ID   NR2F6_MOUSE             Reviewed;         390 AA.
AC   P43136; Q61504; Q922G8;
DT   01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT   27-JUL-2011, sequence version 2.
DT   24-JAN-2024, entry version 182.
DE   RecName: Full=Nuclear receptor subfamily 2 group F member 6;
DE   AltName: Full=COUP transcription factor 3;
DE            Short=COUP-TF3;
DE   AltName: Full=V-erbA-related protein 2;
DE            Short=EAR-2;
GN   Name=Nr2f6; Synonyms=Ear-2, Ear2, Erbal2;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=7947324; DOI=10.1016/0925-4773(94)90098-1;
RA   Jonk L.J.C., de Jonge M.E.J., Pals C.E.G.M., Wissink S., Vervaart J.M.A.,
RA   Schoorlemmer J., Kruijer W.;
RT   "Cloning and expression during development of three murine members of the
RT   COUP family of nuclear orphan receptors.";
RL   Mech. Dev. 47:81-97(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Pituitary;
RX   PubMed=8194772; DOI=10.1016/0378-1119(94)90283-6;
RA   Barnhart K.M., Mellon P.L.;
RT   "The sequence of a murine cDNA encoding Ear-2, a nuclear orphan receptor.";
RL   Gene 142:313-314(1994).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J;
RX   PubMed=16141072; DOI=10.1126/science.1112014;
RA   Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA   Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA   Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA   Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA   Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA   Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA   Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA   Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA   Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA   Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA   Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA   Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA   Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA   Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA   Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA   Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA   Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA   Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA   Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA   Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA   Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA   Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA   Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA   Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA   Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA   van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA   Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA   Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA   Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA   Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA   Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA   Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA   Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA   Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT   "The transcriptional landscape of the mammalian genome.";
RL   Science 309:1559-1563(2005).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=FVB/N; TISSUE=Mammary tumor;
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   [6]
RP   SUBUNIT, AND INTERACTION WITH NR2F2.
RX   PubMed=10318855; DOI=10.1074/jbc.274.20.14331;
RA   Avram D., Ishmael J.E., Nevrivy D.J., Peterson V.J., Lee S.H., Dowell P.,
RA   Leid M.;
RT   "Heterodimeric interactions between chicken ovalbumin upstream promoter-
RT   transcription factor family members ARP1 and ear2.";
RL   J. Biol. Chem. 274:14331-14336(1999).
RN   [7]
RP   INTERACTION WITH ZFPM2.
RX   PubMed=11382775; DOI=10.1074/jbc.m103577200;
RA   Huggins G.S., Bacani C.J., Boltax J., Aikawa R., Leiden J.M.;
RT   "Friend of GATA 2 physically interacts with chicken ovalbumin upstream
RT   promoter-TF2 (COUP-TF2) and COUP-TF3 and represses COUP-TF2-dependent
RT   activation of the atrial natriuretic factor promoter.";
RL   J. Biol. Chem. 276:28029-28036(2001).
RN   [8]
RP   FUNCTION, DNA-BINDING, AND SUBCELLULAR LOCATION.
RX   PubMed=12690040; DOI=10.1161/01.res.0000071355.82009.43;
RA   Liu X., Huang X., Sigmund C.D.;
RT   "Identification of a nuclear orphan receptor (Ear2) as a negative regulator
RT   of renin gene transcription.";
RL   Circ. Res. 92:1033-1040(2003).
RN   [9]
RP   FUNCTION, DISRUPTION PHENOTYPE, AND DEVELOPMENTAL STAGE.
RX   PubMed=15741322; DOI=10.1101/gad.317905;
RA   Warnecke M., Oster H., Revelli J.P., Alvarez-Bolado G., Eichele G.;
RT   "Abnormal development of the locus coeruleus in Ear2(Nr2f6)-deficient mice
RT   impairs the functionality of the forebrain clock and affects nociception.";
RL   Genes Dev. 19:614-625(2005).
RN   [10]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA   Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT   "Large-scale phosphorylation analysis of mouse liver.";
RL   Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN   [11]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
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   [12]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-35, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain, Kidney, and Testis;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
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:12690040,
CC       ECO:0000269|PubMed:15741322, ECO:0000269|PubMed:18701084}.
