Affinage

NR2F2

COUP transcription factor 2 · UniProt P24468

Length
414 aa
Mass
45.6 kDa
Annotated
2026-04-29
100 papers in source corpus 51 papers cited in narrative 51 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR2F2 (COUP-TFII) is an orphan nuclear receptor that functions as a context-dependent transcriptional regulator essential for vascular identity, organogenesis, neuronal migration, and metabolic homeostasis. Its ligand-binding domain adopts an autorepressed conformation in which helix α10 occludes the ligand pocket and AF-2 folds into the cofactor site; retinoic acids release this autoinhibition to enable coactivator recruitment (PMID:18798693). In venous endothelium, NR2F2 homodimers directly bind HEY1/HEY2 promoters to repress Notch signaling and maintain venous identity, whereas heterodimerization with PROX1 redirects its activity toward lymphatic endothelial gene programs including VEGFR-3 and neuropilins (PMID:15875024, PMID:23345397, PMID:18815287). Beyond vascular specification, NR2F2 directly regulates atrial chamber identity through Tbx5/Hey2/Irx4, kidney mesenchyme specification through Eya1/Wt1, steroidogenesis through StAR, diaphragm and stomach patterning, neuronal migratory direction via neuropilin induction, and metabolic gene networks including PGC-1α repression in heart and kidney (PMID:23725765, PMID:22669823, PMID:24899578, PMID:16251273, PMID:22492355, PMID:26356605, PMID:34031962).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1995 High

    Establishing NR2F2 as a transcriptional repressor that competes with RAR:RXR heterodimers on retinoic acid response elements, first demonstrating its capacity to actively silence gene expression (Oct-3/4) through high-affinity DNA binding and a C-terminal silencing domain.

    Evidence Reporter assays, EMSA, and deletion mutagenesis in cell lines

    PMID:7823919

    Open questions at the time
    • No in vivo validation of Oct-3/4 repression
    • Identity of endogenous ligands unknown at this stage
  2. 1999 High

    Demonstrating that NR2F2 is required for cardiovascular development in vivo, with knockout embryos failing to remodel the primitive vascular plexus and showing defective atrial/sinus venosus development, identifying Angiopoietin-1 as a downstream target.

    Evidence Targeted gene deletion in mice with in situ hybridization

    PMID:10215630

    Open questions at the time
    • Could not distinguish cell-autonomous vs. non-autonomous roles
    • Mechanism of Ang-1 regulation not defined
  3. 2005 High

    Resolving the vascular identity question: NR2F2 is selectively expressed in venous endothelium and represses Notch signaling to prevent arterial fate acquisition, establishing the first molecular determinant of venous versus arterial specification.

    Evidence Endothelial-specific conditional knockout and transgenic overexpression in mice with arterial/venous marker analysis

    PMID:15875024

    Open questions at the time
    • Precise Notch target genes directly bound by NR2F2 not identified
    • Post-translational regulation of NR2F2 in ECs unknown
  4. 2005 High

    Extending NR2F2's developmental roles beyond vasculature: mesenchyme-specific ablation revealed essential functions in diaphragm formation (Bochdalek-type hernia upon loss) and stomach patterning downstream of Hedgehog signaling.

    Evidence Tissue-specific conditional knockouts with morphological and epistasis analysis

    PMID:15829524 PMID:16251273

    Open questions at the time
    • Direct transcriptional targets in diaphragm mesenchyme not identified
    • Mechanism linking Hedgehog to NR2F2 expression not fully defined
  5. 2008 High

    Structural resolution of the autorepression mechanism: the crystal structure revealed that helix α10 bends into the ligand pocket and AF-2 occludes the coactivator groove, and that retinoic acids release this conformation to enable transcriptional activation — answering how an 'orphan' receptor is regulated.

    Evidence X-ray crystallography at 1.48 Å; site-directed mutagenesis; cell-based transcription assays

    PMID:18798693

    Open questions at the time
    • Whether retinoic acid is the physiological ligand in vivo remains uncertain
    • Structural basis for ligand selectivity not fully explored
  6. 2008 High

    Defining NR2F2 as a partner of PROX1 in lymphatic endothelial cell fate specification: the two proteins form a stable complex that controls LEC-specific genes including VEGFR-3, FGFR-3, and neuropilin-1, extending NR2F2's vascular role to lymphatic identity.

