 2.";
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ARG-181.
RG SeattleSNPs variation discovery resource;
RL Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Uterus;
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 [8]
RP INTERACTION WITH NCOA1, AND MUTAGENESIS OF LEU-802 AND LEU-805.
RX PubMed=12138096; DOI=10.1074/jbc.M203556200;
RA Litterst C.M., Pfitzner E.;
RT "An LXXLL motif in the transactivation domain of STAT6 mediates
RT recruitment of NCoA-1/SRC-1.";
RL J. Biol. Chem. 277:36052-36060(2002).
RN [9]
RP FUNCTION IN IL4 SIGNALING, PHOSPHORYLATION, AND DEPHOSPHORYLATION BY
RP PTPN2.
RX PubMed=17210636; DOI=10.1128/MCB.01234-06;
RA Lu X., Chen J., Sasmono R.T., Hsi E.D., Sarosiek K.A., Tiganis T.,
RA Lossos I.S.;
RT "T-cell protein tyrosine phosphatase, distinctively expressed in
RT activated-B-cell-like diffuse large B-cell lymphomas, is the nuclear
RT phosphatase of STAT6.";
RL Mol. Cell. Biol. 27:2166-2179(2007).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 795-808 IN COMPLEX WITH
RP 257-385 OF NCOA1.
RX PubMed=14757047; DOI=10.1016/j.jmb.2003.12.057;
RA Razeto A., Ramakrishnan V., Litterst C.M., Giller K., Griesinger C.,
RA Carlomagno T., Lakomek N., Heimburg T., Lodrini M., Pfitzner E.,
RA Becker S.;
RT "Structure of the NCoA-1/SRC-1 PAS-B domain bound to the LXXLL motif
RT of the STAT6 transactivation domain.";
RL J. Mol. Biol. 336:319-329(2004).
CC -!- FUNCTION: Carries out a dual function: signal transduction and
CC activation of transcription. Involved in IL4/interleukin-4- and
CC IL3/interleukin-3-mediated signaling.
CC -!- SUBUNIT: Forms a homodimer or a heterodimer with a related family
CC member (By similarity). Interacts with NCOA1 via its C-terminal
CC LXXLL motif.
CC -!- INTERACTION:
CC Self; NbExp=2; IntAct=EBI-1186478, EBI-1186478;
CC Q09472:EP300; NbExp=2; IntAct=EBI-1186478, EBI-447295;
CC P24394:IL4R; NbExp=4; IntAct=EBI-1186478, EBI-367009;
CC Q9UHD2:TBK1; NbExp=7; IntAct=EBI-1186478, EBI-356402;
CC Q86WV6:TMEM173; NbExp=12; IntAct=EBI-1186478, EBI-2800345;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Translocated into
CC the nucleus in response to phosphorylation.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P42226-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P42226-2; Sequence=VSP_031871, VSP_031872;
CC Name=3;
CC IsoId=P42226-3; Sequence=VSP_045282;
CC Note=No experimental confirmation available;
CC -!- PTM: Tyrosine phosphorylated following stimulation by
CC IL4/interleukin-4 and IL3/interleukin-3 (By similarity).
CC Dephosphorylation on tyrosine residues by PTPN2 negatively
CC regulates the IL4/interleukin-4 mediated signaling.
CC -!- SIMILARITY: Belongs to the transcription factor STAT family.
CC -!- SIMILARITY: Contains 1 SH2 domain.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/stat6/";
CC -----------------------------------------------------------------------
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DR EMBL; U16031; AAA57193.1; -; mRNA.
DR EMBL; AF067575; AAC67525.1; -; Genomic_DNA.
DR EMBL; AF067572; AAC67525.1; JOINED; Genomic_DNA.
DR EMBL; AF067573; AAC67525.1; JOINED; Genomic_DNA.
DR EMBL; AB103089; BAD89432.1; -; mRNA.
DR EMBL; AK290431; BAF83120.1; -; mRNA.
DR EMBL; AK316142; BAH14513.1; -; mRNA.
DR EMBL; AF417842; AAL06595.1; -; Genomic_DNA.
DR EMBL; AC023237; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC075852; AAH75852.1; -; mRNA.
DR PIR; A54740; A54740.
DR RefSeq; NP_001171549.1; NM_001178078.1.
DR RefSeq; NP_001171550.1; NM_001178079.1.
DR RefSeq; NP_001171551.1; NM_001178080.1.
DR RefSeq; NP_003144.3; NM_003153.4.
DR UniGene; Hs.524518; -.
DR PDB; 1OJ5; X-ray; 2.20 A; B=795-808.
DR PDBsum; 1OJ5; -.
DR ProteinModelPortal; P42226; -.
DR SMR; P42226; 13-631.
DR IntAct; P42226; 31.
DR MINT; MINT-8020389; -.
DR STRING; 9606.ENSP00000300134; -.
DR BindingDB; P42226; -.
DR ChEMBL; CHEMBL5401; -.
DR PhosphoSite; P42226; -.
DR DMDM; 1174459; -.
DR PaxDb; P42226; -.
DR PRIDE; P42226; -.
DR DNASU; 6778; -.
DR Ensembl; ENST00000300134; ENSP00000300134; ENSG00000166888.
DR Ensembl; ENST00000454075; ENSP00000401486; ENSG00000166888.
DR Ensembl; ENST00000537215; ENSP00000444530; ENSG00000166888.
DR Ensembl; ENST00000538913; ENSP00000445409; ENSG00000166888.
DR Ensembl; ENST00000543873; ENSP00000438451; ENSG00000166888.
DR Ensembl; ENST00000556155; ENSP00000451742; ENSG00000166888.
DR GeneID; 6778; -.
DR KEGG; hsa:6778; -.
DR UCSC; uc001sna.3; human.
DR CTD; 6778; -.
DR GeneCards; GC12M057489; -.
DR HGNC; HGNC:11368; STAT6.
DR HPA; HPA001861; -.
DR MIM; 601512; gene.
DR neXtProt; NX_P42226; -.
DR Orphanet; 2126; Solitary fibrous tumor.
DR PharmGKB; PA339; -.
DR eggNOG; NOG278979; -.
DR HOGENOM; HOG000230988; -.
DR HOVERGEN; HBG107486; -.
DR InParanoid; P42226; -.
DR KO; K11225; -.
DR OMA; KFQAGVR; -.
DR OrthoDB; EOG73JKTT; -.
DR PhylomeDB; P42226; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P42226; -.
DR ChiTaRS; STAT6; human.
DR EvolutionaryTrace; P42226; -.
DR GeneWiki; STAT6; -.
DR GenomeRNAi; 6778; -.
DR NextBio; 26458; -.
DR PRO; PR:P42226; -.
DR ArrayExpress; P42226; -.
DR Bgee; P42226; -.
DR CleanEx; HS_STAT6; -.
DR Genevestigator; P42226; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0000790; C:nuclear chromatin; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0000979; F:RNA polymerase II core promoter sequence-specific DNA binding; IEA:Ensembl.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; TAS:ProtInc.
DR GO; GO:0004871; F:signal transducer activity; IEA:InterPro.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0035771; P:interleukin-4-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0033598; P:mammary gland epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0060443; P:mammary gland morphogenesis; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0002829; P:negative regulation of type 2 immune response; IEA:Ensembl.
DR GO; GO:0048295; P:positive regulation of isotype switching to IgE isotypes; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0032481; P:positive regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0042127; P:regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0006357; P:regulation of transcription from RNA polymerase II promoter; TAS:ProtInc.
