NR2C2_MOUSE
ID NR2C2_MOUSE Reviewed; 596 AA.
AC P49117; P55093;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1996, sequence version 1.
DT 03-AUG-2022, entry version 183.
DE RecName: Full=Nuclear receptor subfamily 2 group C member 2;
DE AltName: Full=Orphan nuclear receptor TAK1;
DE AltName: Full=Orphan nuclear receptor TR4;
DE AltName: Full=Testicular receptor 4;
GN Name=Nr2c2; Synonyms=Mtr2r1, Tak1, Tr4;
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].
RC STRAIN=CD-1;
RX PubMed=7590273; DOI=10.1016/0378-1119(95)00414-2;
RA Hirose T., O'Brien D.A., Jetten A.M.;
RT "Cloning of the gene encoding the murine orphan receptor TAK1 and cell-
RT type-specific expression in testis.";
RL Gene 163:239-242(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7841789;
RA Law S.W., Conneely O.M., O'Malley B.W.;
RT "Molecular cloning of a novel member of the nuclear receptor superfamily
RT related to the orphan receptor, TR2.";
RL Gene Expr. 4:77-84(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=C57BL/6J; TISSUE=Testis;
RA Young W.J., Smith S., Chang C.;
RL Submitted (JAN-1996) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP TISSUE SPECIFICITY.
RX PubMed=10347174; DOI=10.1074/jbc.274.23.16198;
RA Lee Y.F., Young W.J., Lin W.J., Shyr C.R., Chang C.;
RT "Differential regulation of direct repeat 3 vitamin D3 and direct repeat 4
RT thyroid hormone signaling pathways by the human TR4 orphan receptor.";
RL J. Biol. Chem. 274:16198-16205(1999).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY AS A COMPONENT OF THE DRED COMPLEX,
RP FUNCTION, SUBCELLULAR LOCATION, HETERODIMERIZATION, AND DEVELOPMENTAL
RP STAGE.
RX PubMed=12093744; DOI=10.1093/emboj/cdf340;
RA Tanabe O., Katsuoka F., Campbell A.D., Song W., Yamamoto M., Tanimoto K.,
RA Engel J.D.;
RT "An embryonic/fetal beta-type globin gene repressor contains a nuclear
RT receptor TR2/TR4 heterodimer.";
RL EMBO J. 21:3434-3442(2002).
RN [6]
RP DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND
RP FUNCTION.
RX PubMed=15199144; DOI=10.1128/mcb.24.13.5887-5899.2004;
RA Mu X., Lee Y.F., Liu N.C., Chen Y.T., Kim E., Shyr C.R., Chang C.;
RT "Targeted inactivation of testicular nuclear orphan receptor 4 delays and
RT disrupts late meiotic prophase and subsequent meiotic divisions of
RT spermatogenesis.";
RL Mol. Cell. Biol. 24:5887-5899(2004).
RN [7]
RP PHOSPHORYLATION AT SER-19; SER-55 AND SER-68, FUNCTION, IDENTIFICATION BY
RP MASS SPECTROMETRY, INTERACTION WITH NRIP1 AND PCAF, AND MUTAGENESIS OF
RP SER-19; SER-55 AND SER-68.
RX PubMed=16887930; DOI=10.1074/mcp.m600180-mcp200;
RA Huq M.D., Gupta P., Tsai N.P., Wei L.N.;
RT "Modulation of testicular receptor 4 activity by mitogen-activated protein
RT kinase-mediated phosphorylation.";
RL Mol. Cell. Proteomics 5:2072-2082(2006).
RN [8]
RP DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, AND FUNCTION.
RX PubMed=17706948; DOI=10.1016/j.brainres.2007.06.069;
RA Chen Y.T., Collins L.L., Uno H., Chou S.M., Meshul C.K., Chang S.S.,
RA Chang C.;
RT "Abnormal cerebellar cytoarchitecture and impaired inhibitory signaling in
RT adult mice lacking TR4 orphan nuclear receptor.";
RL Brain Res. 1168:72-82(2007).
RN [9]
RP HETERODIMERIZATION, AND FUNCTION.
RX PubMed=17974920; DOI=10.1101/gad.1593307;
RA Tanabe O., Shen Y., Liu Q., Campbell A.D., Kuroha T., Yamamoto M.,
RA Engel J.D.;
RT "The TR2 and TR4 orphan nuclear receptors repress Gata1 transcription.";
RL Genes Dev. 21:2832-2844(2007).