    Evidence Reciprocal co-immunoprecipitation and functional gene expression analysis in LECs; conditional knockout at different developmental stages with ChIP

    PMID:18815287 PMID:20364082

    Open questions at the time
    • Genome-wide binding profile of the NR2F2-PROX1 complex not determined
    • How PROX1 switches NR2F2 from homodimer repressor to LEC activator mechanistically unclear
  7. 2008 High

    Establishing NR2F2 as a neuronal migration determinant: NR2F2 is necessary and sufficient for caudal migration of CGE-derived cortical interneurons, and essential for Leydig cell differentiation independently of testosterone.

    Evidence Transplantation assays with RNAi in brain; tamoxifen-inducible conditional KO with testosterone rescue in testis

    PMID:18818749 PMID:19074032

    Open questions at the time
    • Direct transcriptional targets mediating migration not identified at this point
    • Mechanism of Leydig progenitor arrest not molecularly defined
  8. 2012 High

    Identifying the direct genomic targets underpinning NR2F2's venous identity function — E2F1 (cell cycle), Foxc1, NP-1, Hey2, EphrinB2/EphB4 — and establishing that NR2F2 directly regulates kidney mesenchyme specification through Eya1 and Wt1.

    Evidence ChIP, microarray, and siRNA knockdown in HUVECs; conditional KO with ChIP in metanephric mesenchyme

    PMID:22669823 PMID:22734039

    Open questions at the time
    • Genome-wide ChIP-seq in venous ECs not yet performed
    • How NR2F2 coordinates cell cycle and identity programs simultaneously unclear
  9. 2013 High

    Defining the molecular switch between venous and lymphatic fate: NR2F2 homodimers directly bind HEY1/HEY2 promoters to repress arterial genes in veins, while NR2F2-PROX1 heterodimers lack this capacity and instead activate LEC genes — resolving how one factor specifies two distinct endothelial identities.

    Evidence ChIP assays on HEY promoters; Co-IP for heterodimer formation; gain/loss-of-function

    PMID:23345397

    Open questions at the time
    • Whether additional cofactors determine the homodimer/heterodimer equilibrium unknown
    • No structural model of the heterodimer
  10. 2013 High

    Establishing NR2F2 as a determinant of atrial chamber identity: cardiomyocyte-specific ablation ventricularizes atria with ventricle-type action potentials, and ChIP identifies Tbx5, Hey2, Irx4, and myosin light chains as direct targets.

    Evidence Cardiomyocyte-specific conditional KO; ChIP at E13.5; electrophysiology; genome-wide expression

    PMID:23725765

    Open questions at the time
    • Whether NR2F2 maintains atrial identity in adults or only during development unclear
    • Interaction with other atrial transcription factors not biochemically defined
  11. 2013 High

    Providing the molecular basis for NR2F2-directed neuronal migration: NR2F2 directly binds Nrp1 and Nrp2 promoters in the developing telencephalon (by ChIP), and loss impairs Pax6+ cell migration into the amygdala.

    Evidence Conditional KO with in vivo ChIP and molecular marker analysis in brain

    PMID:22492355

    Open questions at the time
    • Signaling ligands (semaphorins/VEGF-C) acting through neuropilins in this context not defined
    • Whether NR2F2 regulates additional guidance molecules unknown
  12. 2015 High

    Revealing NR2F2 as a metabolic repressor: cardiac overexpression suppresses mitochondrial electron transport chain genes, PGC-1α network, and oxygen consumption, causing dilated cardiomyopathy — linking NR2F2 to energy metabolism beyond its developmental roles.

    Evidence Cardiac-specific transgenic overexpression; mitochondrial functional assays; genetic rescue by calcineurin haploinsufficiency

    PMID:26356605

    Open questions at the time
    • Whether NR2F2 directly binds PGC-1α regulatory regions in heart not shown in this study
    • Physiological contexts in which NR2F2 normally regulates cardiac metabolism unclear
  13. 2016 High

    Resolving how NR2F2 protein stability is maintained: Tie2/Akt signaling phosphorylates NR2F2 to protect it from proteasomal degradation in venous endothelium, connecting receptor tyrosine kinase signaling to venous identity maintenance.

    Evidence Conditional Tek KO; Ang-1 stimulation; PI3K/Akt inhibitors; proteasome inhibitor rescue in cultured ECs

    PMID:28005008

    Open questions at the time
    • Specific phosphorylation site(s) on NR2F2 not mapped
    • Whether other RTK pathways also regulate NR2F2 stability unknown
  14. 2017 High

    Demonstrating an androgen-independent developmental role: NR2F2 in Wolffian duct mesenchyme actively promotes female reproductive tract regression via suppression of phospho-ERK signaling, overturning the dogma that Wolffian duct regression is purely passive.