DR GO; GO:0002296; P:T-helper 1 cell lineage commitment; IEA:Ensembl.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR Gene3D; 1.10.238.10; -; 1.
DR Gene3D; 1.10.532.10; -; 1.
DR Gene3D; 1.20.1050.20; -; 1.
DR Gene3D; 2.60.40.630; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR008967; p53-like_TF_DNA-bd.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR001217; STAT.
DR InterPro; IPR028187; STAT6_C.
DR InterPro; IPR013800; STAT_TF_alpha.
DR InterPro; IPR015988; STAT_TF_coiled-coil.
DR InterPro; IPR013801; STAT_TF_DNA-bd.
DR InterPro; IPR012345; STAT_TF_DNA-bd_sub.
DR InterPro; IPR013799; STAT_TF_prot_interaction.
DR PANTHER; PTHR11801; PTHR11801; 1.
DR Pfam; PF00017; SH2; 1.
DR Pfam; PF14596; STAT6_C; 1.
DR Pfam; PF01017; STAT_alpha; 1.
DR Pfam; PF02864; STAT_bind; 1.
DR Pfam; PF02865; STAT_int; 1.
DR SMART; SM00252; SH2; 1.
DR SMART; SM00964; STAT_int; 1.
DR SUPFAM; SSF47655; SSF47655; 1.
DR SUPFAM; SSF48092; SSF48092; 1.
DR SUPFAM; SSF49417; SSF49417; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Complete proteome;
KW Cytoplasm; DNA-binding; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; SH2 domain; Transcription;
KW Transcription regulation.
FT CHAIN 1 847 Signal transducer and activator of
FT transcription 6.
FT /FTId=PRO_0000182433.
FT DOMAIN 517 632 SH2.
FT MOTIF 802 806 LXXLL motif.
FT MOD_RES 641 641 Phosphotyrosine; by JAK (By similarity).
FT VAR_SEQ 1 174 Missing (in isoform 2).
FT /FTId=VSP_031871.
FT VAR_SEQ 1 110 Missing (in isoform 3).
FT /FTId=VSP_045282.
FT VAR_SEQ 175 177 PSE -> MEQ (in isoform 2).
FT /FTId=VSP_031872.
FT VARIANT 181 181 M -> R (in dbSNP:rs3024952).
FT /FTId=VAR_013094.
FT VARIANT 419 419 D -> N (in dbSNP:rs11172102).
FT /FTId=VAR_059812.
FT MUTAGEN 802 802 L->A: Abolishes the interaction with
FT NCOA1; when associated with A-805.
FT MUTAGEN 805 805 L->A: Abolishes the interaction with
FT NCOA1; when associated with A-802.
FT CONFLICT 149 149 E -> Q (in Ref. 2; AAC67525).
FT CONFLICT 246 246 G -> D (in Ref. 4; BAH14513).
FT CONFLICT 733 733 S -> N (in Ref. 2; AAC67525).
FT HELIX 799 807
SQ SEQUENCE 847 AA; 94135 MW; F35075F1C1F2A677 CRC64;
MSLWGLVSKM PPEKVQRLYV DFPQHLRHLL GDWLESQPWE FLVGSDAFCC NLASALLSDT
VQHLQASVGE QGEGSTILQH ISTLESIYQR DPLKLVATFR QILQGEKKAV MEQFRHLPMP
FHWKQEELKF KTGLRRLQHR VGEIHLLREA LQKGAEAGQV SLHSLIETPA NGTGPSEALA
MLLQETTGEL EAAKALVLKR IQIWKRQQQL AGNGAPFEES LAPLQERCES LVDIYSQLQQ
EVGAAGGELE PKTRASLTGR LDEVLRTLVT SCFLVEKQPP QVLKTQTKFQ AGVRFLLGLR
FLGAPAKPPL VRADMVTEKQ ARELSVPQGP GAGAESTGEI INNTVPLENS IPGNCCSALF
KNLLLKKIKR CERKGTESVT EEKCAVLFSA SFTLGPGKLP IQLQALSLPL VVIVHGNQDN
NAKATILWDN AFSEMDRVPF VVAERVPWEK MCETLNLKFM AEVGTNRGLL PEHFLFLAQK
IFNDNSLSME AFQHRSVSWS QFNKEILLGR GFTFWQWFDG VLDLTKRCLR SYWSDRLIIG
FISKQYVTSL LLNEPDGTFL LRFSDSEIGG ITIAHVIRGQ DGSPQIENIQ PFSAKDLSIR
SLGDRIRDLA QLKNLYPKKP KDEAFRSHYK PEQMGKDGRG YVPATIKMTV ERDQPLPTPE
LQMPTMVPSY DLGMAPDSSM SMQLGPDMVP QVYPPHSHSI PPYQGLSPEE SVNVLSAFQE
PHLQMPPSLG QMSLPFDQPH PQGLLPCQPQ EHAVSSPDPL LCSDVTMVED SCLSQPVTAF
PQGTWIGEDI FPPLLPPTEQ DLTKLLLEGQ GESGGGSLGA QPLLQPSHYG QSGISMSHMD
LRANPSW
//
MIM
601512
*RECORD*
*FIELD* NO
601512
*FIELD* TI
*601512 SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6; STAT6
;;STAT, INTERLEUKIN 4-INDUCED;;
read moreIL4-STAT
STAT6b, INCLUDED;;
STAT6c, INCLUDED;;
STAT6/NAB2 FUSION GENE, INCLUDED
*FIELD* TX
CLONING
By searching a database of expressed sequence tags (ESTs), Quelle et al.
(1995) identified a number of expressed genes in the signal transducers
and activators of a transcription (STAT) family. Human and murine
full-length cDNA clones were obtained and sequenced. The sequence of the
human cDNA was identical to the sequence published by Hou et al. (1994)
for the interleukin-4-induced transcription factor (called by them IL4
Stat), while the murine STAT6 amino acid and nucleotide sequences
reported by Quelle et al. (1995) were 83% and 84% identical to the human
sequences, respectively.
By screening an embryonic lung fibroblast cDNA library with a wildtype
STAT6 probe, Patel et al. (1998) identified 2 variant cDNAs, which they
termed STAT6b and STAT6c, encoding an N-terminal 110-amino acid
truncation and a 27-amino acid deletion in the SH2 domain, respectively.
RNase protection analysis detected ubiquitous expression of all 3
variants with STAT6b expression greatest in spleen and STAT6c expression
greatest in lung.
GENE STRUCTURE
Patel et al. (1998) characterized the genomic structure and flanking
regions of the human STAT6 gene. The gene spans 19 kb and contains 23
exons.
MAPPING
Copeland et al. (1995) found that 7 mouse Stat genes map in 3 clusters,
with each cluster located on a different autosome. They suggested that
the Stat family arose by a tandem duplication of the ancestral Stat
gene, followed by dispersion of the linked loci to different
chromosomes. They mapped Stat6 and Stat2 (600556) to the distal region
of chromosome 10. During an analysis of NAB2 (602381), Svaren et al.
(1997) obtained the sequence adjacent to this gene by PCR of genomic
DNA. They found that the STAT6 gene is located unusually close to the
NAB2 gene, such that the 3-prime ends of their mRNAs overlap. Since the
human NAB2 gene was previously mapped to 12q13.3-q14.1, it is likely
that STAT6 maps to the same position. By fluorescence in situ
hybridization, Leek et al. (1997) mapped STAT6 to 12q13.