RN [10]
RP DISRUPTION PHENOTYPE, INDUCTION, AND FUNCTION.
RX PubMed=19131575; DOI=10.1210/en.2008-1165;
RA Shyr C.R., Kang H.Y., Tsai M.Y., Liu N.C., Ku P.Y., Huang K.E., Chang C.;
RT "Roles of testicular orphan nuclear receptors 2 and 4 in early embryonic
RT development and embryonic stem cells.";
RL Endocrinology 150:2454-2462(2009).
RN [11]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=20393820; DOI=10.1007/s12311-010-0163-z;
RA Kim Y.S., Harry G.J., Kang H.S., Goulding D., Wine R.N., Kissling G.E.,
RA Liao G., Jetten A.M.;
RT "Altered cerebellar development in nuclear receptor TAK1/ TR4 null mice is
RT associated with deficits in GLAST(+) glia, alterations in social behavior,
RT motor learning, startle reactivity, and microglia.";
RL Cerebellum 9:310-323(2010).
RN [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-231, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast;
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
CC -!- FUNCTION: Orphan nuclear receptor that can act as a repressor or
CC activator of transcription. An important repressor of nuclear receptor
CC signaling pathways such as retinoic acid receptor, retinoid X, vitamin
CC D3 receptor, thyroid hormone receptor and estrogen receptor pathways.
CC May regulate gene expression during the late phase of spermatogenesis.
CC Activates transcriptional activity of LHCG and is antagonist of PPARA-
CC mediated transactivation (By similarity). Together with NR2C1, forms
CC the core of the DRED (direct repeat erythroid-definitive) complex that
CC represses embryonic and fetal globin transcription including that of
CC GATA1. Binds to hormone response elements (HREs) consisting of two 5'-
CC AGGTCA-3' half site direct repeat consensus sequences. Plays a
CC fundamental role in early embryonic development and embryonic stem
CC cells. Required for normal spermatogenesis and cerebellum development.
CC Appears to be important for neurodevelopmentally regulated behavior.
CC {ECO:0000250, ECO:0000269|PubMed:12093744, ECO:0000269|PubMed:15199144,
CC ECO:0000269|PubMed:16887930, ECO:0000269|PubMed:17706948,
CC ECO:0000269|PubMed:17974920, ECO:0000269|PubMed:19131575,
CC ECO:0000269|PubMed:20393820}.
CC -!- SUBUNIT: Homodimer; can bind DNA as homodimer (By similarity).
CC Heterodimer; binds DNA as a heterodimer with NR2C1 required for
CC chromatin remodeling and for binding to promoter regions such as globin
CC DR1 repeats. Interacts with NR2C2AP; the interaction represses
CC selective NR2C2-mediated transcriptional activity (By similarity).
CC Interacts with PCAF; the interaction preferentially occurs on the non-
CC phosphorylated form and induces NR2C2-mediated transactivation activity
CC and does not require the ligand-binding domain (PubMed:16887930).
CC Interacts (MAPK-mediated phosphorylated form) with NRIP1; the
CC interaction promotes repression of NR2C2-mediated activity
CC (PubMed:16887930). Interacts with NLRP10. Interacts (via ligand-binding
CC region) with transcriptional corepressor JAZF1; the interaction
CC promotes NR2C2-mediated transcriptional repression (By similarity).
CC {ECO:0000250|UniProtKB:P49116, ECO:0000269|PubMed:16887930}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00407}.
CC -!- TISSUE SPECIFICITY: Expressed, during embryogenesis, in perichondrium,
CC developing glomeruli structures and tubules of kidney, as well as in
CC intestiinal villi. Also expressed in lung and hair follicles.
CC {ECO:0000269|PubMed:10347174, ECO:0000269|PubMed:15199144,
CC ECO:0000269|PubMed:17706948}.
CC -!- INDUCTION: Induced by retinoic acid. {ECO:0000269|PubMed:19131575}.
CC -!- PTM: Phosphorylation on Ser-19 and Ser-68 is an important regulator of
CC NR2C2-mediated transcriptional activity. Phosphorylation on these
CC residues recruits the corepressor, NRIP1, leading to transcripional
CC repression, whereas the non-phosphorylated form preferentially recruits
CC the coactivator, PCAF. {ECO:0000269|PubMed:16887930}.