    Evidence Conditional KO in Wolffian duct mesenchyme; androgen receptor manipulation; phospho-ERK analysis

    PMID:28818950

    Open questions at the time
    • Direct transcriptional targets in Wolffian duct mesenchyme not identified
    • Mechanism linking NR2F2 to ERK suppression not defined
  15. 2019 High

    Establishing NR2F2 as a cofactor at ERα super-enhancers in breast cancer, cooperating with pioneer factors FOXA1 and GATA3; a small-molecule inhibitor was identified that binds the NR2F2 LBD and disrupts NR2F2-FOXA1 interaction, validating NR2F2 as a druggable target.

    Evidence ChIP-seq/ATAC-seq/RNA-seq for genomic binding; high-throughput screening with LBD binding assays and Co-IP disruption; xenograft models

    PMID:31588232 PMID:32494682

    Open questions at the time
    • Selectivity and in vivo pharmacokinetics of the inhibitor not fully characterized
    • Whether inhibitor affects NR2F2 developmental functions unclear
  16. 2021 High

    Confirming direct PGC-1α promoter binding by NR2F2 via ChIP-qPCR in kidney fibroblasts, showing that NR2F2 promotes glycolysis over fatty acid oxidation to drive fibrosis — unifying the metabolic repression theme across tissues.

    Evidence Conditional KO in mice; ChIP-qPCR; proteomics; gain/loss of function in fibroblasts

    PMID:34031962

    Open questions at the time
    • Genome-wide metabolic target set in fibroblasts not fully defined
    • Whether NR2F2-PGC-1α axis operates in all fibrotic contexts unknown
  17. 2023 Medium

    Discovery that an alternative NR2F2 isoform (NR2F2-Iso2) lacking the DNA-binding domain is epigenetically silenced in normal melanocytes but reactivated by hypomethylation in metastatic melanoma, where it modulates full-length NR2F2 activity on EMT targets.

    Evidence DNA methylation profiling; isoform-specific gain/loss of function; EMT/NCC target gene analysis

    PMID:37015919

    Open questions at the time
    • Biochemical mechanism by which Iso2 modulates full-length NR2F2 not reconstituted
    • Structural basis for Iso2 function without DBD unknown
    • Generalizability beyond melanoma not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The physiological ligand(s) activating NR2F2 in vivo, the specific phosphorylation sites governing its proteasomal stability, the structural basis of the PROX1 heterodimer switch, and the full scope of tissue-specific cofactor dependencies remain unresolved.
  • Endogenous ligand identity in physiological contexts not established
  • No crystal structure of NR2F2-PROX1 or NR2F2-FOXA1 complexes
  • Phosphorylation sites mediating Akt-dependent stabilization not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 12 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 5
Pathway
R-HSA-1266738 Developmental Biology 13 R-HSA-162582 Signal Transduction 6 R-HSA-1430728 Metabolism 5
Partners
FBXO21FOG2FOXA1GATA3HNF4ANR3C1PROX1RELA
Complex memberships
NR2F2 homodimerNR2F2-PROX1 heterodimer