GENE FUNCTION
Using STAT6-specific antiserum, Quelle et al. (1995) demonstrated that
STAT6 is rapidly tyrosine phosphorylated following stimulation of
appropriate cell lines with IL4 (147780) or IL3 (147740), but is not
detectably phosphorylated following stimulation with IL2 (147680), IL12
(see IL12A; 161560), or erythropoietin (133170). In contrast, IL2, IL3,
and erythropoietin induced the tyrosine phosphorylation of STAT5
(601511), while IL12 uniquely induced the tyrosine phosphorylation of
STAT4 (600558). Inducible tyrosine phosphorylation of STAT6 required the
membrane-distal region of the IL4 receptor alpha chain (IL4R; 147781).
They found that this region of the receptor is not required for cell
growth, demonstrating that STAT6 tyrosine phosphorylation does not
contribute to mitogenesis.
Ghilardi et al. (1996) demonstrated that along with STAT3 (102582) and
STAT5, STAT6 is involved in signaling from the leptin receptor (601007)
and that this signaling is defective in the db/db mouse which carries a
point mutation within the leptin receptor gene. Darnell (1996) reflected
on STAT3, STAT5, and STAT6 as 'fat STATs,' i.e., the involvement of
these 3 STATs, but not STAT1, STAT2, and STAT4, in the physiologic
action of leptin (164160) as described by Ghilardi et al. (1996).
Kotanides and Reich (1996) identified a specific STAT6 DNA-binding
target site in the promoter of the IL4R gene and showed that STAT6
activates IL4 gene expression via this site.
By functional analysis, Patel et al. (1998) determined that the STAT6b
variant resembles an attenuated STAT6, but that the STAT6c variant
inhibits IL4-mediated mitogenesis and cell surface antigen expression,
and is not tyrosine phosphorylated.
Dickensheets et al. (1999) presented evidence that interferons inhibit
IL4-induced activation of STAT6 and STAT6-dependent gene expression, at
least in part, by inducing expression of SOCS1 (603597).
Upregulation of proinflammatory cytokines in rheumatoid arthritis (RA;
180300) synovium and synovial fluid is a feature of active disease and
intense inflammation. Antiinflammatory mediators are also present and
activated in RA but fail to counterregulate the proinflammatory
cytokines. Muller-Ladner et al. (2000) found that the IL4-STAT pathway
is activated in patients with short-term (less than 1 year) and
long-term (more than 2 years) RA and may contribute to downregulation of
the immunologic activity in RA synovium.
Using immunocytochemistry, Christodoulopoulos et al. (2001) measured the
expression of STAT6 in bronchial biopsy specimens from patients with
atopic and nonatopic asthma and controls and found that there were more
STAT6-immunoreactive cells in patients with atopic and with nonatopic
asthma than in control subjects (p less than 0.0001 and 0.05,
respectively). The authors also observed that there were fewer cells
expressing STAT6 protein in nonatopic versus atopic asthma (p less than
0.0001) and concluded that reduced IL4R signaling, due to lower STAT6
expression, may be a feature of nonatopic asthma.
Mullings et al. (2001) investigated STAT6 expression in bronchial biopsy
specimens or brushings from normal control or asthmatic subjects and
found that the bronchial epithelium is the major site of STAT6
expression. Levels of expression in controls and subjects with mild
asthma did not differ significantly; however, STAT6 expression was
significantly increased in subjects with severe asthma (p less than
0.05).
Using confocal microscopy, Maldonado et al. (2004) found a random
distribution of Tcrb (see 186930), Il4r, and Ifngr1 (107470) in fixed
and permeabilized mouse naive T-helper lymphocytes (Thp) conjugated with
mouse mature splenic dendritic cells (DCs). In cells fixed and
permeabilized 30 minutes after conjugation of Thp and antigen-loaded
DCs, the authors observed a calcium- and Ifng (147570)-dependent
colocalization of Tcrb and Ifngr1, but not Il4r, at the Thp-DC
interface. This observation was more apparent in the Th1-prone C57Bl/6
mouse strain than in the Th2-prone BALB/c strain. In the presence of
Il4, but not Il10 (124092), Ifngr1 migration and copolarization was
completely inhibited. In mice lacking the Il4r signaling molecule,
Stat6, prevention of Tcrb/Ifngr1 copolarization was abolished. Maldonado
et al. (2004) proposed that strong TCR signaling leads to accentuated
IFNGR copolarization and the assembly of a Th1 signalosome, which is
further stabilized by secretion of IFNG, unless an inhibitory signal,
such as IL4 secretion and STAT6 activation, occurs and leads to the
assembly of a Th2 signalosome. They concluded that the immunologic
synapse may be involved in the control of cell fate decisions.
Following its proteolytic release and nuclear translocation, Low et al.
(2006) found that the C-terminal tail of human polycystin-1 (PKD1;
601313) interacted with Stat6 and the coactivator P100 (602181) in
canine kidney cells and stimulated Stat6-dependent gene expression.
Under normal conditions, Stat6 localized to primary cilia of renal
epithelial cells; however, cessation of apical fluid flow resulted in
its nuclear translocation. Cyst-lining cells in autosomal dominant
polycystic kidney disease exhibited elevated levels of nuclear STAT6,
P100, and the polycystin-1 C-terminal tail. Exogenous expression of the
human polycystin-1 C-terminal tail resulted in renal cyst formation in
zebrafish embryos. Low et al. (2006) concluded that upregulation of the
STAT6/P100 pathway by the polycystin-1 C-terminal tail leads to the
cellular changes characteristic of renal cysts.
Most Toxoplasma gondii isolates in Europe and North America belong to 3
clonal lines, designated types I, II, and III. Using microarray,
immunofluorescence, and Western blot analyses, Saeij et al. (2007) found
that STAT3 and STAT6 were activated predominantly in fibroblasts
infected with types I and III, rather than type II, T. gondii. They
determined that the T. gondii Rop16 protein kinase mediated the
strain-specific activation of STAT3 and STAT6. Saeij et al. (2007) noted
that their results correlated with previous findings showing that type
II T. gondii induces high levels of IL12A and IL12B (161561) secretion,
whereas type I T. gondii induces STAT3 activation and prevents IL12
expression.
Using human and mouse cells, Chen et al. (2011) found that viruses or
cytoplasmic nucleic acids triggered STING (TMEM173; 612374) to recruit
STAT6 to the endoplasmic reticulum, where STAT6 was phosphorylated on
ser407 by TBK1 (604834) and on tyr641 in a Janus kinase (see
147795)-independent manner. Phosphorylated STAT6 dimerized and
translocated to the nucleus to induce genes involved in cell homing.
Unlike the cell-type specific role of STAT6 in cytokine signaling,
virus-induced STAT6 activation was detected in all cell types tested.
Mice lacking Stat6 were susceptible to virus infection. Chen et al.
(2011) concluded that STAT6 mediates immune signaling in response to
cytokines at the plasma membrane and to virus infection at the
endoplasmic reticulum.
CYTOGENETICS
- NAB2/STAT6 Gene Fusion in Solitary Fibrous Tumors
Using whole-exome sequencing, Chmielecki et al. (2013) identified fusion
of the NAB2 (602381) and STAT6 genes in 7 of 17 solitary fibrous tumors
(SFTs). Analysis in 53 tumors confirmed the presence of 7 variants of
this fusion transcript in 29 tumors (55%). Fusion analysis of
approximately 713 unique tumor-normal pairs from 5 tumor types did not
identify any fusions involving these genes, suggesting that the
NAB2/STAT6 fusion may be unique to SFTs.