CC   -!- SUBUNIT: Binds DNA as dimer; homodimer and heterodimer with NR2F2 and
CC       probably NR2F1. Interacts with THRB (By similarity). {ECO:0000250}.
CC   -!- INTERACTION:
CC       P43136; O35626: Rasd1; NbExp=5; IntAct=EBI-4319956, EBI-4319979;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00407,
CC       ECO:0000269|PubMed:12690040}.
CC   -!- DEVELOPMENTAL STAGE: Initially expressed at 8.5 dpc in the developing
CC       rhombencephalon. At 11.5 dpc expression in the CNS rapidly decreases
CC       and in newborn and adult expression is not detectable in the brain with
CC       the exceptions of Purkinje neurons and the choroid plexi.
CC       {ECO:0000269|PubMed:15741322}.
CC   -!- DISRUPTION PHENOTYPE: Reduction of neurons in the locus coerulus of the
CC       developing cortex. Defects in circadian behavior. Hyperreactive
CC       lymphocytes, late-onset immunopathology and hypersusceptibility to
CC       Th17-dependent experimental autoimmune encephalomyelitis.
CC       {ECO:0000269|PubMed:15741322, ECO:0000269|PubMed:18701084}.
CC   -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR2
CC       subfamily. {ECO:0000305}.
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DR   EMBL; X76654; CAA54097.1; -; mRNA.
DR   EMBL; L25674; AAA37532.1; -; mRNA.
DR   EMBL; AK131941; BAE20887.1; -; mRNA.
DR   EMBL; AK171552; BAE42523.1; -; mRNA.
DR   EMBL; CH466569; EDL28911.1; -; Genomic_DNA.
DR   EMBL; BC008138; AAH08138.1; -; mRNA.
DR   CCDS; CCDS22392.1; -.
DR   PIR; I48734; S44285.
DR   PIR; I49640; I49640.
DR   RefSeq; NP_034280.2; NM_010150.2.
DR   AlphaFoldDB; P43136; -.
DR   SMR; P43136; -.
DR   BioGRID; 199494; 7.
DR   IntAct; P43136; 5.
DR   STRING; 10090.ENSMUSP00000002466; -.
DR   iPTMnet; P43136; -.
DR   PhosphoSitePlus; P43136; -.
DR   MaxQB; P43136; -.
DR   PaxDb; 10090-ENSMUSP00000002466; -.
DR   PeptideAtlas; P43136; -.
DR   ProteomicsDB; 293721; -.
DR   Pumba; P43136; -.
DR   Antibodypedia; 14278; 440 antibodies from 36 providers.
DR   DNASU; 13864; -.
DR   Ensembl; ENSMUST00000002466.9; ENSMUSP00000002466.9; ENSMUSG00000002393.15.
DR   GeneID; 13864; -.
DR   KEGG; mmu:13864; -.
DR   UCSC; uc009mcx.1; mouse.
DR   AGR; MGI:1352453; -.
DR   CTD; 2063; -.
DR   MGI; MGI:1352453; Nr2f6.
DR   VEuPathDB; HostDB:ENSMUSG00000002393; -.
DR   eggNOG; KOG3575; Eukaryota.
DR   GeneTree; ENSGT00940000160748; -.
DR   HOGENOM; CLU_007368_20_1_1; -.
DR   InParanoid; P43136; -.
DR   OMA; WARTIPY; -.
DR   OrthoDB; 5400963at2759; -.
DR   PhylomeDB; P43136; -.
DR   TreeFam; TF352097; -.
DR   Reactome; R-MMU-383280; Nuclear Receptor transcription pathway.
DR   BioGRID-ORCS; 13864; 2 hits in 81 CRISPR screens.
DR   ChiTaRS; Nr2f6; mouse.
DR   PRO; PR:P43136; -.
DR   Proteomes; UP000000589; Chromosome 8.
DR   RNAct; P43136; Protein.
DR   Bgee; ENSMUSG00000002393; Expressed in floor plate of midbrain and 264 other cell types or tissues.
DR   ExpressionAtlas; P43136; baseline and differential.
DR   GO; GO:0005634; C:nucleus; ISO:MGI.
