NR2F6_HUMAN
ID NR2F6_HUMAN Reviewed; 404 AA.
AC P10588; B2RC68; Q5XGA0; Q6P586; Q9BUE8;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 19-SEP-2002, sequence version 2.
DT 03-AUG-2022, entry version 216.
DE RecName: Full=Nuclear receptor subfamily 2 group F member 6;
DE AltName: Full=V-erbA-related protein 2;
DE Short=EAR-2;
GN Name=NR2F6; Synonyms=EAR2, ERBAL2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Fetal lung;
RX PubMed=2905047; DOI=10.1093/nar/16.23.11057;
RA Miyajima N., Kadowaki Y., Fukushige S., Shimizu S., Semba K., Yamanashi Y.,
RA Matsubara K., Toyoshima K., Yamamoto T.;
RT "Identification of two novel members of erbA superfamily by molecular
RT cloning: the gene products of the two are highly related to each other.";
RL Nucleic Acids Res. 16:11057-11074(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., 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., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA 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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney, Pancreas, and 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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=10644740; DOI=10.1074/jbc.275.4.2763;
RA Zhang Y., Dufau M.L.;
RT "Nuclear orphan receptors regulate transcription of the gene for the human
RT luteinizing hormone receptor.";
RL J. Biol. Chem. 275:2763-2770(2000).
RN [6]
RP FUNCTION, TISSUE SPECIFICITY, DNA-BINDING, INTERACTION WITH THRB, AND
RP MUTAGENESIS OF 74-GLU--SER-78.
RX PubMed=10713182; DOI=10.1128/mcb.20.7.2604-2618.2000;
RA Zhu X.G., Park K.S., Kaneshige M., Bhat M.K., Zhu Q., Mariash C.N.,
RA McPhie P., Cheng S.Y.;
RT "The orphan nuclear receptor Ear-2 is a negative coregulator for thyroid
RT hormone nuclear receptor function.";
RL Mol. Cell. Biol. 20:2604-2618(2000).
RN [7]
RP FUNCTION, SUBUNIT, AND INDUCTION BY GONADOTROPIN.
RX PubMed=11682620; DOI=10.1210/mend.15.11.0720;
RA Zhang Y., Dufau M.L.;
RT "EAR2 and EAR3/COUP-TFI regulate transcription of the rat LH receptor.";
RL Mol. Endocrinol. 15:1891-1905(2001).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-83.
RX PubMed=18701084; DOI=10.1016/j.immuni.2008.06.008;
RA Hermann-Kleiter N., Gruber T., Lutz-Nicoladoni C., Thuille N., Fresser F.,
RA Labi V., Schiefermeier N., Warnecke M., Huber L., Villunger A., Eichele G.,
RA Kaminski S., Baier G.;
RT "The nuclear orphan receptor NR2F6 suppresses lymphocyte activation and T
RT helper 17-dependent autoimmunity.";
RL Immunity 29:205-216(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-40, AND IDENTIFICATION BY
RP 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 [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-40, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
CC -!- FUNCTION: Transcription factor predominantly involved in
CC transcriptional repression. Binds to promoter/enhancer response
CC elements that contain the imperfect 5'-AGGTCA-3' direct or inverted
CC repeats with various spacings which are also recognized by other
CC nuclear hormone receptors. Involved in modulation of hormonal
CC responses. Represses transcriptional activity of the lutropin-
CC choriogonadotropic hormone receptor/LHCGR gene, the renin/REN gene and
CC the oxytocin-neurophysin/OXT gene. Represses the triiodothyronine-
CC dependent and -independent transcriptional activity of the thyroid
CC hormone receptor gene in a cell type-specific manner. The corepressing
CC function towards thyroid hormone receptor beta/THRB involves at least
CC in part the inhibition of THRB binding to triiodothyronine response
CC elements (TREs) by NR2F6. Inhibits NFATC transcription factor DNA
CC binding and subsequently its transcriptional activity. Acts as
CC transcriptional repressor of IL-17 expression in Th-17 differentiated
CC CD4(+) T cells and may be involved in induction and/or maintenance of
CC peripheral immunological tolerance and autoimmunity. Involved in
CC development of forebrain circadian clock; is required early in the
CC development of the locus coeruleus (LC). {ECO:0000269|PubMed:10644740,
CC ECO:0000269|PubMed:10713182, ECO:0000269|PubMed:11682620,
CC ECO:0000269|PubMed:18701084}.