Following the identification of a gene fusion of the transcriptional
repressor NAB2 with the transcriptional activator STAT6 in a recurrent
SFT, Robinson et al. (2013) identified a NAB2/STAT6 fusion gene in all
of 51 SFTs using transcriptome sequencing and RT-PCR combined with
capillary sequencing. The NAB2/STAT6 fusion was present regardless of
the anatomic site of origin or malignant versus benign status.
Expression of NAB2/STAT6 fusion protein was confirmed in SFTs. The
predicted fusion products harbored the early growth response
(EGR)-binding domain of NAB2 fused to the activation domain of STAT6.
Overexpression of the NAB2/STAT6 gene fusion induced proliferation in
cultured cells and activated the expression of EGR responsive genes.
Proliferation could be inhibited by small interfering RNA (siRNA)
knockdown of EGR1 expression. Robinson et al. (2013) concluded their
studies established the NAB2/STAT6 fusion as the defining driver
mutation of SFT and provided an example of how neoplasia can be
initiated by converting a transcriptional repressor of mitogenic
pathways into a transcriptional activator.
MOLECULAR GENETICS
Duetsch et al. (2002) identified 13 single-nucleotide polymorphisms
(SNPs) in STAT6 and tested them for linkage/association with asthma
(600807) and related traits (total serum IgE level, eosinophil cell
count, and SLOPE of the dose-response curve after bronchial challenge)
in 108 Caucasian sib-pairs. Neither the SNPs nor a GT repeat in exon 1
showed linkage/association to asthma. A significant association was
found between a SNP in intron 18 and an increase in total IgE levels (P
= 0.0070), as well as an association between allele A4 of the GT repeat
polymorphism and an increase in eosinophil cell count (P = 0.0010). The
authors concluded that rather than contributing to the pathogenesis of
asthma, the human STAT6 gene is more likely involved in the development
of eosinophilia and changes in total IgE levels.
In a case-control association study of 214 white British subjects, Gao
et al. (2004) demonstrated a significant association with asthma of an
allele with a 13-GT repeat sequence in exon 1 of the STAT6 gene (OR,
1.52; 95% CI, 1.02-2.28; p = 0.027), whereas the 16-GT allele showed an
inverse association with asthma (p = 0.018). Furthermore, individuals
with the 13-GT allele had higher IgE levels compared with individuals
with the 16-GT allele (p = 0.004). Transient transfection assays of
different alleles revealed significantly higher transcriptional activity
with the 13-GT allele compared to the 16-GT allele in Jurkat, HMC-1, and
BEAS-2B cell lines. Gao et al. (2004) suggested that the GT repeat
polymorphism of the STAT6 gene contributes to susceptibility to atopic
asthma and total serum IgE levels, and that variation in the length of
the GT repeat sequence influences the regulation of promoter activity.
Several studies have shown linkage of 12q13-q24 with atopy (see
147050)-related phenotypes. STAT6 is 1 of the candidate genes in this
region, because of its involvement in Th2 cell differentiation,
recruitment, and effector function. Studying a population-based
cross-sectional cohort of 1,407 German adults, Weidinger et al. (2004)
evaluated 6 polymorphisms of STAT6 for evidence of association with
serum IgE levels and atopic disease. One polymorphism in intron 2 (dbSNP
rs324011) showed a significant association with total serum IgE (p =
0.015). A STAT6 risk haplotype for elevated IgE showed odds ratios of
1.54 (p = 0.032), 1.6 (p = 0.025), and 2.54 (p = 0.007) for IgE
percentiles of 50%, 60%, and 90%, respectively.
ANIMAL MODEL
Kuperman et al. (2002) developed mice conditionally expressing STAT6
only in the lung epithelium and demonstrated that these mice were
protected from all pulmonary effects of IL13 (147683), a critical
mediator of allergic asthma. Reconstitution of STAT6 only in epithelial
cells was sufficient for IL13-induced airway hyperreactivity and mucus
production in the absence of inflammation, fibrosis, or other lung
pathology.
Bour-Jordan et al. (2003) showed that T cells from double-knockout mice
deficient in Ctla4 (123890) and Stat6 were skewed toward a Th2 phenotype
in vitro and in vivo by bypassing the need for Stat6. Instead, induction
of Gata3 (131320) occurred in vitro and Cd4 (186940)-positive cells
migrated to peripheral tissues in vivo. In addition, T-cell receptor
crosslinking induced a relative increase of Nfatc1 (600489) versus
Nfatc2 (600490) nuclear translocation and enhanced NFKB (164011)
activation compared with Stat6 -/- T cells. Bour-Jordan et al. (2003)
proposed that CTLA4 regulates T-cell differentiation by controlling the
overall strength of the T-cell activation signal, bypassing the cytokine
dependency of Th2 differentiation.
Wang et al. (2004) noted that BALB/c mice are prone to develop Th2
rather than Th1 responses to antigen and are resistant to experimental
myasthenia gravis (MG; 254200). However, they found that after
immunization with muscle acetylcholine receptor (AChR; see 100725),
BALB/c mice lacking Stat6 were susceptible to EMG and developed more
anti-AChR antibodies and complement-fixing anti-AChR antibodies than
wildtype or Stat4 -/- mice. Stat6 -/- mouse Cd4-positive T cells
proliferated to AChR in a manner comparable to wildtype and Stat4 -/-
mice, but Stat6 -/- mice had abundant AChR-specific Ifng-producing Th1
cells that were nearly absent in wildtype and Stat4 -/- mice. Wang et
al. (2004) concluded that anti-AChR Th1 cells are important in MG
pathogenesis.
Chen et al. (2011) reported that mice lacking Stat6 were susceptible to
virus infection.
Rosen et al. (2013) investigated the role of Stat6 in oxazolone colitis,
a murine model of ulcerative colitis (266600). Colitic wildtype mice had
increased Stat6 phosphorylation in epithelial cells, T cells,
macrophages, and NKT cells. Mice lacking Stat6 had reduced colitis and
decreased induction of the pore-forming tight junction protein Cldn2
(300520). Likewise, STAT6 knockdown in human colon epithelial cells
reduced CLDN2 induction. Wildtype mice, but not Stat6 -/- mice, had
increased mRNA expression of the Th2-inducing cytokines Il33 (608678)
and thymic stromal lymphopoietin (TSLP; 607003). Mesenteric lymph node
(MLN) cells from Stat6 -/- mice with colitis exhibited reduced secretion
of Il4, Il5 (147850), Il13, and Ifng. Il33 augmented secretion of Il5,
Il6 (147620), Il13, and Ifng from both wildtype and Stat6 -/- MLN cells.
Rosen et al. (2013) concluded that STAT6 is involved in the pathogenesis
of ulcerative colitis and has important roles in altering epithelial
barrier function and regulating Th2-inducing cytokine production.
*FIELD* RF
1. Bour-Jordan, H.; Grogan, J. L.; Tang, Q.; Auger, J. A.; Locksley,
R. M.; Bluestone, J. A.: CTLA-4 regulates the requirement for cytokine-induced
signals in T(H)2 lineage commitment. Nature Immun. 4: 182-188, 2003.