Evidence

Reading pass · 51 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 COUP-TFII (NR2F2) is specifically expressed in venous (not arterial) endothelium and represses Notch signaling to maintain vein identity; endothelial-specific ablation causes veins to acquire arterial characteristics including NP-1 and Notch signaling molecules, while ectopic expression causes vein-artery fusion. Conditional endothelial-specific knockout and transgenic overexpression in mice; arterial/venous marker analysis Nature High 15875024
1999 COUP-TFII is required for angiogenesis and heart (atria/sinus venosus) development; COUP-TFII mutants fail to remodel the primitive capillary plexus and show downregulation of Angiopoietin-1, suggesting COUP-TFII is required for mesenchymal-endothelial signaling. Targeted gene deletion in mice; in situ hybridization and morphological analysis Genes & development High 10215630
2008 Crystal structure of the human COUP-TFII ligand-binding domain (1.48 Å) reveals an autorepressed conformation where helix α10 is bent into the ligand-binding pocket and the AF-2 helix is folded into the cofactor binding site. Retinoic acids promote COUP-TFII to recruit coactivators and activate transcription, releasing it from autorepression. Mutations disrupting cofactor binding, dimerization, or ligand binding substantially reduce transcriptional activity. X-ray crystallography; cell-based transcription assays; site-directed mutagenesis PLoS biology High 18798693
2008 COUP-TFII physically interacts with Prox1 to form a stable complex in lymphatic endothelial cells (LECs), and this complex functions as a coregulator to control LEC lineage-specific genes including VEGFR-3, FGFR-3, and neuropilin-1, thereby specifying LEC fate. Co-immunoprecipitation; functional gene expression analysis in LECs Blood High 18815287
2010 COUP-TFII directly stimulates expression of neuropilin-2 (a VEGF-C coreceptor) to enhance pro-lymphangiogenic VEGF-C actions; conditional ablation at early embryonic stage blocks pre-lymphatic EC formation, while late ablation causes loss of LEC identity and gain of blood EC fate. Conditional knockout mouse models; siRNA knockdown in primary human LECs; ChIP assay The Journal of clinical investigation High 20364082
2013 COUP-TFII homodimers inhibit arterial differentiation in venous ECs by directly binding to promoter regions of Notch target genes HEY1 and HEY2, whereas COUP-TFII/PROX1 heterodimers lack this inhibitory effect and instead induce LEC-specific gene expression, defining a molecular switch between venous and lymphatic EC identity. ChIP assays; promoter binding analysis; gain- and loss-of-function experiments; Co-IP Journal of cell science High 23345397
2013 Cardiomyocyte-specific COUP-TFII ablation produces ventricularized atria with ventricle-like action potentials, increased cardiomyocyte size, and T tubules; ChIP in E13.5 atria identified Tbx5, Hey2, Irx4, MLC2v, MLC2a, and MLC1a as direct COUP-TFII targets, establishing COUP-TFII as a determinant of atrial identity. Cardiomyocyte-specific conditional KO; chromatin immunoprecipitation; electrophysiology; genome-wide expression analysis Developmental cell High 23725765
2012 COUP-TFII directly regulates E2F1 transcription by tethering to Sp1 binding sites in the E2F1 promoter (shown by ChIP), thereby modulating cell cycle and proliferation; it also directly targets Foxc1, NP-1 (upstream Notch genes) and Hey2 (downstream Notch effector), and suppresses EphrinB2 while enhancing EphB4 expression to regulate venous identity. Microarray; chromatin immunoprecipitation; siRNA knockdown in HUVECs Molecular endocrinology High 22734039
1995 COUP-TFII (ARP-1) represses Oct-3/4 promoter activity through the RAREoct element in a dose-dependent manner, with the C-terminal domain harboring the silencing region. COUP-TFII binds RAREoct with higher affinity than RAR:RXR heterodimers and can compete with and displace RAR:RXR to actively silence the Oct-3/4 promoter. Reporter assays; EMSA; deletion mutagenesis; competition binding assays Molecular and cellular biology High 7823919
2010 COUP-TFII directly represses Notch signaling to suppress NP-1 in veins; in the undifferentiated hESC state, OCT4 and OCT4-induced miR-302 directly repress NR2F2 transcriptionally and post-transcriptionally respectively; conversely NR2F2 directly inhibits OCT4 during differentiation, creating a positive feedback loop for its own expression. Luciferase reporter assays; ChIP; miRNA overexpression and knockdown; siRNA in hESCs The EMBO journal High 21151097
