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Protein

Nuclear receptor subfamily 4 group A member 3

Gene

Nr4a3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transcriptional activator that binds to regulatory elements in promoter regions in a cell- and response element (target)-specific manner (PubMed:12709428). Induces gene expression by binding as monomers to the NR4A1 response element (NBRE) 5'-AAAAGGTCA-3' site and as homodimers to the Nur response element (NurRE) site in the promoter of their regulated target genes (By similarity). Plays a role in the regulation of proliferation, survival and differentiation of many different cell types and also in metabolism and inflammation. Mediates proliferation of vascular smooth muscle, myeloid progenitor cell and type B pancreatic cells; promotes mitogen-induced vascular smooth muscle cell proliferation through transactivation of SKP2 promoter by binding a NBRE site (PubMed:21868379). Upon PDGF stimulation, stimulates vascular smooth muscle cell proliferation by regulating CCND1 and CCND2 expression. In islets, induces type B pancreatic cell proliferation through up-regulation of genes that activate cell cycle, as well as genes that cause degradation of the CDKN1A (By similarity). Negatively regulates myeloid progenitor cell proliferation by repressing RUNX1 in a NBRE site-independent manner (PubMed:24806827). During inner ear, plays a role as a key mediator of the proliferative growth phase of semicircular canal development (PubMed:11784868). Mediates also survival of neuron and smooth muscle cells; mediates CREB-induced neuronal survival, and during hippocampus development, plays a critical role in pyramidal cell survival and axonal guidance (PubMed:20566846, PubMed:15456880). Is required for S phase entry of the cell cycle and survival of smooth muscle cells by inducing CCND1, resulting in RB1 phosphorylation. Binds to NBRE motif in CCND1 promoter, resulting in the activation of the promoter and CCND1 transcription (PubMed:19153266). Plays also a role in inflammation; upon TNF stimulation, mediates monocyte adhesion by inducing the expression of VCAM1 and ICAM1 by binding to the NBRE consensus site (PubMed:20558821). In mast cells activated by Fc-epsilon receptor cross-linking, promotes the synthesis and release of cytokines but impairs events leading to degranulation (PubMed:24586680). Plays also a role in metabolism; by modulating feeding behavior; and by playing a role in energy balance by inhibiting the glucocorticoid-induced orexigenic neuropeptides AGRP expression, at least in part by forming a complex with activated NR3C1 on the AGRP- glucocorticoid response element (GRE), and thus weakening the DNA binding activity of NR3C1 (PubMed:23897430, PubMed:19523439). Upon catecholamines stimulation, regulates gene expression that controls oxidative metabolism in skeletal muscle (PubMed:18325999). Plays a role in glucose transport by regulating translocation of the SLC2A4 glucose transporter to the cell surface (By similarity). Finally, during gastrulation plays a crucial role in the formation of anterior mesoderm by controlling cell migration (PubMed:13129926). Inhibits adipogenesis (PubMed:18945812). Also participates in cardiac hypertrophy by activating PARP1 (By similarity).By similarity14 Publications

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi290 – 36576Nuclear receptorPROSITE-ProRule annotationAdd
BLAST
Zinc fingeri293 – 31321NR C4-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri329 – 35325NR C4-typePROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