2. Chen, H.; Sun, H.; You, F.; Sun, W.; Zhou, X.; Chen, L.; Yang,
J.; Wang, Y.; Tang, H.; Guan, Y.; Xia, W.; Gu, J.; Ishikawa, H.; Gutman,
D.; Barber, G.; Qin, Z.; Jiang, Z.: Activation of STAT6 by STING
is critical for antiviral innate immunity. Cell 147: 436-446, 2011.
3. Chmielecki, J.; Crago, A. M.; Rosenberg, M.; O'Connor, R.; Walker,
S. R.; Ambrogio, L.; Auclair, D.; McKenna, A.; Heinrich, M. C.; Frank,
D. A.; Meyerson, M.: Whole-exome sequencing identifies a recurrent
NAB2-STAT6 fusion in solitary fibrous tumors. Nature Genet. 45:
131-135, 2013.
4. Christodoulopoulos, P.; Cameron, L.; Nakamura, Y.; Lemiere, C.;
Muro, S.; Dugas, M.; Boulet, L.-P.; Laviolette, M.; Olivenstein, R.;
Hamid, Q.: Th2 cytokine-associated transcription factors in atopic
and nonatopic asthma: evidence for differential signal transducer
and activator of transcription 6 expression. J. Allergy Clin. Immun. 107:
586-591, 2001.
5. Copeland, N. G.; Gilbert, D. J.; Schindler, C.; Zhong, Z.; Wen,
Z.; Darnell, J. E., Jr.; Mui, A. L.-F.; Miyajima, A.; Quelle, F. W.;
Ihle, J. N.; Jenkins, N. A.: Distribution of the mammalian Stat gene
family in mouse chromosomes. Genomics 29: 225-228, 1995.
6. Darnell, J. E., Jr.: Reflections on STAT3, STAT5, and STAT6 as
fat STATs. Proc. Nat. Acad. Sci. 93: 6221-6224, 1996.
7. Dickensheets, H. L.; Venkataraman, C.; Schindler, U.; Donnelly,
R. P.: Interferons inhibit activation of STAT6 by interleukin 4 in
human monocytes by inducing SOCS-1 gene expression. Proc. Nat. Acad.
Sci. 96: 10800-10805, 1999.
8. Duetsch, G.; Illig, T.; Loesgen, S.; Rohde, K.; Kloop, N.; Herbon,
N.; Cohlke, H.; Altmueller, J.; Wjst, M.: STAT6 as an asthma candidate
gene: polymorphism-screening, association and haplotype analysis in
a Caucasian sib-pair study. Hum. Molec. Genet. 11: 613-621, 2002.
9. Gao, P. S.; Heller, N. M.; Walker, W.; Chen, C. H.; Moller, M.;
Plunkett, B.; Roberts, M. H.; Schleimer, R. P.; Hopkin, J. M.; Huang,
S. K.: Variation in dinucleotide (GT) repeat sequence in the first
exon of the STAT6 gene is associated with atopic asthma and differentially
regulates the promoter activity in vitro. (Letter) J. Med. Genet. 41:
535-539, 2004.
10. Ghilardi, N.; Ziegler, S.; Wiestner, A.; Stoffel, R.; Heim, M.
H.; Skoda, R. C.: Defective STAT signaling by the leptin receptor
in diabetic mice. Proc. Nat. Acad. Sci. 93: 6231-6235, 1996.
11. Hou, J.; Schindler, U.; Henzel, W. J.; Ho, T. C.; Brasseur, M.;
McKnight, S. L.: An interleukin-4-induced transcription factor: IL-4
Stat. Science 265: 1701-1706, 1994.
12. Kotanides, H.; Reich, N. C.: Interleukin-4-induced STAT6 recognizes
and activates a target site in the promoter of the interleukin-4 receptor
gene. J. Biol. Chem. 271: 25555-25561, 1996.
13. Kuperman, D. A.; Huang, X.; Koth, L. L.; Chang, G. H.; Dolganov,
G. M.; Zhu, Z.; Elias, J. A.; Sheppard, D.; Erle, D. J.: Direct effects
of interleukin-13 on epithelial cells cause airway hyperreactivity
and mucus overproduction in asthma. Nature Med. 8: 885-889, 2002.
14. Leek, J. P.; Hamlin, P. J.; Bell, S. M.; Lench, N. J.: Assignment
of the STAT6 gene (STAT6) to human chromosome band 12q13 by in situ
hybridization. Cytogenet. Cell Genet. 79: 208-209, 1997.
15. Low, S. H.; Vasanth, S.; Larson, C. H.; Mukherjee, S.; Sharma,
N.; Kinter, M. T.; Kane, M. E.; Obara, T.; Weimbs, T.: Polycystin-1,
STAT6, and P100 function in a pathway that transduces ciliary mechanosensation
and is activated in polycystic kidney disease. Dev. Cell 10: 57-69,
2006.
16. Maldonado, R. A.; Irvine, D. J.; Schreiber, R.; Glimcher, L. H.
: A role for the immunological synapse in lineage commitment of CD4
lymphocytes. Nature 431: 527-532, 2004.
17. Muller-Ladner, U.; Judex, M.; Ballhorn, W.; Kullmann, F.; Distler,
O.; Schlottmann, K.; Gay, R. E.; Scholmerich, J.; Gay, S.: Activation
of the IL-4 STAT pathway in rheumatoid synovium. J. Immun. 164:
3894-3901, 2000.
18. Mullings, R. E.; Wilson, S. J.; Puddicombe, S. M.; Lordan, J.
L.; Bucchieri, F.; Djukanovic, R.; Howarth, P. H.; Harper, S.; Holgate,
S. T.; Davies, D. E.: Signal transducer and activator of transcription
6 (STAT-6) expression and function in asthmatic bronchial epithelium. J.
Allergy Clin. Immun. 108: 832-838, 2001.
19. Patel, B. K. R.; Keck, C. L.; O'Leary, R. S.; Popescu, N. C.;
LaRochelle, W. J.: Localization of the human Stat6 gene to chromosome
12q13.3-q14.1, a region implicated in multiple solid tumors. Genomics 52:
192-200, 1998.
20. Patel, B. K. R.; Pierce, J. H.; LaRochelle, W. J.: Regulation
of interleukin 4-mediated signaling by naturally occurring dominant
negative and attenuated forms of human Stat6. Proc. Nat. Acad. Sci. 95:
172-177, 1998.
21. Quelle, F. W.; Shimoda, K.; Thierfelder, W.; Fischer, C.; Kim,
A.; Ruben, S. M.; Cleveland, J. L.; Pierce, J. H.; Keegan, A. D.;
Nelms, K.; Paul, W. E.; Ihle, J. N.: Cloning of murine Stat6 and
human Stat6, Stat proteins that are tyrosine phosphorylated in responses
to IL-4 and IL-4 but are not required for mitogenesis. Molec. Cell.
Biol. 15: 3336-3343, 1995.
22. Robinson, D. R.; Wu, Y.-M.; Kalyana-Sundaram, S.; Cao, X.; Lonigro,
R. J.; Sung, Y.-S.; Chen, C.-L.; Zhang, L.; Wang, R.; Su, F.; Iyer,
M. K.; Roychowdhury, S.; and 9 others: Identification of recurrent
NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nature
Genet. 45: 180-185, 2013.