CC -!- DISRUPTION PHENOTYPE: Impaired spermatogenesis. Mutant animals have
CC smaller cerebellums with disruption of lobes VI-VII. They exhibit a
CC delay in monolayer maturation of dysmorphic calbindin 28K-positive
CC Purkinje cells 7 days after birth. Deficiencies in acoustic startle
CC response, prepulse startle inhibition, and social interactions were
CC observed. Also responses to novel environmental situations are
CC inhibited. NR2C1 and NR2C2 double knockout results in embryonic
CC lethality around 7.5 dpc and increased apoptosis.
CC {ECO:0000269|PubMed:15199144, ECO:0000269|PubMed:17706948,
CC ECO:0000269|PubMed:19131575, ECO:0000269|PubMed:20393820}.
CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR2
CC subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB33314.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAC18408.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; U11688; AAA93150.1; -; mRNA.
DR EMBL; S75970; AAB33314.1; ALT_INIT; mRNA.
DR EMBL; U32939; AAC18408.1; ALT_INIT; mRNA.
DR CCDS; CCDS20372.1; -.
DR PIR; I54075; I54075.
DR PIR; JC4299; JC4299.
DR RefSeq; NP_001334271.1; NM_001347342.1.
DR RefSeq; NP_035760.1; NM_011630.3.
DR RefSeq; XP_006505967.1; XM_006505904.3.
DR RefSeq; XP_006505968.1; XM_006505905.3.
DR RefSeq; XP_006505969.1; XM_006505906.3.
DR AlphaFoldDB; P49117; -.
DR BioGRID; 204300; 4.
DR IntAct; P49117; 1.
DR MINT; P49117; -.
DR STRING; 10090.ENSMUSP00000109087; -.
DR ChEMBL; CHEMBL4295769; -.
DR iPTMnet; P49117; -.
DR PhosphoSitePlus; P49117; -.
DR EPD; P49117; -.
DR jPOST; P49117; -.
DR PaxDb; P49117; -.
DR PRIDE; P49117; -.
DR ProteomicsDB; 293966; -.
DR Antibodypedia; 1697; 497 antibodies from 39 providers.
DR DNASU; 22026; -.
DR Ensembl; ENSMUST00000113460; ENSMUSP00000109087; ENSMUSG00000005893.
DR GeneID; 22026; -.
DR KEGG; mmu:22026; -.
DR UCSC; uc009cyp.2; mouse.
DR CTD; 7182; -.
DR MGI; MGI:1352466; Nr2c2.
DR VEuPathDB; HostDB:ENSMUSG00000005893; -.
DR eggNOG; KOG3575; Eukaryota.
DR GeneTree; ENSGT00940000158393; -.
DR HOGENOM; CLU_007368_16_2_1; -.
DR InParanoid; P49117; -.
DR OMA; DIQPEDQ; -.
DR PhylomeDB; P49117; -.
DR TreeFam; TF316650; -.
DR Reactome; R-MMU-383280; Nuclear Receptor transcription pathway.
DR BioGRID-ORCS; 22026; 1 hit in 71 CRISPR screens.
DR ChiTaRS; Nr2c2; mouse.
DR PRO; PR:P49117; -.
DR Proteomes; UP000000589; Chromosome 6.
DR RNAct; P49117; protein.
DR Bgee; ENSMUSG00000005893; Expressed in rostral migratory stream and 245 other tissues.
DR ExpressionAtlas; P49117; baseline and differential.
DR Genevisible; P49117; MM.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISO:MGI.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISO:MGI.
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; ISO:MGI.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; ISO:MGI.
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:0021549; P:cerebellum development; IMP:UniProtKB.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IMP:MGI.
DR GO; GO:0051321; P:meiotic cell cycle; IMP:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:MGI.
DR GO; GO:0038066; P:p38MAPK cascade; IEP:CACAO.
DR GO; GO:0048520; P:positive regulation of behavior; IMP:UniProtKB.
DR GO; GO:0040019; P:positive regulation of embryonic development; IMP:UniProtKB.
DR GO; GO:0045663; P:positive regulation of myoblast differentiation; IDA:CACAO.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0007283; P:spermatogenesis; IMP:MGI.
