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Protein

Nuclear receptor subfamily 4 group A member 3

Gene

Nr4a3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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)DescriptionActionsGraphical viewLength
DNA bindingi290 – 365Nuclear receptorPROSITE-ProRule annotationAdd BLAST76
Zinc fingeri293 – 313NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri329 – 353NR C4-typePROSITE-ProRule annotationAdd BLAST25

GO - Molecular functioni

GO - Biological processi

  • adult behavior Source: MGI
  • animal organ regeneration Source: Ensembl
  • 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 by RNA polymerase II Source: UniProtKB
  • neuromuscular process controlling balance Source: MGI
  • platelet-derived growth factor receptor signaling pathway 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 transmembrane 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 by RNA polymerase II Source: UniProtKB
  • positive regulation of vascular associated smooth muscle cell migration Source: Ensembl
  • positive regulation of vascular smooth muscle cell proliferation Source: Ensembl
  • pyruvate oxidation 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

Keywordsi

Molecular functionDNA-binding, Receptor
Biological processTranscription, Transcription regulation
LigandMetal-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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:1352457 Nr4a3

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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)DescriptionActionsGraphical viewLength
ChainiPRO_00000537231 – 627Nuclear receptor subfamily 4 group A member 3Add BLAST627

Post-translational modificationi

Phosphorylated by PRKDC.By similarity

Proteomic databases

PaxDbiQ9QZB6
PRIDEiQ9QZB6

PTM databases

PhosphoSitePlusiQ9QZB6

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

  • glucocorticoid receptor binding Source: Ensembl
  • 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 interactors
STRINGi10090.ENSMUSP00000030025

Structurei

3D structure databases

ProteinModelPortaliQ9QZB6
SMRiQ9QZB6
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini395 – 624NR LBDPROSITE-ProRule annotationAdd BLAST230

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 292Interaction with NCOA1, NCOA2, NCOA3 and KAT2B1 PublicationAdd BLAST292
Regioni1 – 139Required for DNA-PK heterotrimerBy similarityAdd BLAST139
Regioni1 – 112Activation function (AF)-1 domain1 PublicationAdd BLAST112
Regioni380 – 627Interaction with KAT2B1 PublicationAdd BLAST248

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi99 – 111Poly-HisAdd BLAST13
Compositional biasi112 – 115Poly-Gln4
Compositional biasi285 – 288Poly-Ser4

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

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri293 – 313NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri329 – 353NR C4-typePROSITE-ProRule annotationAdd BLAST25

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG4217 Eukaryota
ENOG410YWNC LUCA
GeneTreeiENSGT00760000118887
HOGENOMiHOG000230925
HOVERGENiHBG052663
InParanoidiQ9QZB6
KOiK08559
PhylomeDBiQ9QZB6
TreeFamiTF315430

Family and domain databases

Gene3Di3.30.50.10, 1 hit
InterProiView protein in InterPro
IPR035500 NHR_like_dom_sf
IPR003072 NOR1_rcpt
IPR003070 Nuc_orph_rcpt
IPR000536 Nucl_hrmn_rcpt_lig-bd
IPR001723 Nuclear_hrmn_rcpt
IPR001628 Znf_hrmn_rcpt
IPR013088 Znf_NHR/GATA
PfamiView protein in Pfam
PF00104 Hormone_recep, 1 hit
PF00105 zf-C4, 1 hit
PRINTSiPR01286 NORNUCRECPTR
PR01284 NUCLEARECPTR
PR00398 STRDHORMONER
PR00047 STROIDFINGER
SMARTiView protein in SMART
SM00430 HOLI, 1 hit
SM00399 ZnF_C4, 1 hit
SUPFAMiSSF48508 SSF48508, 1 hit
PROSITEiView protein in PROSITE
PS51843 NR_LBD, 1 hit
PS00031 NUCLEAR_REC_DBD_1, 1 hit
PS51030 NUCLEAR_REC_DBD_2, 1 hit

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)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_010083420 – 429YCPTDQATAG → VSSMNAFEPL in isoform 2. 1 Publication10
Alternative sequenceiVSP_010084430 – 627Missing in isoform 2. 1 PublicationAdd BLAST198

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_006537656.3 [Q9QZB6-1]
XP_006537720.1, XM_006537657.3 [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

Similar proteinsi

Entry informationi

Entry nameiNR4A3_MOUSE
AccessioniPrimary (citable) accession number: Q9QZB6
Secondary accession number(s): Q9QZB5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 26, 2004
Last sequence update: May 1, 2000
Last modified: May 23, 2018
This is version 138 of the entry and version 1 of the sequence. See 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

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