2013 COUP-TFII directly regulates neuropilin-1 and neuropilin-2 gene expression in the developing amygdala; ChIP assays confirmed Nrp1 and Nrp2 as direct COUP-TFII targets in the telencephalon in vivo; loss of COUP-TFII in CGE-derived cells impairs migration of Pax6+ cells into the basomedial amygdala nucleus. Conditional KO (Rx-Cre); ChIP; molecular marker analysis Development (Cambridge, England) High 22492355
2008 COUP-TFII is required and sufficient for CGE-derived cortical interneuron caudal migration; knockdown inhibits caudal migration while ectopic expression in MGE cells redirects their migration caudally when transplanted into the CGE environment. Transcriptome comparison; transplantation assays; RNAi knockdown in mouse brain The Journal of neuroscience High 19074032
2008 COUP-TFII is essential for Leydig cell differentiation; conditional pre-pubertal ablation arrests Leydig cells at the progenitor stage, causing testosterone deficiency and infertility; testosterone administration rescues spermatogenetic defects, but Leydig cell maturation requires COUP-TFII itself, as testosterone cannot substitute for it. Tamoxifen-inducible Cre conditional KO; testosterone rescue experiments; histology PloS one High 18818749
2000 COUP-TFII synergistically activates transcription of the CYP7A1 (cholesterol 7α-hydroxylase) promoter together with HNF4; COUP-TFII binds adjacent DR0 element and interacts with HNF4 through protein-protein interactions facilitated by juxtaposed binding elements. Transient transfection reporter assays; EMSA with in vitro-translated COUP-TFII; cotransfection in HepG2 cells Journal of lipid research High 10627496
2010 COUP-TFII suppression of ERα activity is required for successful embryo implantation and uterine decidualization; administration of ERα antagonist ICI 182,780 rescues implantation defects in uterine COUP-TFII knockout mice and restores Wnt4 and BMP2 expression. Uterine conditional KO (PR-Cre); ERα antagonist rescue experiment; gene expression analysis Molecular endocrinology High 20219888
2010 COUP-TFII directly regulates Angiopoietin-1 transcription in pericytes to enhance tumor neoangiogenesis; conditional adult ablation of COUP-TFII severely compromises neoangiogenesis and suppresses tumor growth; provision of Angiopoietin-1 partially restores angiogenic defects in COUP-TFII-deficient mice. Conditional adult KO; xenograft and spontaneous tumor models; Ang-1 rescue experiment; ChIP Proceedings of the National Academy of Sciences of the United States of America High 20133706
2005 COUP-TFII is expressed in foregut mesenchyme and its ablation in the posthepatic mesenchymal plate causes Bochdalek-type congenital diaphragmatic hernia through failure of diaphragm formation and attachment to body wall. Tissue-specific conditional KO (foregut mesenchyme Cre); morphological and histological analysis Proceedings of the National Academy of Sciences of the United States of America High 16251273
2005 COUP-TFII in gastric mesenchyme is required for radial and anteroposterior stomach patterning; COUP-TFII acts downstream of hedgehog signaling in the stomach mesenchyme, as cyclopamine treatment downregulates COUP-TFII expression. Conditional KO (Nkx3-2-Cre); organ culture with cyclopamine; X-gal staining of lacZ knockin Development (Cambridge, England) High 15829524
2007 Uterine stromal/smooth muscle COUP-TFII is required for proper placentation; deletion increases trophoblast giant cell differentiation, reduces spongiotrophoblast layer, and causes absence of labyrinth formation with impaired placental vascularization. Conditional KO (uterine stromal Cre/loxP); histological analysis of placentation Proceedings of the National Academy of Sciences of the United States of America High 17404209
2015 COUP-TFII represses genes critical for mitochondrial electron transport chain enzyme activity, oxidative stress detoxification, mitochondrial dynamics, and the PGC-1 network, resulting in increased ROS, decreased oxygen consumption, and reduced glucose/oleate oxidation, leading to dilated cardiomyopathy. Cardiac-specific transgenic overexpression; mitochondrial function assays; gene expression profiling; calcineurin transgenic cross for haploinsufficiency rescue Nature communications High 26356605
2017 COUP-TFII in the Wolffian duct mesenchyme actively promotes elimination of male reproductive tracts in female embryos; COUP-TFII loss causes retention of Wolffian ducts independent of androgen; instead, enhanced phospho-ERK signaling in Wolffian duct epithelium mediates the retention via mesenchyme-epithelium cross-talk. Conditional KO in Wolffian duct mesenchyme; androgen receptor manipulation; phospho-ERK analysis Science High 28818950
