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Protein

Nuclear receptor subfamily 4 group A member 3

Gene

NR4A3

Organism
Homo sapiens (Human)
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. 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 (By similarity). 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. During inner ear, plays a role as a key mediator of the proliferative growth phase of semicircular canal development (By similarity). 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. 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 (By similarity). 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 (By similarity) (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 (By similarity). 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. Upon catecholamines stimulation, regulates gene expression that controls oxidative metabolism in skeletal muscle (By similarity). Plays a role in glucose transport by regulating translocation of the SLC2A4 glucose transporter to the cell surface (PubMed:24022864). Finally, during gastrulation plays a crucial role in the formation of anterior mesoderm by controlling cell migration. Inhibits adipogenesis (By similarity). Also participates in cardiac hypertrophy by activating PARP1 (By similarity).By similarity2 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi289 – 364Nuclear receptorPROSITE-ProRule annotationAdd BLAST76
Zinc fingeri292 – 312NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri328 – 352NR C4-typePROSITE-ProRule annotationAdd BLAST25

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionDNA-binding, Receptor
Biological processTranscription, Transcription regulation
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-383280 Nuclear Receptor transcription pathway
R-HSA-8936459 RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function
SignaLinkiQ92570
SIGNORiQ92570

Names & Taxonomyi

Protein namesi
Recommended name:
Nuclear receptor subfamily 4 group A member 3
Alternative name(s):
Mitogen-induced nuclear orphan receptor
Neuron-derived orphan receptor 1
Nuclear hormone receptor NOR-1
Gene namesi
Name:NR4A3
Synonyms:CHN, CSMF, MINOR, NOR1, TEC
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 9

Organism-specific databases

EuPathDBiHostDB:ENSG00000119508.17
HGNCiHGNC:7982 NR4A3
MIMi600542 gene+phenotype
neXtProtiNX_Q92570

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

Involvement in diseasei

Ewing sarcoma (ES)
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving NR4A3 is found in patients with Erwing sarcoma. Translocation t(9;22)(q22-31;q11-12) with EWSR1.
Disease descriptionA highly malignant, metastatic, primitive small round cell tumor of bone and soft tissue that affects children and adolescents. It belongs to the Ewing sarcoma family of tumors, a group of morphologically heterogeneous neoplasms that share the same cytogenetic features. They are considered neural tumors derived from cells of the neural crest. Ewing sarcoma represents the less differentiated form of the tumors.
See also OMIM:612219
A chromosomal aberration involving NR4A3 is a cause of a form of extraskeletal myxoid chondrosarcomas (EMC). Translocation t(9;17)(q22;q11) with TAF2N.

Keywords - Diseasei

Proto-oncogene

Organism-specific databases

DisGeNETi8013
MalaCardsiNR4A3
MIMi600542 gene+phenotype
612219 phenotype
OpenTargetsiENSG00000119508
Orphaneti209916 Extraskeletal myxoid chondrosarcoma
PharmGKBiPA31763

Chemistry databases

ChEMBLiCHEMBL1961792

Polymorphism and mutation databases

BioMutaiNR4A3
DMDMi90110039

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000537221 – 626Nuclear receptor subfamily 4 group A member 3Add BLAST626

Post-translational modificationi

Phosphorylated by PRKDC.1 Publication

Proteomic databases

MaxQBiQ92570
PaxDbiQ92570
PeptideAtlasiQ92570
PRIDEiQ92570
ProteomicsDBi75330
75331 [Q92570-2]
75332 [Q92570-3]

PTM databases

iPTMnetiQ92570
PhosphoSitePlusiQ92570

Expressioni

Tissue specificityi

Isoform alpha is highly expressed in skeletal muscle. Isoform beta is highly expressed in skeletal muscle and low expressed in fetal brain and placenta.

Inductioni

Induced by inflammatory stimuli in endothelial cells through an NF-kappa-B-dependent transactivation of the NR4A3 Promoter.1 Publication

Gene expression databases

BgeeiENSG00000119508 Expressed in 191 organ(s), highest expression level in pleura
CleanExiHS_NR4A3
HS_TEC
ExpressionAtlasiQ92570 baseline and differential
GenevisibleiQ92570 HS

Organism-specific databases

HPAiHPA043360

Interactioni

Subunit structurei

Interacts with SIX3 (via homeobox); differentially regulates the transcriptional activities of NR4A3 (PubMed:12543801). Interacts with the constituents of DNA-PK heterotrimer PRKDC, XRCC6 and XRCC5; phosphorylates and prevents NR4A3 ubiquitinylation and degradation (PubMed:25852083). Interacts with NCOA2; potentiates the activity of the NR4A3. Interacts with NCOA1, NCOA3, MED1 and KAT2B. Interacts with EP300 and NCOA2; mediates the recruitment of MED1 in the coactivator complex (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 similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
SIX3O953433EBI-13644623,EBI-13644574

GO - Molecular functioni

Protein-protein interaction databases

BioGridi113713, 4 interactors
IntActiQ92570, 38 interactors
STRINGi9606.ENSP00000333122