23. Rosen, M. J.; Chaturvedi, R.; Washington, M. K.; Kuhnhein, L.
A.; Moore, P. D.; Coggeshall, S. S.; McDonough, E. M.; Weitkamp, J.-H.;
Singh, A. B.; Coburn, L. A.; Williams, C. S.; Yan, F.; Van Kaer, L.;
Peebles, R. S., Jr.; Wilson, K. T.: STAT6 deficiency ameliorates
severity of oxazolone colitis by decreasing expression of claudin-2
and Th2-inducing cytokines. J. Immun. 190: 1849-1858, 2013.
24. Saeij, J. P. J.; Coller, S.; Boyle, J. P.; Jerome, M. E.; White,
M. W.; Boothroyd, J. C.: Toxoplasma co-opts host gene expression
by injection of a polymorphic kinase homologue. Nature 445: 324-327,
2007.
25. Svaren, J.; Apel, E. D.; Simburger, K. S.; Jenkins, N. A.; Gilbert,
D. J.; Copeland, N. A.; Milbrandt, J.: The Nab2 and Stat6 genes share
a common transcription termination region. Genomics 41: 33-39, 1997.
26. Wang, W.; Ostlie, N. S.; Conti-Fine, B. M.; Milani, M.: The susceptibility
to experimental myasthenia gravis of STAT6-/- and STAT4-/- BALB/c
mice suggests a pathogenic role of Th1 cells. J. Immun. 172: 97-103,
2004.
27. Weidinger, S.; Klopp, N.; Wagenpfeil, S.; Rummler, L.; Schedel,
M.; Kabesch, M.; Schafer, T.; Darsow, U.; Jakob, T.; Behrendt, H.;
Wichmann, H. E.; Ring, J.; Illig, T.: Association of a STAT 6 haplotype
with elevated serum IgE levels in a population based cohort of white
adults. J. Med. Genet. 41: 658-663, 2004.
*FIELD* CN
Paul J. Converse - updated: 11/6/2013
Ada Hamosh - updated: 4/10/2013
Paul J. Converse - updated: 11/21/2012
Paul J. Converse - updated: 1/30/2007
Paul J. Converse - updated: 10/5/2006
Patricia A. Hartz - updated: 2/8/2006
Victor A. McKusick - updated: 10/12/2004
Paul J. Converse - updated: 9/30/2004
Marla J. F. O'Neill - updated: 8/27/2004
Paul J. Converse - updated: 1/16/2003
George E. Tiller - updated: 10/9/2002
Paul J. Converse - updated: 6/2/2000
Joanna S. Amberger - updated: 5/25/2000
Paul J. Converse - updated: 5/18/2000
Victor A. McKusick - updated: 11/8/1999
Victor A. McKusick - updated: 5/28/1998
Jennifer P. Macke - updated: 4/24/1997
*FIELD* CD
Victor A. McKusick: 11/18/1996
*FIELD* ED
mgross: 11/11/2013
mcolton: 11/6/2013
mgross: 10/7/2013
alopez: 4/10/2013
mgross: 11/21/2012
mgross: 2/4/2009
mgross: 1/30/2007
mgross: 10/24/2006
terry: 10/5/2006
wwang: 3/2/2006
wwang: 2/15/2006
terry: 2/8/2006
alopez: 10/29/2004
tkritzer: 10/13/2004
terry: 10/12/2004
mgross: 9/30/2004
carol: 9/1/2004
terry: 8/27/2004
alopez: 2/28/2003
mgross: 1/16/2003
cwells: 10/9/2002
carol: 6/2/2000
terry: 6/1/2000
joanna: 5/25/2000
mgross: 5/18/2000
mgross: 11/8/1999
carol: 7/28/1999
dkim: 9/9/1998
terry: 5/28/1998
dholmes: 2/23/1998
alopez: 4/24/1997
jamie: 11/22/1996
mark: 11/21/1996
terry: 11/21/1996
mark: 11/20/1996
*RECORD*
*FIELD* NO
601512
*FIELD* TI
*601512 SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6; STAT6
;;STAT, INTERLEUKIN 4-INDUCED;;
read moreIL4-STAT
STAT6b, INCLUDED;;
STAT6c, INCLUDED;;
STAT6/NAB2 FUSION GENE, INCLUDED
*FIELD* TX
CLONING
By searching a database of expressed sequence tags (ESTs), Quelle et al.
(1995) identified a number of expressed genes in the signal transducers
and activators of a transcription (STAT) family. Human and murine
full-length cDNA clones were obtained and sequenced. The sequence of the
human cDNA was identical to the sequence published by Hou et al. (1994)
for the interleukin-4-induced transcription factor (called by them IL4
Stat), while the murine STAT6 amino acid and nucleotide sequences
reported by Quelle et al. (1995) were 83% and 84% identical to the human
sequences, respectively.
By screening an embryonic lung fibroblast cDNA library with a wildtype
STAT6 probe, Patel et al. (1998) identified 2 variant cDNAs, which they
termed STAT6b and STAT6c, encoding an N-terminal 110-amino acid
truncation and a 27-amino acid deletion in the SH2 domain, respectively.
RNase protection analysis detected ubiquitous expression of all 3
variants with STAT6b expression greatest in spleen and STAT6c expression
greatest in lung.
GENE STRUCTURE
Patel et al. (1998) characterized the genomic structure and flanking
regions of the human STAT6 gene. The gene spans 19 kb and contains 23
exons.
MAPPING
Copeland et al. (1995) found that 7 mouse Stat genes map in 3 clusters,
with each cluster located on a different autosome. They suggested that
the Stat family arose by a tandem duplication of the ancestral Stat
gene, followed by dispersion of the linked loci to different
chromosomes. They mapped Stat6 and Stat2 (600556) to the distal region
of chromosome 10. During an analysis of NAB2 (602381), Svaren et al.
(1997) obtained the sequence adjacent to this gene by PCR of genomic
DNA. They found that the STAT6 gene is located unusually close to the
NAB2 gene, such that the 3-prime ends of their mRNAs overlap. Since the
human NAB2 gene was previously mapped to 12q13.3-q14.1, it is likely
that STAT6 maps to the same position. By fluorescence in situ
hybridization, Leek et al. (1997) mapped STAT6 to 12q13.
GENE FUNCTION
Using STAT6-specific antiserum, Quelle et al. (1995) demonstrated that
STAT6 is rapidly tyrosine phosphorylated following stimulation of
appropriate cell lines with IL4 (147780) or IL3 (147740), but is not
detectably phosphorylated following stimulation with IL2 (147680), IL12
(see IL12A; 161560), or erythropoietin (133170). In contrast, IL2, IL3,
and erythropoietin induced the tyrosine phosphorylation of STAT5
(601511), while IL12 uniquely induced the tyrosine phosphorylation of
STAT4 (600558). Inducible tyrosine phosphorylation of STAT6 required the
membrane-distal region of the IL4 receptor alpha chain (IL4R; 147781).
They found that this region of the receptor is not required for cell
growth, demonstrating that STAT6 tyrosine phosphorylation does not
contribute to mitogenesis.
Ghilardi et al. (1996) demonstrated that along with STAT3 (102582) and
STAT5, STAT6 is involved in signaling from the leptin receptor (601007)
and that this signaling is defective in the db/db mouse which carries a
point mutation within the leptin receptor gene. Darnell (1996) reflected
on STAT3, STAT5, and STAT6 as 'fat STATs,' i.e., the involvement of
these 3 STATs, but not STAT1, STAT2, and STAT4, in the physiologic
action of leptin (164160) as described by Ghilardi et al. (1996).
Kotanides and Reich (1996) identified a specific STAT6 DNA-binding
target site in the promoter of the IL4R gene and showed that STAT6
activates IL4 gene expression via this site.