GO - Biological processi

  • adult behavior Source: MGI
  • axon guidance Source: MGI
  • cellular respiration Source: UniProtKB
  • cellular response to catecholamine stimulus Source: UniProtKB
  • cellular response to corticotropin-releasing hormone stimulus Source: UniProtKB
  • cellular response to leptin stimulus Source: UniProtKB
  • common myeloid progenitor cell proliferation Source: UniProtKB
  • energy homeostasis Source: UniProtKB
  • fat cell differentiation Source: UniProtKB
  • gastrulation Source: UniProtKB
  • hippocampus development Source: MGI
  • inner ear morphogenesis Source: MGI
  • mast cell degranulation Source: UniProtKB
  • mesoderm formation Source: MGI
  • negative regulation of apoptotic process Source: MGI
  • negative regulation of hydrogen peroxide-induced neuron death Source: UniProtKB
  • negative regulation of neuron apoptotic process Source: MGI
  • negative regulation of oxidative stress-induced neuron death Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • neuromuscular process controlling balance Source: MGI
  • organ regeneration Source: Ensembl
  • positive regulation of cardiac muscle hypertrophy Source: UniProtKB
  • positive regulation of cell cycle Source: MGI
  • positive regulation of epithelial cell proliferation Source: UniProtKB
  • positive regulation of fatty acid oxidation Source: UniProtKB
  • positive regulation of feeding behavior Source: UniProtKB
  • positive regulation of glucose transport Source: UniProtKB
  • positive regulation of leukocyte apoptotic process Source: MGI
  • positive regulation of mast cell activation by Fc-epsilon receptor signaling pathway Source: UniProtKB
  • positive regulation of mast cell cytokine production Source: UniProtKB
  • positive regulation of monocyte aggregation Source: UniProtKB
  • positive regulation of smooth muscle cell proliferation Source: UniProtKB
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • pyruvate oxidation Source: UniProtKB
  • regulation of energy homeostasis Source: UniProtKB
  • regulation of smooth muscle cell proliferation Source: UniProtKB
  • regulation of type B pancreatic cell proliferation Source: UniProtKB
  • response to hydrogen peroxide Source: MGI
  • semicircular canal morphogenesis Source: MGI
  • vestibular reflex Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Receptor

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding, Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-MMU-383280. Nuclear Receptor transcription pathway.

Names & Taxonomyi

Protein namesi
Recommended name:
Nuclear receptor subfamily 4 group A member 3
Alternative name(s):
Orphan nuclear receptor TEC
Translocated in extraskeletal chondrosarcoma
Gene namesi
Name:Nr4a3
Synonyms:Tec
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:1352457. Nr4a3.

Subcellular locationi

  • Nucleus PROSITE-ProRule annotation

GO - Cellular componenti

  • mast cell granule Source: GOC
  • nucleus Source: UniProtKB-SubCell
  • transcription factor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Disruption phenotypei

Nr4a3 homozygous knockout mice are viable and normal in appearance; however, abnormal hyperactive and partial bidirectional circling behavior is observed by 3 weeks of age in 15% of these mice. The circling behavior is interspersed with noncircling periods of feeding, grooming, and sleep (PubMed:11784868). A small percentage of adult Nr4a3 homozygotes displayes brief freezing spells with tonic posturing that are exacerbated with handling (PubMed:15456880). The overall food consumption of Nr4a3 homozygous knockout mice is higher. Moreover, Nr4a3 homozygous mice lose more body weight upon fasting but clearly consumed more food during refeeding. By the end of the fasting period, Nr4a3 homozygous mice display signs of exhaustion (PubMed:23897430). Nr4a3 homozygous leads to embryonic lethality around E8.5 of gestation (PubMed:13129926).4 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 627627Nuclear receptor subfamily 4 group A member 3PRO_0000053723Add
BLAST

Post-translational modificationi

Phosphorylated by PRKDC.By similarity

Proteomic databases

MaxQBiQ9QZB6.
PaxDbiQ9QZB6.
PRIDEiQ9QZB6.

PTM databases

PhosphoSiteiQ9QZB6.

Expressioni

Tissue specificityi

Ubiquitous. Highest levels of expression in brain. Widely expressed throughout the arcuate nucleus region of the hypothalamus, namely in AgRP neurons.