CC -!- SUBUNIT: Binds DNA as dimer; homodimer and heterodimer with NR2F2 and
CC probably NR2F1 (By similarity). Interacts with THRB. {ECO:0000250,
CC ECO:0000269|PubMed:10713182, ECO:0000269|PubMed:11682620}.
CC -!- INTERACTION:
CC P10588; P83916: CBX1; NbExp=2; IntAct=EBI-2681496, EBI-78129;
CC P10588; P55209: NAP1L1; NbExp=2; IntAct=EBI-2681496, EBI-356392;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00407,
CC ECO:0000269|PubMed:10644740, ECO:0000269|PubMed:18701084}.
CC -!- TISSUE SPECIFICITY: Expressed in heart, placenta, liver, skeletal
CC muscle, kidney and pancreas. {ECO:0000269|PubMed:10713182}.
CC -!- INDUCTION: Inhibited by gonadotropin in granulosa cells.
CC {ECO:0000269|PubMed:11682620}.
CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR2
CC subfamily. {ECO:0000305}.
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DR EMBL; X12794; CAA31282.1; -; Genomic_DNA.
DR EMBL; AK314961; BAG37465.1; -; mRNA.
DR EMBL; CH471106; EAW84580.1; -; Genomic_DNA.
DR EMBL; BC002669; AAH02669.3; -; mRNA.
DR EMBL; BC063018; AAH63018.2; -; mRNA.
DR EMBL; BC084544; AAH84544.2; -; mRNA.
DR CCDS; CCDS12352.1; -.
DR PIR; S02709; S02709.
DR RefSeq; NP_005225.2; NM_005234.3.
DR AlphaFoldDB; P10588; -.
DR SMR; P10588; -.
DR BioGRID; 108375; 42.
DR IntAct; P10588; 25.
DR MINT; P10588; -.
DR STRING; 9606.ENSP00000291442; -.
DR ChEMBL; CHEMBL1961791; -.
DR iPTMnet; P10588; -.
DR PhosphoSitePlus; P10588; -.
DR BioMuta; NR2F6; -.
DR DMDM; 23503053; -.
DR EPD; P10588; -.
DR jPOST; P10588; -.
DR MassIVE; P10588; -.
DR MaxQB; P10588; -.
DR PaxDb; P10588; -.
DR PeptideAtlas; P10588; -.
DR PRIDE; P10588; -.
DR ProteomicsDB; 52614; -.
DR Antibodypedia; 14278; 399 antibodies from 36 providers.
DR DNASU; 2063; -.
DR Ensembl; ENST00000291442.4; ENSP00000291442.2; ENSG00000160113.6.
DR GeneID; 2063; -.
DR KEGG; hsa:2063; -.
DR MANE-Select; ENST00000291442.4; ENSP00000291442.2; NM_005234.4; NP_005225.2.
DR UCSC; uc002nfq.4; human.
DR CTD; 2063; -.
DR DisGeNET; 2063; -.
DR GeneCards; NR2F6; -.
DR HGNC; HGNC:7977; NR2F6.
DR HPA; ENSG00000160113; Tissue enhanced (liver).
DR MIM; 132880; gene.
DR neXtProt; NX_P10588; -.
DR OpenTargets; ENSG00000160113; -.
DR PharmGKB; PA31760; -.
DR VEuPathDB; HostDB:ENSG00000160113; -.
DR eggNOG; KOG3575; Eukaryota.
DR GeneTree; ENSGT00940000160748; -.
DR HOGENOM; CLU_007368_20_1_1; -.
DR InParanoid; P10588; -.
DR OMA; GWGNPNR; -.
DR OrthoDB; 666130at2759; -.
DR PhylomeDB; P10588; -.
DR TreeFam; TF352097; -.
DR PathwayCommons; P10588; -.
DR Reactome; R-HSA-383280; Nuclear Receptor transcription pathway.
DR SignaLink; P10588; -.
DR SIGNOR; P10588; -.