2013 BRG1 chromatin-remodeling enzyme directly promotes COUP-TFII expression in venous endothelial cells by binding conserved regulatory elements in the COUP-TFII promoter and remodeling chromatin accessibility; BRG1 endothelial deletion downregulates COUP-TFII and causes aberrant arterial marker expression on veins. Endothelial-specific conditional KO of Brg1; ChIP for BRG1 at COUP-TFII promoter; chromatin accessibility analysis Development (Cambridge, England) High 23406903
2016 Tie2 signaling maintains COUP-TFII protein stability via Akt-mediated phosphorylation; Tie2 knockdown or PI3K/Akt pathway blockade reduces COUP-TFII protein levels, while proteasome inhibition restores COUP-TFII, indicating that Tie2/Akt signaling prevents proteasomal degradation of COUP-TFII to maintain venous identity. Conditional Tek KO in mice; Ang-1 stimulation; Tie2 knockdown; proteasome inhibitor rescue in cultured ECs eLife High 28005008
2014 NR2F2 directly activates Star (steroidogenic acute regulatory protein) gene expression in Leydig cells by binding to a DR1-like element between -131 and -95 bp of the Star promoter; NR2F2 knockdown reduces STAR mRNA/protein and basal steroid production; DR1 mutations that prevent NR2F2 binding blunt promoter activation. siRNA knockdown; promoter deletion constructs; ChIP; site-directed mutagenesis in Leydig cell lines Biology of reproduction High 24899578
2012 COUP-TFII is required for metanephric mesenchyme specification and kidney precursor cell survival; conditional ablation at E7.5 results in loss of Eya1, Six2, Pax2, and Gdnf expression; COUP-TFII directly regulates both Eya1 and Wt1 expression in metanephric mesenchyme as shown by ChIP. Conditional KO; ChIP; gene expression analysis Development (Cambridge, England) High 22669823
2008 COUP-TFII regulates postnatal cerebellar growth and maturation by directly regulating IGF-1 expression in a Sp1-dependent manner (shown by ChIP); COUP-TFII knockout in brain reduces GCP proliferation, increases apoptosis, and decreases Akt1, GSK-3β, and mTOR activities downstream of IGF-1. NSE-Cre conditional KO; ChIP; IGF-1 pathway analysis; proliferation and apoptosis assays Developmental biology High 19041640
2015 COUP-TFII overexpression in satellite cells causes Duchenne-like dystrophy with regenerative failure due to deficient satellite cell proliferation and myoblast fusion; COUP-TFII transcriptionally represses promyogenic fusion factors including Npnt, Itgb1D, and Cav3, and reduces activation of focal adhesion kinase (FAK). Satellite cell-specific transgenic overexpression; dystrophin-deficient mouse cross; gene expression and FAK activation analysis The Journal of clinical investigation High 27617862
2016 miR-101 and miR-27a negatively regulate COUP-TFII; COUP-TFII in turn drives a FOXM1-CENPF transcriptional cascade to promote prostate cancer metastasis; COUP-TFII loss decreases FOXM1 and CENPF expression and invasion, while this axis also contributes to enzalutamide resistance. miRNA overexpression/knockdown; shRNA; clinical dataset correlation; invasion assays Nature communications Medium 27108958
2004 Glucocorticoid receptor (GR) physically interacts with COUP-TFII; GR stimulates COUP-TFII-induced transactivation via its AF-1 domain attracting coactivators, while COUP-TFII represses GR-governed transcription by tethering SMRT and NCoR corepressors via its C-terminal domain. Co-immunoprecipitation; transactivation reporter assays; domain deletion analysis Annals of the New York Academy of Sciences Medium 15265774
2016 COUP-TFII represses myoblast fusion during skeletal muscle development by transcriptionally repressing Npnt, Itgb1D, and Cav3; elevated COUP-TFII in myogenic precursors results in inefficient muscle development and reduced FAK activation. Transgenic myogenic precursor-specific overexpression; in vitro differentiation assays; gene expression analysis Scientific reports Medium 28600496
2012 COUP-TFII controls pancreatic β-cell mass by inducing β-catenin gene expression and its targets (cyclin D1, axin 2); GLP-1-induced activation of β-catenin pathway is impaired in COUP-TFII-deficient islets; COUP-TFII expression is positively regulated by TCF7L2 in a feedback loop. Pdx1-Cre conditional KO; islet isolation and culture; gain/loss of function in β-cells; gene expression analysis PloS one Medium 22292058
2014 COUP-TFII directly binds the COX-2 promoter to inhibit its transcription; proinflammatory cytokines (IL-1β, TNF-α, TGF-β1) reduce COUP-TFII via miR-302a induction, which targets the 3'UTR of COUP-TFII mRNA, leading to de-repression of COX-2 in endometriosis. ChIP; promoter luciferase assay; miRNA inhibitor/mimic; siRNA in primary human endometrial stromal cells The Journal of clinical endocrinology and metabolism High 24423359