Developmental stagei

Not expressed during the earliest stages of vesicle formation (E10.5). Expression begins coincidentally with the initiation of regional shape changes in the otic vesicle at E11.5 and is restricted to the dorsolateral region. At E13.5, expression is limited to the inner edge of the semicircular canal epithelium, flanking the site of fusion, and this restricted expression continues at P1 (PubMed:11784868). At E14.5 expression is observed in the primitive plexiform layer of the hippocampus. At P0, expression is observed in both the pyramidal and granule cell layers. Expression persistes in these cells in the adult hippocampus after their postnatal maturation. In addition, expression is also observed in the hilar mossy cells of the dentate gyrus (PubMed:15456880). At E7.5 dpc expression is ubiquitous, whereas at E9 and E9.5 dpc, expression is restricted to the brain (PubMed:13129926).3 Publications

Inductioni

Induced by inflammatory stimuli (PubMed:20558821). Up-regulated by the anorexigenic signal leptin via the transcription factor cyclic AMP response element-binding protein (CREB). Suppressed by orexigenic signal glucocorticoid that mobilizes NR3C1 to inhibit NR4A3 expression by antagonizing the action of CREB (PubMed:23897430).2 Publications

Gene expression databases

BgeeiENSMUSG00000028341.
CleanExiMM_NR4A3.
ExpressionAtlasiQ9QZB6. baseline and differential.
GenevisibleiQ9QZB6. MM.

Interactioni

Subunit structurei

Interacts with SIX3 (via homeobox); differentially regulates the transcriptional activities of NR4A3. Interacts with NCOA2; potentiates the activity of the NR4A3 (PubMed:12709428). Interacts with NCOA1, NCOA3, MED1 and KAT2B. Interacts with EP300 and NCOA2; mediates the recruitment of MED1 in the coactivator complex (PubMed:12709428). Interacts with the constituents of DNA-PK heterotrimer PRKDC, XRCC6 and XRCC5; phosphorylates and prevents NR4A3 ubiquitinylation and degradation (By similarity). Interacts with NR3C1 (via nuclear receptor DNA-binding domain); the interactions represses transcription activity of NR4A3 on the POMC promoter Nur response element (NurRE). Interacts with TRIM28; the interactions potentiates NR4A3 activity on NurRE promoter. Binds DNA as a monomer and homodimer. Interacts with PARP1; activates PARP1 by improving acetylation of PARP1 and suppressing the interaction between PARP1 and SIRT1 (By similarity).By similarity1 Publication

GO - Molecular functioni

  • histone acetyltransferase binding Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB
  • protein kinase binding Source: MGI
  • transcription coactivator binding Source: UniProtKB

Protein-protein interaction databases

BioGridi201804. 3 interactions.
STRINGi10090.ENSMUSP00000030025.

Structurei

3D structure databases

ProteinModelPortaliQ9QZB6.
SMRiQ9QZB6. Positions 291-627.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni1 – 292292Interaction with NCOA1, NCOA2, NCOA3 and KAT2B1 PublicationAdd
BLAST
Regioni1 – 139139Required for DNA-PK heterotrimerBy similarityAdd
BLAST
Regioni1 – 112112Activation function (AF)-1 domain1 PublicationAdd
BLAST
Regioni380 – 627248Interaction with KAT2B1 PublicationAdd
BLAST
Regioni441 – 49151Ligand-bindingSequence analysisAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi99 – 11113Poly-HisAdd
BLAST
Compositional biasi112 – 1154Poly-Gln
Compositional biasi285 – 2884Poly-Ser

Domaini

The AF-1 domain mediates transcription activation. The N-terminal region (1-292) directly interacts with the C-terminal LBD (380-627): the interaction is potentiated by AF-1-mediated recruitment of NCOA2.1 Publication

Sequence similaritiesi

Contains 1 nuclear receptor DNA-binding domain.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri293 – 31321NR C4-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri329 – 35325NR C4-typePROSITE-ProRule annotationAdd
BLAST

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG4217. Eukaryota.
ENOG410YWNC. LUCA.
GeneTreeiENSGT00840000129681.
HOGENOMiHOG000230925.
HOVERGENiHBG052663.
InParanoidiQ9QZB6.
KOiK08559.
PhylomeDBiQ9QZB6.
TreeFamiTF315430.