Structurei

3D structure databases

ProteinModelPortaliQ92570
SMRiQ92570
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini394 – 623NR LBDPROSITE-ProRule annotationAdd BLAST230

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 291Interaction with NCOA1, NCOA2, NCOA3 and KAT2BBy similarityAdd BLAST291
Regioni1 – 138Required for DNA-PK heterotrimer1 PublicationAdd BLAST138
Regioni1 – 108Activation function (AF)-1 domainBy similarityAdd BLAST108
Regioni379 – 626Interaction with KAT2BBy similarityAdd BLAST248

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi95 – 108Poly-HisAdd BLAST14
Compositional biasi282 – 287Poly-Ser6

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.By similarity

Sequence similaritiesi

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri292 – 312NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri328 – 352NR C4-typePROSITE-ProRule annotationAdd BLAST25

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG4217 Eukaryota
ENOG410YWNC LUCA
GeneTreeiENSGT00760000118887
HOVERGENiHBG052663
InParanoidiQ92570
KOiK08559
OMAiYQMQPSG
OrthoDBiEOG091G0GUM
PhylomeDBiQ92570
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 (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket
Isoform Alpha (identifier: Q92570-1) [UniParc]FASTAAdd to basket

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 SPPGSSYAAQ TYSSEYTTEI MNPDYTKLTM DLGSTEITAT
60 70 80 90 100
ATTSLPSIST FVEGYSSNYE LKPSCVYQMQ RPLIKVEEGR APSYHHHHHH
110 120 130 140 150
HHHHHHHHQQ QHQQPSIPPA SSPEDEVLPS TSMYFKQSPP STPTTPAFPP
160 170 180 190 200
QAGALWDEAL PSAPGCIAPG PLLDPPMKAV PTVAGARFPL FHFKPSPPHP
210 220 230 240 250
PAPSPAGGHH LGYDPTAAAA LSLPLGAAAA AGSQAAALES HPYGLPLAKR
260 270 280 290 300
AAPLAFPPLG LTPSPTASSL LGESPSLPSP PSRSSSSGEG TCAVCGDNAA
310 320 330 340 350
CQHYGVRTCE GCKGFFKRTV QKNAKYVCLA NKNCPVDKRR RNRCQYCRFQ
360 370 380 390 400
KCLSVGMVKE VVRTDSLKGR RGRLPSKPKS PLQQEPSQPS PPSPPICMMN
410 420 430 440 450
ALVRALTDST PRDLDYSRYC PTDQAAAGTD AEHVQQFYNL LTASIDVSRS
460 470 480 490 500
WAEKIPGFTD LPKEDQTLLI ESAFLELFVL RLSIRSNTAE DKFVFCNGLV
510 520 530 540 550
LHRLQCLRGF GEWLDSIKDF SLNLQSLNLD IQALACLSAL SMITERHGLK
560 570 580 590 600
EPKRVEELCN KITSSLKDHQ SKGQALEPTE SKVLGALVEL RKICTLGLQR
610 620
IFYLKLEDLV SPPSIIDKLF LDTLPF
Length:626
Mass (Da):68,230
Last modified:March 21, 2006 - v3
Checksum:iFB4A1AB7667D96F6
GO
Isoform Beta (identifier: Q92570-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     419-443: YCPTDQAAAGTDAEHVQQFYNLLTA → VSFMISCFQMNDQGLYLWLLVIRVD
     444-626: Missing.

Show »
Length:443
Mass (Da):47,822
Checksum:i42E97CAE053BA5EF
GO
Isoform 3 (identifier: Q92570-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MHDSIRFGNVDM

Note: No experimental confirmation available.
Show »
Length:637
Mass (Da):69,502
Checksum:i584261AA3DAA3AD5
GO

Sequence cautioni

The sequence AAB02581 differs from that shown. Reason: Frameshift at positions 4 and 20.Curated
The sequence AAB36006 differs from that shown. Reason: Erroneous initiation.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti240S → G (PubMed:8809112).Curated1
Sequence conflicti240S → G (PubMed:8614405).Curated1
Sequence conflicti454K → R in BAA11419 (PubMed:8809112).Curated1
Sequence conflicti579T → N in BAA11419 (PubMed:8809112).Curated1
Sequence conflicti585G → V in BAA11419 (PubMed:8809112).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0378771M → MHDSIRFGNVDM in isoform 3. Curated1
Alternative sequenceiVSP_003712419 – 443YCPTD…NLLTA → VSFMISCFQMNDQGLYLWLL VIRVD in isoform Beta. 2 PublicationsAdd BLAST25
Alternative sequenceiVSP_003713444 – 626Missing in isoform Beta. 2 PublicationsAdd BLAST183

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D78579 mRNA Translation: BAA11419.1
U12767 mRNA Translation: AAB02581.1 Frameshift.
S81243 mRNA Translation: AAB36006.1 Different initiation.
X89894 mRNA Translation: CAA61984.1
AL359710 Genomic DNA No translation available.
AL358937 Genomic DNA No translation available.
CH471105 Genomic DNA Translation: EAW58915.1
D85241 mRNA Translation: BAA28608.1
D85242 mRNA Translation: BAA31221.1
CCDSiCCDS6742.1 [Q92570-3]
CCDS6743.1 [Q92570-1]
CCDS6744.1 [Q92570-2]
PIRiS71930
RefSeqiNP_008912.2, NM_006981.3 [Q92570-1]
NP_775291.1, NM_173199.2 [Q92570-2]
NP_775292.1, NM_173200.2 [Q92570-3]
XP_016870651.1, XM_017015162.1 [Q92570-1]
UniGeneiHs.279522