2017 NR2F2 transcriptionally activates miR-21 by binding to its promoter (shown by ChIP and luciferase assay); miR-21 suppresses Smad7 to promote TGF-β-dependent epithelial-mesenchymal transition in colorectal cancer. ChIP; luciferase reporter assay; siRNA knockdown; migration/invasion assays in CRC cells Biochemical and biophysical research communications Medium 28192117
2013 COUP-TFII directly targets the Snail1 promoter in colorectal cancer cells (shown by ChIP), regulating Snail1 expression and consequently suppressing adherence molecules ZO-1, E-cadherin, and β-catenin to promote metastasis. ChIP; reporter assays; siRNA knockdown; invasion/migration assays; tamoxifen-inducible KO mouse model British journal of cancer Medium 25032732
2013 COUP-TFII inhibits NFκB-DNA binding and impairs coactivator-induced NFκB transactivation; endogenous COUP-TFII co-immunoprecipitates with NFκB subunits RelB and NFκB1 in MCF-7 breast cancer cells, and ectopic COUP-TFII expression in endocrine-resistant cells inhibits NFκB activation. Co-immunoprecipitation; NFκB reporter assay; EMSA; transient transfection Molecular and cellular endocrinology Medium 24141032
2019 A small-molecule COUP-TFII inhibitor identified by high-throughput screening directly binds the COUP-TFII ligand-binding domain and disrupts COUP-TFII interaction with transcription regulators including FOXA1, thereby repressing COUP-TFII transcriptional activity on target genes. High-throughput screening; LBD binding assays; Co-IP disruption; xenograft mouse models Science advances High 32494682
2019 NR2F2 functions as a cofactor with pioneer factors FOXA1 and GATA3 at ERα binding sites in breast cancer; NR2F2 perturbation decreases ERα DNA binding and chromatin accessibility; most NR2F2 binding occurs independently of estrogen, and co-occupancy of all three TFs marks the most transcriptionally active ERα super-enhancer sites. ChIP-seq analysis (ENCODE); ATAC-seq; RNA-seq; perturbation of NR2F2 expression with measurement of ERα binding Theranostics Medium 31588232
2019 KRAS/MEK signaling upregulates COUP-TFII, which in turn increases LDHA expression to drive lactate production; lactate then inhibits the TSC2-Rheb interaction, leading to mTORC1 activation and cellular growth independent of growth factor stimulation. COUP-TFII knockdown/overexpression; LDHA reporter assays; TSC2-Rheb co-immunoprecipitation; mTORC1 activity assays in KRAS-activated cells EMBO reports Medium 30988000
2015 COUP-TFII/Nrp2 expression determines the pathway and destination of preoptic area-derived GABAergic neurons; COUP-TFII-induced Nrp2 drives caudal migration toward amygdala, while suppression of COUP-TFII/Nrp2 redirects cells to the neocortex; overexpression retains cells in the medial amygdala. In utero electroporation gain/loss of function; conditional transgenic manipulation; cell migration tracking Proceedings of the National Academy of Sciences of the United States of America Medium 26305926
2015 Nr2f2 hinge region (five-amino acid deletion) is required for interaction with Fog2; Nr2f2 mutant rats with this deletion show lower blood pressure, and the mutant Nr2f2 protein shows greater interaction with Fog2 than wild-type, indicating that the Nr2f2-Fog2 interaction level critically influences blood pressure regulation. Zinc-finger nuclease gene editing; blood pressure measurement; protein-protein interaction assays Nature communications Medium 25687237
2021 COUP-TFII enhances glycolysis and suppresses fatty acid oxidation in myofibroblasts to promote kidney fibrosis; COUP-TFII directly binds the PGC1α promoter (shown by ChIP-qPCR) to reduce PGC1α levels; COUP-TFII overexpression induces αSMA and collagen 1 production, while KO decreases glycolysis and collagen levels. Conditional KO in mice; proteomic analysis; ChIP-qPCR; gain/loss of function in fibroblasts EMBO reports High 34031962
2010 NR2F2 is involved in villous cytotrophoblast differentiation to syncytiotrophoblast; NR2F2 directly activates TFAP2A (AP-2α) promoter activity in a dose-dependent manner, and this induction is potentiated by RARA and RXRA; siRNA silencing of NR2F2 blocks induction of TFAP2A and STB marker genes by 51-59%. NR2F2 overexpression and siRNA knockdown in primary CTB cells and JEG-3 cells; luciferase reporter assay PloS one Medium 20195529
2020 COUP-TFII overexpression in Parkinson's disease dopaminergic neurons disrupts mitochondrial function by repressing cytosolic aldehyde dehydrogenase gene expression, leading to DOPAL buildup; elevated COUP-TFII causes reduced mitochondrial cristae and accelerates neurodegeneration in MitoPark mice. DA neuron-specific transgenic overexpression and under-expression; MitoPark mouse model cross; mitochondrial morphology and gene expression analysis PLoS genetics Medium 32579581