Family and domain databases

Gene3Di1.10.565.10. 1 hit.
3.30.50.10. 1 hit.
InterProiIPR003072. NOR1_rcpt.
IPR003070. Nuc_orph_rcpt.
IPR000536. Nucl_hrmn_rcpt_lig-bd.
IPR001723. Nuclear_hrmn_rcpt.
IPR001628. Znf_hrmn_rcpt.
IPR013088. Znf_NHR/GATA.
[Graphical view]
PfamiPF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]
PRINTSiPR01286. NORNUCRECPTR.
PR01284. NUCLEARECPTR.
PR00398. STRDHORMONER.
PR00047. STROIDFINGER.
SMARTiSM00430. HOLI. 1 hit.
SM00399. ZnF_C4. 1 hit.
[Graphical view]
SUPFAMiSSF48508. SSF48508. 1 hit.
PROSITEiPS00031. NUCLEAR_REC_DBD_1. 1 hit.
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9QZB6-1) [UniParc]FASTAAdd to basket
Also known as: Long

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MPCVQAQYSP SPPGSTYATQ TYGSEYTTEI MNPDYTKLTM DLGSTGIMAT
60 70 80 90 100
ATTSLPSFST FMEGYPSSCE LKPSCLYQMP PSGPRPLIKM EEGREHGYHH
110 120 130 140 150
HHHHHHHHHH HQQQQPSIPP PSGPEDEVLP STSMYFKQSP PSTPTTPGFP
160 170 180 190 200
PQAGALWDDE LPSAPGCIAP GPLLDPQMKA VPPMAAAARF PIFFKPSPPH
210 220 230 240 250
PPAPSPAGGH HLGYDPTAAA ALSLPLGAAA AAGSQAAALE GHPYGLPLAK
260 270 280 290 300
RTATLTFPPL GLTASPTASS LLGESPSLPS PPNRSSSSGE GTCAVCGDNA
310 320 330 340 350
ACQHYGVRTC EGCKGFFKRT VQKNAKYVCL ANKNCPVDKR RRNRCQYCRF
360 370 380 390 400
QKCLSVGMVK EVVRTDSLKG RRGRLPSKPK SPLQQEPSQP SPPSPPICMM
410 420 430 440 450
NALVRALTDA TPRDLDYSRY CPTDQATAGT DAEHVQQFYN LLTASIDVSR
460 470 480 490 500
SWAEKIPGFT DLPKEDQTLL IESAFLELFV LRLSIRSNTA EDKFVFCNGL
510 520 530 540 550
VLHRLQCLRG FGEWLDSIKD FSLNLQSLNL DIQALACLSA LSMITERHGL
560 570 580 590 600
KEPKRVEELC TKITSSLKDH QRKGQALEPS EPKVLRALVE LRKICTQGLQ
610 620
RIFYLKLEDL VPPPSVIDKL FLDTLPF
Length:627
Mass (Da):68,454
Last modified:May 1, 2000 - v1
Checksum:i2F49CB4C8DE315A8
GO
Isoform 2 (identifier: Q9QZB6-2) [UniParc]FASTAAdd to basket
Also known as: Short, TECdeltaC

The sequence of this isoform differs from the canonical sequence as follows:
     420-429: YCPTDQATAG → VSSMNAFEPL
     430-627: Missing.

Show »
Length:429
Mass (Da):45,957
Checksum:i23CC2C4BF847668E
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei420 – 42910YCPTDQATAG → VSSMNAFEPL in isoform 2. 1 PublicationVSP_010083
Alternative sequencei430 – 627198Missing in isoform 2. 1 PublicationVSP_010084Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF191211 mRNA. Translation: AAF05622.1.
AF191212 mRNA. Translation: AAF05623.1.
CCDSiCCDS18163.1. [Q9QZB6-1]
RefSeqiNP_001294918.1. NM_001307989.1. [Q9QZB6-2]
NP_056558.1. NM_015743.3. [Q9QZB6-1]
XP_006537719.1. XM_006537656.2. [Q9QZB6-1]
XP_006537720.1. XM_006537657.2. [Q9QZB6-1]
XP_006537721.1. XM_006537658.1. [Q9QZB6-1]
UniGeneiMm.247261.
Mm.487935.