By functional analysis, Patel et al. (1998) determined that the STAT6b
variant resembles an attenuated STAT6, but that the STAT6c variant
inhibits IL4-mediated mitogenesis and cell surface antigen expression,
and is not tyrosine phosphorylated.
Dickensheets et al. (1999) presented evidence that interferons inhibit
IL4-induced activation of STAT6 and STAT6-dependent gene expression, at
least in part, by inducing expression of SOCS1 (603597).
Upregulation of proinflammatory cytokines in rheumatoid arthritis (RA;
180300) synovium and synovial fluid is a feature of active disease and
intense inflammation. Antiinflammatory mediators are also present and
activated in RA but fail to counterregulate the proinflammatory
cytokines. Muller-Ladner et al. (2000) found that the IL4-STAT pathway
is activated in patients with short-term (less than 1 year) and
long-term (more than 2 years) RA and may contribute to downregulation of
the immunologic activity in RA synovium.
Using immunocytochemistry, Christodoulopoulos et al. (2001) measured the
expression of STAT6 in bronchial biopsy specimens from patients with
atopic and nonatopic asthma and controls and found that there were more
STAT6-immunoreactive cells in patients with atopic and with nonatopic
asthma than in control subjects (p less than 0.0001 and 0.05,
respectively). The authors also observed that there were fewer cells
expressing STAT6 protein in nonatopic versus atopic asthma (p less than
0.0001) and concluded that reduced IL4R signaling, due to lower STAT6
expression, may be a feature of nonatopic asthma.
Mullings et al. (2001) investigated STAT6 expression in bronchial biopsy
specimens or brushings from normal control or asthmatic subjects and
found that the bronchial epithelium is the major site of STAT6
expression. Levels of expression in controls and subjects with mild
asthma did not differ significantly; however, STAT6 expression was
significantly increased in subjects with severe asthma (p less than
0.05).
Using confocal microscopy, Maldonado et al. (2004) found a random
distribution of Tcrb (see 186930), Il4r, and Ifngr1 (107470) in fixed
and permeabilized mouse naive T-helper lymphocytes (Thp) conjugated with
mouse mature splenic dendritic cells (DCs). In cells fixed and
permeabilized 30 minutes after conjugation of Thp and antigen-loaded
DCs, the authors observed a calcium- and Ifng (147570)-dependent
colocalization of Tcrb and Ifngr1, but not Il4r, at the Thp-DC
interface. This observation was more apparent in the Th1-prone C57Bl/6
mouse strain than in the Th2-prone BALB/c strain. In the presence of
Il4, but not Il10 (124092), Ifngr1 migration and copolarization was
completely inhibited. In mice lacking the Il4r signaling molecule,
Stat6, prevention of Tcrb/Ifngr1 copolarization was abolished. Maldonado
et al. (2004) proposed that strong TCR signaling leads to accentuated
IFNGR copolarization and the assembly of a Th1 signalosome, which is
further stabilized by secretion of IFNG, unless an inhibitory signal,
such as IL4 secretion and STAT6 activation, occurs and leads to the
assembly of a Th2 signalosome. They concluded that the immunologic
synapse may be involved in the control of cell fate decisions.
Following its proteolytic release and nuclear translocation, Low et al.
(2006) found that the C-terminal tail of human polycystin-1 (PKD1;
601313) interacted with Stat6 and the coactivator P100 (602181) in
canine kidney cells and stimulated Stat6-dependent gene expression.
Under normal conditions, Stat6 localized to primary cilia of renal
epithelial cells; however, cessation of apical fluid flow resulted in
its nuclear translocation. Cyst-lining cells in autosomal dominant
polycystic kidney disease exhibited elevated levels of nuclear STAT6,
P100, and the polycystin-1 C-terminal tail. Exogenous expression of the
human polycystin-1 C-terminal tail resulted in renal cyst formation in
zebrafish embryos. Low et al. (2006) concluded that upregulation of the
STAT6/P100 pathway by the polycystin-1 C-terminal tail leads to the
cellular changes characteristic of renal cysts.
Most Toxoplasma gondii isolates in Europe and North America belong to 3
clonal lines, designated types I, II, and III. Using microarray,
immunofluorescence, and Western blot analyses, Saeij et al. (2007) found
that STAT3 and STAT6 were activated predominantly in fibroblasts
infected with types I and III, rather than type II, T. gondii. They
determined that the T. gondii Rop16 protein kinase mediated the
strain-specific activation of STAT3 and STAT6. Saeij et al. (2007) noted
that their results correlated with previous findings showing that type
II T. gondii induces high levels of IL12A and IL12B (161561) secretion,
whereas type I T. gondii induces STAT3 activation and prevents IL12
expression.
Using human and mouse cells, Chen et al. (2011) found that viruses or
cytoplasmic nucleic acids triggered STING (TMEM173; 612374) to recruit
STAT6 to the endoplasmic reticulum, where STAT6 was phosphorylated on
ser407 by TBK1 (604834) and on tyr641 in a Janus kinase (see
147795)-independent manner. Phosphorylated STAT6 dimerized and
translocated to the nucleus to induce genes involved in cell homing.
Unlike the cell-type specific role of STAT6 in cytokine signaling,
virus-induced STAT6 activation was detected in all cell types tested.
Mice lacking Stat6 were susceptible to virus infection. Chen et al.
(2011) concluded that STAT6 mediates immune signaling in response to
cytokines at the plasma membrane and to virus infection at the
endoplasmic reticulum.
CYTOGENETICS
- NAB2/STAT6 Gene Fusion in Solitary Fibrous Tumors
Using whole-exome sequencing, Chmielecki et al. (2013) identified fusion
of the NAB2 (602381) and STAT6 genes in 7 of 17 solitary fibrous tumors
(SFTs). Analysis in 53 tumors confirmed the presence of 7 variants of
this fusion transcript in 29 tumors (55%). Fusion analysis of
approximately 713 unique tumor-normal pairs from 5 tumor types did not
identify any fusions involving these genes, suggesting that the
NAB2/STAT6 fusion may be unique to SFTs.
Following the identification of a gene fusion of the transcriptional
repressor NAB2 with the transcriptional activator STAT6 in a recurrent
SFT, Robinson et al. (2013) identified a NAB2/STAT6 fusion gene in all
of 51 SFTs using transcriptome sequencing and RT-PCR combined with
capillary sequencing. The NAB2/STAT6 fusion was present regardless of
the anatomic site of origin or malignant versus benign status.
Expression of NAB2/STAT6 fusion protein was confirmed in SFTs. The
predicted fusion products harbored the early growth response
(EGR)-binding domain of NAB2 fused to the activation domain of STAT6.
Overexpression of the NAB2/STAT6 gene fusion induced proliferation in
cultured cells and activated the expression of EGR responsive genes.
Proliferation could be inhibited by small interfering RNA (siRNA)
knockdown of EGR1 expression. Robinson et al. (2013) concluded their
studies established the NAB2/STAT6 fusion as the defining driver
mutation of SFT and provided an example of how neoplasia can be
initiated by converting a transcriptional repressor of mitogenic
pathways into a transcriptional activator.