DR   GO; GO:0003700; F:DNA-binding transcription factor activity; ISO:MGI.
DR   GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:NTNU_SB.
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; IDA:NTNU_SB.
DR   GO; GO:0043565; F:sequence-specific DNA binding; ISO:MGI.
DR   GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
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; IMP:MGI.
DR   GO; GO:0043153; P:entrainment of circadian clock by photoperiod; IMP:MGI.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:NTNU_SB.
DR   GO; GO:0048666; P:neuron development; IMP:MGI.
DR   CDD; cd06958; NR_DBD_COUP_TF; 1.
DR   CDD; cd06948; NR_LBD_COUP-TF; 1.
DR   Gene3D; 3.30.50.10; Erythroid Transcription Factor GATA-1, subunit A; 1.
DR   Gene3D; 1.10.565.10; Retinoid X Receptor; 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   PANTHER; PTHR24083; NUCLEAR HORMONE RECEPTOR; 1.
DR   PANTHER; PTHR24083:SF44; NUCLEAR RECEPTOR SUBFAMILY 2 GROUP F MEMBER 6; 1.
DR   Pfam; PF00104; Hormone_recep; 1.
DR   Pfam; PF00105; zf-C4; 1.
DR   PRINTS; PR01282; COUPTNFACTOR.
DR   PRINTS; PR00398; STRDHORMONER.
DR   PRINTS; PR00047; STROIDFINGER.
DR   SMART; SM00430; HOLI; 1.
DR   SMART; SM00399; ZnF_C4; 1.
DR   SUPFAM; SSF57716; Glucocorticoid receptor-like (DNA-binding domain); 1.
DR   SUPFAM; SSF48508; Nuclear receptor ligand-binding domain; 1.
DR   PROSITE; PS51843; NR_LBD; 1.
DR   PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1.
DR   PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1.
DR   Genevisible; P43136; MM.
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..390
FT                   /note="Nuclear receptor subfamily 2 group F member 6"
FT                   /id="PRO_0000053614"
FT   DOMAIN          157..380
FT                   /note="NR LBD"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01189"
FT   DNA_BIND        54..129
FT                   /note="Nuclear receptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT   ZN_FING         57..77
FT                   /note="NR C4-type"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT   ZN_FING         93..117
FT                   /note="NR C4-type"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT   REGION          1..50
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          314..390
FT                   /note="Important for dimerization"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         35
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         41
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P10588"
FT   MOD_RES         84
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P10588"
FT   CONFLICT        10
FT                   /note="D -> G (in Ref. 2; AAA37532)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        84
FT                   /note="S -> T (in Ref. 1; CAA54097 and 2; AAA37532)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        152
FT                   /note="P -> H (in Ref. 2; AAA37532)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        164..165
FT                   /note="QL -> HV (in Ref. 2; AAA37532)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        196..198
FT                   /note="LLF -> AV (in Ref. 2; AAA37532)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        239..241
FT                   /note="LPL -> VAV (in Ref. 2; AAA37532)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        357
FT                   /note="Q -> K (in Ref. 1; CAA54097)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   390 AA;  41968 MW;  4C30B25C6CAE5338 CRC64;
     MAMVTGGWGD PGGDTNGVDK AGGSYPRATE DDSASPPGAT SDAEPGDEER PGLQVDCVVC
     GDKSSGKHYG VFTCEGCKSF FKRSIRRNLS YTCRSNRDCQ IDQHHRNQCQ YCRLKKCFRV
     GMRKEAVQRG RIPHALPGPA ACSPPGATGV EPFTGPPVSE LIAQLLRAEP YPAAGRFGGG
     GAVLGIDNVC ELAARLLFST VEWARHAPFF PELPAADQVA LLRLSWSELF VLNAAQAALP
     LHTAPLLAAA GLHAAPMAAE RAVAFMDQVR AFQEQVDKLG RLQVDAAEYG CLKAIALFTP
     DACGLSDPAH VESLQEKAQV ALTEYVRAQY PSQPQRFGRL LLRLPALRAV PASLISQLFF
     MRLVGKTPIE TLIRDMLLSG STFNWPYGSG
//