Genome annotation databases

EnsembliENSMUST00000030025; ENSMUSP00000030025; ENSMUSG00000028341. [Q9QZB6-1]
GeneIDi18124.
KEGGimmu:18124.
UCSCiuc008suu.1. mouse. [Q9QZB6-1]
uc008suv.1. mouse. [Q9QZB6-2]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF191211 mRNA. Translation: AAF05622.1.
AF191212 mRNA. Translation: AAF05623.1.
CCDSiCCDS18163.1. [Q9QZB6-1]
RefSeqiNP_001294918.1. NM_001307989.1. [Q9QZB6-2]
NP_056558.1. NM_015743.3. [Q9QZB6-1]
XP_006537719.1. XM_006537656.2. [Q9QZB6-1]
XP_006537720.1. XM_006537657.2. [Q9QZB6-1]
XP_006537721.1. XM_006537658.1. [Q9QZB6-1]
UniGeneiMm.247261.
Mm.487935.

3D structure databases

ProteinModelPortaliQ9QZB6.
SMRiQ9QZB6. Positions 291-627.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi201804. 3 interactions.
STRINGi10090.ENSMUSP00000030025.

PTM databases

PhosphoSiteiQ9QZB6.

Proteomic databases

MaxQBiQ9QZB6.
PaxDbiQ9QZB6.
PRIDEiQ9QZB6.

Protocols and materials databases

DNASUi18124.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000030025; ENSMUSP00000030025; ENSMUSG00000028341. [Q9QZB6-1]
GeneIDi18124.
KEGGimmu:18124.
UCSCiuc008suu.1. mouse. [Q9QZB6-1]
uc008suv.1. mouse. [Q9QZB6-2]

Organism-specific databases

CTDi8013.
MGIiMGI:1352457. Nr4a3.

Phylogenomic databases

eggNOGiKOG4217. Eukaryota.
ENOG410YWNC. LUCA.
GeneTreeiENSGT00840000129681.
HOGENOMiHOG000230925.
HOVERGENiHBG052663.
InParanoidiQ9QZB6.
KOiK08559.
PhylomeDBiQ9QZB6.
TreeFamiTF315430.

Enzyme and pathway databases

ReactomeiR-MMU-383280. Nuclear Receptor transcription pathway.

Miscellaneous databases

PROiQ9QZB6.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000028341.
CleanExiMM_NR4A3.
ExpressionAtlasiQ9QZB6. baseline and differential.
GenevisibleiQ9QZB6. MM.

Family and domain databases

Gene3Di1.10.565.10. 1 hit.
3.30.50.10. 1 hit.
InterProiIPR003072. NOR1_rcpt.
IPR003070. Nuc_orph_rcpt.
IPR000536. Nucl_hrmn_rcpt_lig-bd.
IPR001723. Nuclear_hrmn_rcpt.
IPR001628. Znf_hrmn_rcpt.
IPR013088. Znf_NHR/GATA.
[Graphical view]
PfamiPF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]
PRINTSiPR01286. NORNUCRECPTR.
PR01284. NUCLEARECPTR.
PR00398. STRDHORMONER.
PR00047. STROIDFINGER.
SMARTiSM00430. HOLI. 1 hit.
SM00399. ZnF_C4. 1 hit.
[Graphical view]
SUPFAMiSSF48508. SSF48508. 1 hit.
PROSITEiPS00031. NUCLEAR_REC_DBD_1. 1 hit.
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiNR4A3_MOUSE
AccessioniPrimary (citable) accession number: Q9QZB6
Secondary accession number(s): Q9QZB5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 26, 2004
Last sequence update: May 1, 2000
Last modified: September 7, 2016
This is version 126 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.