MOLECULAR GENETICS
Duetsch et al. (2002) identified 13 single-nucleotide polymorphisms
(SNPs) in STAT6 and tested them for linkage/association with asthma
(600807) and related traits (total serum IgE level, eosinophil cell
count, and SLOPE of the dose-response curve after bronchial challenge)
in 108 Caucasian sib-pairs. Neither the SNPs nor a GT repeat in exon 1
showed linkage/association to asthma. A significant association was
found between a SNP in intron 18 and an increase in total IgE levels (P
= 0.0070), as well as an association between allele A4 of the GT repeat
polymorphism and an increase in eosinophil cell count (P = 0.0010). The
authors concluded that rather than contributing to the pathogenesis of
asthma, the human STAT6 gene is more likely involved in the development
of eosinophilia and changes in total IgE levels.
In a case-control association study of 214 white British subjects, Gao
et al. (2004) demonstrated a significant association with asthma of an
allele with a 13-GT repeat sequence in exon 1 of the STAT6 gene (OR,
1.52; 95% CI, 1.02-2.28; p = 0.027), whereas the 16-GT allele showed an
inverse association with asthma (p = 0.018). Furthermore, individuals
with the 13-GT allele had higher IgE levels compared with individuals
with the 16-GT allele (p = 0.004). Transient transfection assays of
different alleles revealed significantly higher transcriptional activity
with the 13-GT allele compared to the 16-GT allele in Jurkat, HMC-1, and
BEAS-2B cell lines. Gao et al. (2004) suggested that the GT repeat
polymorphism of the STAT6 gene contributes to susceptibility to atopic
asthma and total serum IgE levels, and that variation in the length of
the GT repeat sequence influences the regulation of promoter activity.
Several studies have shown linkage of 12q13-q24 with atopy (see
147050)-related phenotypes. STAT6 is 1 of the candidate genes in this
region, because of its involvement in Th2 cell differentiation,
recruitment, and effector function. Studying a population-based
cross-sectional cohort of 1,407 German adults, Weidinger et al. (2004)
evaluated 6 polymorphisms of STAT6 for evidence of association with
serum IgE levels and atopic disease. One polymorphism in intron 2 (dbSNP
rs324011) showed a significant association with total serum IgE (p =
0.015). A STAT6 risk haplotype for elevated IgE showed odds ratios of
1.54 (p = 0.032), 1.6 (p = 0.025), and 2.54 (p = 0.007) for IgE
percentiles of 50%, 60%, and 90%, respectively.
ANIMAL MODEL
Kuperman et al. (2002) developed mice conditionally expressing STAT6
only in the lung epithelium and demonstrated that these mice were
protected from all pulmonary effects of IL13 (147683), a critical
mediator of allergic asthma. Reconstitution of STAT6 only in epithelial
cells was sufficient for IL13-induced airway hyperreactivity and mucus
production in the absence of inflammation, fibrosis, or other lung
pathology.
Bour-Jordan et al. (2003) showed that T cells from double-knockout mice
deficient in Ctla4 (123890) and Stat6 were skewed toward a Th2 phenotype
in vitro and in vivo by bypassing the need for Stat6. Instead, induction
of Gata3 (131320) occurred in vitro and Cd4 (186940)-positive cells
migrated to peripheral tissues in vivo. In addition, T-cell receptor
crosslinking induced a relative increase of Nfatc1 (600489) versus
Nfatc2 (600490) nuclear translocation and enhanced NFKB (164011)
activation compared with Stat6 -/- T cells. Bour-Jordan et al. (2003)
proposed that CTLA4 regulates T-cell differentiation by controlling the
overall strength of the T-cell activation signal, bypassing the cytokine
dependency of Th2 differentiation.
Wang et al. (2004) noted that BALB/c mice are prone to develop Th2
rather than Th1 responses to antigen and are resistant to experimental
myasthenia gravis (MG; 254200). However, they found that after
immunization with muscle acetylcholine receptor (AChR; see 100725),
BALB/c mice lacking Stat6 were susceptible to EMG and developed more
anti-AChR antibodies and complement-fixing anti-AChR antibodies than
wildtype or Stat4 -/- mice. Stat6 -/- mouse Cd4-positive T cells
proliferated to AChR in a manner comparable to wildtype and Stat4 -/-
mice, but Stat6 -/- mice had abundant AChR-specific Ifng-producing Th1
cells that were nearly absent in wildtype and Stat4 -/- mice. Wang et
al. (2004) concluded that anti-AChR Th1 cells are important in MG
pathogenesis.
Chen et al. (2011) reported that mice lacking Stat6 were susceptible to
virus infection.
Rosen et al. (2013) investigated the role of Stat6 in oxazolone colitis,
a murine model of ulcerative colitis (266600). Colitic wildtype mice had
increased Stat6 phosphorylation in epithelial cells, T cells,
macrophages, and NKT cells. Mice lacking Stat6 had reduced colitis and
decreased induction of the pore-forming tight junction protein Cldn2
(300520). Likewise, STAT6 knockdown in human colon epithelial cells
reduced CLDN2 induction. Wildtype mice, but not Stat6 -/- mice, had
increased mRNA expression of the Th2-inducing cytokines Il33 (608678)
and thymic stromal lymphopoietin (TSLP; 607003). Mesenteric lymph node
(MLN) cells from Stat6 -/- mice with colitis exhibited reduced secretion
of Il4, Il5 (147850), Il13, and Ifng. Il33 augmented secretion of Il5,
Il6 (147620), Il13, and Ifng from both wildtype and Stat6 -/- MLN cells.
Rosen et al. (2013) concluded that STAT6 is involved in the pathogenesis
of ulcerative colitis and has important roles in altering epithelial
barrier function and regulating Th2-inducing cytokine production.
*FIELD* RF
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*FIELD* CN
Paul J. Converse - updated: 11/6/2013
Ada Hamosh - updated: 4/10/2013
Paul J. Converse - updated: 11/21/2012
Paul J. Converse - updated: 1/30/2007
Paul J. Converse - updated: 10/5/2006
Patricia A. Hartz - updated: 2/8/2006
Victor A. McKusick - updated: 10/12/2004
Paul J. Converse - updated: 9/30/2004
Marla J. F. O'Neill - updated: 8/27/2004
Paul J. Converse - updated: 1/16/2003
George E. Tiller - updated: 10/9/2002
Paul J. Converse - updated: 6/2/2000
Joanna S. Amberger - updated: 5/25/2000
Paul J. Converse - updated: 5/18/2000
Victor A. McKusick - updated: 11/8/1999
Victor A. McKusick - updated: 5/28/1998
Jennifer P. Macke - updated: 4/24/1997
*FIELD* CD
Victor A. McKusick: 11/18/1996
*FIELD* ED
mgross: 11/11/2013
mcolton: 11/6/2013
mgross: 10/7/2013
alopez: 4/10/2013
mgross: 11/21/2012
mgross: 2/4/2009
mgross: 1/30/2007
mgross: 10/24/2006
terry: 10/5/2006
wwang: 3/2/2006
wwang: 2/15/2006
terry: 2/8/2006
alopez: 10/29/2004
tkritzer: 10/13/2004
terry: 10/12/2004
mgross: 9/30/2004
carol: 9/1/2004
terry: 8/27/2004
alopez: 2/28/2003
mgross: 1/16/2003
cwells: 10/9/2002
carol: 6/2/2000
terry: 6/1/2000
joanna: 5/25/2000
mgross: 5/18/2000
mgross: 11/8/1999
carol: 7/28/1999
dkim: 9/9/1998
terry: 5/28/1998
dholmes: 2/23/1998
alopez: 4/24/1997
jamie: 11/22/1996
mark: 11/21/1996
terry: 11/21/1996
mark: 11/20/1996