Genome annotation databases

EnsembliENST00000330847; ENSP00000333122; ENSG00000119508 [Q92570-3]
ENST00000338488; ENSP00000340301; ENSG00000119508 [Q92570-2]
ENST00000395097; ENSP00000378531; ENSG00000119508 [Q92570-1]
ENST00000618101; ENSP00000482027; ENSG00000119508 [Q92570-3]
GeneIDi8013
KEGGihsa:8013
UCSCiuc004bae.3 human [Q92570-1]

Keywords - Coding sequence diversityi

Alternative splicing, Chromosomal rearrangement

Similar proteinsi

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D78579 mRNA Translation: BAA11419.1
U12767 mRNA Translation: AAB02581.1 Frameshift.
S81243 mRNA Translation: AAB36006.1 Different initiation.
X89894 mRNA Translation: CAA61984.1
AL359710 Genomic DNA No translation available.
AL358937 Genomic DNA No translation available.
CH471105 Genomic DNA Translation: EAW58915.1
D85241 mRNA Translation: BAA28608.1
D85242 mRNA Translation: BAA31221.1
CCDSiCCDS6742.1 [Q92570-3]
CCDS6743.1 [Q92570-1]
CCDS6744.1 [Q92570-2]
PIRiS71930
RefSeqiNP_008912.2, NM_006981.3 [Q92570-1]
NP_775291.1, NM_173199.2 [Q92570-2]
NP_775292.1, NM_173200.2 [Q92570-3]
XP_016870651.1, XM_017015162.1 [Q92570-1]
UniGeneiHs.279522

3D structure databases

ProteinModelPortaliQ92570
SMRiQ92570
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi113713, 4 interactors
IntActiQ92570, 38 interactors
STRINGi9606.ENSP00000333122

Chemistry databases

ChEMBLiCHEMBL1961792

PTM databases

iPTMnetiQ92570
PhosphoSitePlusiQ92570

Polymorphism and mutation databases

BioMutaiNR4A3
DMDMi90110039

Proteomic databases

MaxQBiQ92570
PaxDbiQ92570
PeptideAtlasiQ92570
PRIDEiQ92570
ProteomicsDBi75330
75331 [Q92570-2]
75332 [Q92570-3]

Protocols and materials databases

DNASUi8013
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000330847; ENSP00000333122; ENSG00000119508 [Q92570-3]
ENST00000338488; ENSP00000340301; ENSG00000119508 [Q92570-2]
ENST00000395097; ENSP00000378531; ENSG00000119508 [Q92570-1]
ENST00000618101; ENSP00000482027; ENSG00000119508 [Q92570-3]
GeneIDi8013
KEGGihsa:8013
UCSCiuc004bae.3 human [Q92570-1]

Organism-specific databases

CTDi8013
DisGeNETi8013
EuPathDBiHostDB:ENSG00000119508.17
GeneCardsiNR4A3
HGNCiHGNC:7982 NR4A3
HPAiHPA043360
MalaCardsiNR4A3
MIMi600542 gene+phenotype
612219 phenotype
neXtProtiNX_Q92570
OpenTargetsiENSG00000119508
Orphaneti209916 Extraskeletal myxoid chondrosarcoma
PharmGKBiPA31763
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG4217 Eukaryota
ENOG410YWNC LUCA
GeneTreeiENSGT00760000118887
HOVERGENiHBG052663
InParanoidiQ92570
KOiK08559
OMAiYQMQPSG
OrthoDBiEOG091G0GUM
PhylomeDBiQ92570
TreeFamiTF315430

Enzyme and pathway databases

ReactomeiR-HSA-383280 Nuclear Receptor transcription pathway
R-HSA-8936459 RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function
SignaLinkiQ92570
SIGNORiQ92570

Miscellaneous databases

ChiTaRSiNR4A3 human
GeneWikiiNeuron-derived_orphan_receptor_1
GenomeRNAii8013
PROiPR:Q92570
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000119508 Expressed in 191 organ(s), highest expression level in pleura
CleanExiHS_NR4A3
HS_TEC
ExpressionAtlasiQ92570 baseline and differential
GenevisibleiQ92570 HS

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
ProtoNetiSearch...

Entry informationi

Entry nameiNR4A3_HUMAN
AccessioniPrimary (citable) accession number: Q92570
Secondary accession number(s): A2A3I7
, Q12935, Q14979, Q16420, Q4VXA8, Q4VXA9, Q9UEK2, Q9UEK3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: March 21, 2006
Last modified: November 7, 2018
This is version 186 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. Human chromosome 9
    Human chromosome 9: entries, gene names and cross-references to MIM
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Main funding by: National Institutes of Health

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