DR BioGRID-ORCS; 2063; 17 hits in 1105 CRISPR screens.
DR ChiTaRS; NR2F6; human.
DR GeneWiki; V-erbA-related_gene; -.
DR GenomeRNAi; 2063; -.
DR Pharos; P10588; Tbio.
DR PRO; PR:P10588; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; P10588; protein.
DR Bgee; ENSG00000160113; Expressed in parotid gland and 198 other tissues.
DR ExpressionAtlas; P10588; baseline and differential.
DR Genevisible; P10588; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IEA:Ensembl.
DR GO; GO:0004879; F:nuclear receptor activity; IBA:GO_Central.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0048856; P:anatomical structure development; IBA:GO_Central.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0050965; P:detection of temperature stimulus involved in sensory perception of pain; IEA:Ensembl.
DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0048666; P:neuron development; IEA:Ensembl.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR Gene3D; 1.10.565.10; -; 1.
DR Gene3D; 3.30.50.10; -; 1.
DR InterPro; IPR035500; NHR-like_dom_sf.
DR InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd.
DR InterPro; IPR001723; Nuclear_hrmn_rcpt.
DR InterPro; IPR001628; Znf_hrmn_rcpt.
DR InterPro; IPR013088; Znf_NHR/GATA.
DR Pfam; PF00104; Hormone_recep; 1.
DR Pfam; PF00105; zf-C4; 1.
DR PRINTS; PR00398; STRDHORMONER.
DR PRINTS; PR00047; STROIDFINGER.
DR SMART; SM00430; HOLI; 1.
DR SMART; SM00399; ZnF_C4; 1.
DR SUPFAM; SSF48508; SSF48508; 1.
DR PROSITE; PS51843; NR_LBD; 1.
DR PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1.
DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1.
PE 1: Evidence at protein level;
KW DNA-binding; Metal-binding; Nucleus; Phosphoprotein; Receptor;
KW Reference proteome; Repressor; Transcription; Transcription regulation;
KW Zinc; Zinc-finger.
FT CHAIN 1..404
FT /note="Nuclear receptor subfamily 2 group F member 6"
FT /id="PRO_0000053613"
FT DOMAIN 165..393
FT /note="NR LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189"
FT DNA_BIND 53..128
FT /note="Nuclear receptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 56..76
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 92..116
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT REGION 1..49
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 327..404
FT /note="Important for dimerization"
FT /evidence="ECO:0000250"
FT MOD_RES 34
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P43136"
FT MOD_RES 40
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 83
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:18701084"
FT MUTAGEN 74..78
FT /note="EGCKS->GSCKV: Loss of DNA (TRE) binding. Reduces the
FT corepressor activity towards THRB."
FT /evidence="ECO:0000269|PubMed:10713182"
FT CONFLICT 83
FT /note="S -> T (in Ref. 1; CAA31282)"
FT /evidence="ECO:0000305"
FT CONFLICT 220..221
FT /note="AP -> G (in Ref. 1; CAA31282)"
FT /evidence="ECO:0000305"
FT CONFLICT 237
FT /note="L -> M (in Ref. 1; CAA31282)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 404 AA; 42979 MW; D1FFE523E782E969 CRC64;
MAMVTGGWGG PGGDTNGVDK AGGYPRAAED DSASPPGAAS DAEPGDEERP GLQVDCVVCG
DKSSGKHYGV FTCEGCKSFF KRSIRRNLSY TCRSNRDCQI DQHHRNQCQY CRLKKCFRVG
MRKEAVQRGR IPHSLPGAVA ASSGSPPGSA LAAVASGGDL FPGQPVSELI AQLLRAEPYP
AAAGRFGAGG GAAGAVLGID NVCELAARLL FSTVEWARHA PFFPELPVAD QVALLRLSWS
ELFVLNAAQA ALPLHTAPLL AAAGLHAAPM AAERAVAFMD QVRAFQEQVD KLGRLQVDSA
EYGCLKAIAL FTPDACGLSD PAHVESLQEK AQVALTEYVR AQYPSQPQRF GRLLLRLPAL
RAVPASLISQ LFFMRLVGKT PIETLIRDML LSGSTFNWPY GSGQ