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 Acetylation; Activator; Differentiation; DNA-binding; Isopeptide bond;
KW Metal-binding; Nucleus; Phosphoprotein; Receptor; Reference proteome;
KW Repressor; Spermatogenesis; Transcription; Transcription regulation;
KW Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1..596
FT /note="Nuclear receptor subfamily 2 group C member 2"
FT /id="PRO_0000053589"
FT DOMAIN 341..583
FT /note="NR LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189"
FT DNA_BIND 114..189
FT /note="Nuclear receptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 117..137
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 153..177
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT MOD_RES 19
FT /note="Phosphoserine; by MAPK"
FT /evidence="ECO:0000269|PubMed:16887930"
FT MOD_RES 46
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P49116"
FT MOD_RES 55
FT /note="Phosphoserine; by MAPK"
FT /evidence="ECO:0000269|PubMed:16887930"
FT MOD_RES 68
FT /note="Phosphoserine; by MAPK"
FT /evidence="ECO:0000269|PubMed:16887930"
FT MOD_RES 98
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P49116"
FT MOD_RES 219
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P49116"
FT MOD_RES 231
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT CROSSLNK 192
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P49116"
FT MUTAGEN 15
FT /note="S->A: Enhanced transcriptional activation; Greatly
FT enhanced transcriptional activation; when associated with
FT A-68."
FT MUTAGEN 19
FT /note="S->E: Some repression of transcriptional activation;
FT Repressed transcriptional activity by about 10-fold; when
FT associated with E-68."
FT /evidence="ECO:0000269|PubMed:16887930"
FT MUTAGEN 55
FT /note="S->A: No effect on transcriptional activation."
FT /evidence="ECO:0000269|PubMed:16887930"
FT MUTAGEN 68
FT /note="S->A: Enhanced transcriptional activation; Greatly
FT enhanced transcriptional activation; when associated with
FT A-15."
FT /evidence="ECO:0000269|PubMed:16887930"
FT MUTAGEN 68
FT /note="S->E: Some repression of transcriptional activation;
FT Repressed transcriptional activity by about 10-fold; when
FT associated with E-19."
FT /evidence="ECO:0000269|PubMed:16887930"
FT CONFLICT 60
FT /note="G -> E (in Ref. 2; AAC18408)"
FT /evidence="ECO:0000305"
FT CONFLICT 106
FT /note="A -> Q (in Ref. 2; AAC18408)"
FT /evidence="ECO:0000305"
FT CONFLICT 122
FT /note="D -> V (in Ref. 2; AAC18408)"
FT /evidence="ECO:0000305"
FT CONFLICT 247
FT /note="N -> K (in Ref. 2; AAC18408)"
FT /evidence="ECO:0000305"
FT CONFLICT 263
FT /note="A -> T (in Ref. 2; AAC18408)"
FT /evidence="ECO:0000305"
FT CONFLICT 323
FT /note="T -> I (in Ref. 2; AAC18408)"
FT /evidence="ECO:0000305"
FT CONFLICT 327..328
FT /note="SP -> CF (in Ref. 2; AAC18408)"
FT /evidence="ECO:0000305"
FT CONFLICT 337
FT /note="A -> T (in Ref. 2; AAC18408)"
FT /evidence="ECO:0000305"
FT CONFLICT 484..485
FT /note="KL -> NW (in Ref. 2; AAC18408)"
FT /evidence="ECO:0000305"
FT CONFLICT 510
FT /note="G -> S (in Ref. 2; AAC18408)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 596 AA; 65239 MW; DE93C438A9CF1ED7 CRC64;
MTSPSPRIQI ISTDSAVASP QRIQIVTDQQ TGQKIQIVTA VDASGSSKQQ FILTSPDGAG
TGKVILASPE TSSAKQLIFT TSDNLVPGRI QIVTDSASVE RLLGKADVQR PQVVEYCVVC
GDKASGRHYG AVSCEGCKGF FKRSVRKNLT YSCRSSQDCI INKHHRNRCQ FCRLKKCLEM
GMKMESVQSE RKPFDVQREK PSNCAASTEK IYIRKDLRSP LIATPTFVAD KDGARQTGLL
DPGMLVNIQQ PLIREDGTVL LAADSKAETS QGALGTLANV VTSLANLSES LNNGDASEMQ
PEDQSASEIT RAFDTLAKAL NTTDSASPPS LADGIDASGG GSIHVISRDQ STPIIEVEGP
LLSDTHVTFK LTMPSPMPEY LNVHYICESA SRLLFLSMHW ARSIPAFQAL GQDCNTSLVR
ACWNELFTLG LAQCAQVMSL STILAAIVNH LQNSIQEDKL SGDRIKQVME HIWKLQEFCN
SMAKLDIDGY EYAYLKAIVL FSPDHPGLTG TSQIEKFQEK AQMELQDYVQ KTYSEDTYRL
ARILVRLPAL RLMSSNITEE LFFTGLIGNV SIDSIIPYIL KMETAEYNGQ ITGASL
