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FLASH GENE
Symbol NR4A2 contributors: mct - updated : 16-01-2015
HGNC name nuclear receptor subfamily 4, group A, member 2
HGNC id 7981
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a N terminal modulator domain
  • AF1 domain
  • short core activation region localized close to the N-terminus
  • an AF2 domain
  • a highly conserved zing finger DNA binding domain and a less conserved putative C terminal ligand domain
  • a central bipartite (class II) zinc finger DNA binding domain
  • mono polymer heteromer , dimer
    HOMOLOGY
    interspecies homolog to murine Nr4a2
    Homologene
    FAMILY
  • NR4A subfamily of the nuclear receptor superfamily
  • steroid/thyroid receptor superfamily
  • CATEGORY receptor nuclear
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,nucleoplasm
    text
  • translocates to the nucleus in response to EGF-stimulation of certain cell types
  • basic FUNCTION
  • may be functioning as a general coactivator of gene transcription with ligand-independent regulation
  • playing an essential role in the development of midbrain dopamine cells and in the regulation of RET
  • implicated in the development of dopaminergic cells of the ventral tegmental area (VTA) and the substantia nigra (SN)
  • involved in the establishment and maintenance of the dopaminergic phenotype within specific central nervous system neuronal subpopulations including the nigrostriatal dopamine system
  • may also play a role in the pathogenesis of Parkinson disease
  • having a protective function in cartilage homeostasis by selectively repressing MMP gene expression during inflammation
  • plays a pivotal role for mediating cytokine production from pathogenic T cells
  • not only essential in the development of mensencephalic dopaminergic neurons and maintenance of their functions, but it may also play a role in the pathogenesis of Parkinson disease
  • enhances 3,5-cyclic adenosine 5prime-monophosphate-dependent UCP1 gene transcription
  • transcription factor essential for the development, survival, and functional maintenance of midbrain dopaminergic (DAergic) neurons
  • playing a role in neuronal/astrocytic differentiation of neural precursor
  • activating FABP5
  • can enhance RA-induced signaling of PPARbeta/delta and DHA-induced activation of RXR, via the up-regulation of FABP5
  • essential mediator of neuroprotection after exposure to neuropathological stress
  • key downstream mediator of CREB1-induced neuroprotection
  • NR4A1, NR4A2 modulate mesenchymal stromal cell migration
  • induction of NR4A1, NR4A2, NR4A3 in activated mast cells and NR4A family nuclear receptors are implicated in the regulation of mast cell function
  • NR4A2, NR4A1 functions directly at DNA repair sites by a process that requires phosphorylation by PRKDC, and represent an entirely novel component of DNA damage response in the process of DSB repair
  • EGF-stimulation of cells may be a mechanism for the priming of cells for the actions of NR4A2 through increased stability
  • NR4A2 and BDNF show a similar expression pattern during postnatal cerebellar development
  • essential for the nigral dopaminergic neuron phenotype and function maintenance
  • is necessary for both long-term memory for object location and object recognition
  • NR4A1 and NR4A2 differentially contribute to object location versus object recognition memory
  • NR4A1, NR4A2, NR4A3 have key roles in determining CD4(+) T cell fates in the thymus and thus contribute to immune homeostasis
  • functions mainly in transcriptional activation to regulate a battery of genes expressed in dopaminergic neurons
  • regulates key genes, including a battery of nuclear-encoded mitochondrial genes
  • selectively contributes to the maintenance of normal expression levels of nuclear-encoded genes involved in oxidative respiration, but not of any other functional categories of nuclear-encoded mitochondrial genes
  • key midbrain dopamine (mDA) regulators (NR4A2, PITX3, and LMX1A) play overlapping as well as distinct roles during neurogenesis and neurotransmitter phenotype determination of mDA neurons
  • NR4A1, NR4A2, NR4A3 are regulated by different physiological and pathophysiological settings known to be associated with marked alterations in glucose metabolism and energy status
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • heterodimerizing with retinoic X receptor (RXR)
  • INTERACTION
    DNA
  • binding to FABP5 promoter
  • RNA
    small molecule
    protein
  • key regulators of CYP11B2 expression and of adrenal aldosterone production
  • cooperating with PITX3 to promote terminal maturation of the midbrain dopamine neuron phenotype in embryonic stem cell cultures
  • association between NR4A2 overexpression and upregulation of CDKN2C, suggesting a mechanism by which NR4A2 could regulate haematopoietic stem cells quiescence
  • NR4A1, NR4A2 interact with PRKDC and, upon exposure to DNA damage, translocate to DSB foci by a mechanism requiring the activity of PARP1
  • potential molecular target of MIR-132 (MIR-132 could directly regulate the expression of NR4A2)
  • is a downstream target of CREB1 and it is responsible for the NMDA-mediated increase in BDNF, which is necessary for the NMDA-mediated prosurvival effect on neurons
  • NR4A2-TOP2B interaction may shed light on the pathologic role of NR4A2 defect in the nigro-striatal pathway deficiency associated with Parkinson disease
  • PIN1 is a novel binding partner of NR4A1, NR4A2, NR4A3
  • in melanoma cells both CRH and UCN1 regulate TYRP1 gene expression via NR4A2/NR4A1 production, independent of pro-opiomelanocortin or alpha-melanocyte-stimulating hormone stimulation
  • FOXA2 acts as a co-activator potentiating expression of the NR4A2-induced dopamine (DA) phenotype via epigenetic regulation
  • PTH activates the orphan nuclear receptor NR4A2 to induce FGF23 transcription
  • cell & other
    REGULATION
    induced by the cAMP axis in response to glucagon
    CREB1 in neurons exposed to stressful insults and function as mediator of CREB1-induced neuronal survival
    Other direct regulation by CREB1 after NMDAR stimulation
    degraded by the proteasome
    ASSOCIATED DISORDERS
    corresponding disease(s) PARK26
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    in familial Parkinson disease
    constitutional     --over  
    in cartilage derived from patients with osteoarthritis
    constitutional     --over  
    in the T cells isolated from the CNS of multiple sclerosis
    constitutional     --low  
    in end-stage dilated cardiomyopathy
    constitutional     --low  
    in patients with Parkinson disease
    Susceptibility
  • to attention deficit hyperactivity disorder (ADHD)
  • to Parkinson disease
  • to autism spectrum disorder (ASD)
  • Variant & Polymorphism other
  • polymorphisms associated to attention deficit hyperactivity disorder (ADHD)
  • copy-number variants (CNVs) in NR4A2 contribute significantly to autism spectrum disorder (ASD) risk
  • Candidate gene
    Marker
    Therapy target
  • molecular target for blocking inflammation and tissue destruction associated with chronic inflammatory diseases
  • essential transcription factor for triggering the inflammatory cascade of multiple sclerosis and may serve as a therapeutic target
  • ANIMAL & CELL MODELS
  • expression increased in diabetic mice that exhibit elevated gluconeogenesis
  • Nurr1 ablation in mice recapitulates early features of Parkinson disease