2022 Nr2f2 promotes ferroptosis and mitochondrial dysfunction in diabetes-induced heart failure by negatively regulating PGC-1α; Nr2f2 knockdown ameliorates ferroptosis and mitochondrial dysfunction via PGC-1α, while PGC-1α knockdown counteracts Nr2f2 knockdown protection. AAV9 cardiac overexpression; streptozotocin/high-fat diet diabetic model; siRNA knockdown; epistasis with PGC-1α knockdown Mediators of inflammation Medium 36081650
2017 Coup-TF1 and Coup-TF2 (Nr2f1 and Nr2f2) in MGE progenitors promote time-dependent specification of layer V SST+ cortical interneurons and autonomously repress PV+ fate, in part by directly driving Sox6 expression. MGE-specific conditional KO of Coup-TF1 and Coup-TF2; interneuron subtype marker analysis; Sox6 expression assays Development (Cambridge, England) Medium 28694260
2013 COUP-TFII regulates human endometrial stromal gene expression including inflammatory cytokines; ChIP-seq identified a genome-wide set of direct COUP-TFII target genes in endometrial stroma involved in cell adhesion, angiogenesis, and inflammation. siRNA knockdown in primary human endometrial stromal cells; microarray combined with ChIP-seq Molecular endocrinology Medium 24176914
2001 COUP-TFII binds a nuclear hormone-responsive element (DR-type) at -841/-800 of the mouse Na+/H+ exchanger (NHE1) promoter and transactivates NHE1 expression; mutation at -829/-824 prevents COUP binding and abolishes activation; COUP-TFII expression in NIH 3T3 cells increases NHE synthesis. Reporter assays; DNase footprint analysis; EMSA; transactivation in NIH 3T3 and CV1 cells European journal of biochemistry Medium 11168401
2001 COUP-TFII (but not COUP-TFI) is expressed in Ad12-transformed tumorigenic cells and completely represses MHC class I transcription by binding to the class I enhancer; NF-κB p50/p52 double-knockout cells demonstrated COUP-TFII can repress both non-activated and NF-κB-activated class I transcription. EMSA; reporter assays; NF-κB knockout cell lines; COUP-TFII promoter activity measurement Virology Medium 11352663
2018 COUP-TFII directly binds and suppresses the ANG (angiogenin) promoter in endometrial stromal cells; hypoxia-mediated suppression of COUP-TFII increases ANG expression and ANG-mediated angiogenic activity; ChIP and promoter assays confirmed direct regulation. ChIP; luciferase reporter assay; COUP-TFII knockdown/overexpression; tube formation assay in primary human cells Human reproduction Medium 29982401
2021 Fbxo21 (an E3 ubiquitin ligase F-box protein) targets NR2F2 for ubiquitination and proteasomal degradation; Fbxo21 expression inversely correlates with NR2F2 protein level, and Fbxo21-mediated reduction of NR2F2 inhibits EMT in gastric cancer cells. Co-immunoprecipitation; ubiquitination assays; proteasome inhibitor treatment; rescue by NR2F2 re-expression Journal of Cancer Medium 33531987
2023 An alternative NR2F2 isoform (NR2F2-Iso2), transcribed from an alternative TSS and lacking the DNA-binding domain, is epigenetically silenced by DNA methylation in normal melanocytes but becomes hypomethylated and re-expressed during metastatic melanoma progression; NR2F2-Iso2 modulates full-length NR2F2 activity over EMT- and NCC-associated target genes to drive metastatic progression. DNA methylation profiling; functional gain/loss of function; gene expression analysis of EMT/NCC targets; isoform-specific reporter assays Nature communications Medium 37015919

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 521 15875024
1999 The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development. Genes & development 437 10215630
2008 Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor. PLoS biology 171 18798693
2010 A regulatory circuitry comprised of miR-302 and the transcription factors OCT4 and NR2F2 regulates human embryonic stem cell differentiation. The EMBO journal 161 21151097
2014 Rare variants in NR2F2 cause congenital heart defects in humans. American journal of human genetics 138 24702954
2005 Mouse lacking COUP-TFII as an animal model of Bochdalek-type congenital diaphragmatic hernia. Proceedings of the National Academy of Sciences of the United States of America 138 16251273
1995 A dynamic balance between ARP-1/COUP-TFII, EAR-3/COUP-TFI, and retinoic acid receptor:retinoid X receptor heterodimers regulates Oct-3/4 expression in embryonal carcinoma cells. Molecular and cellular biology 138 7823919
2008 Prox1 physically and functionally interacts with COUP-TFII to specify lymphatic endothelial cell fate. Blood 135 18815287
2008 COUP-TFII is preferentially expressed in the caudal ganglionic eminence and is involved in the caudal migratory stream. The Journal of neuroscience : the official journal of the Society for Neuroscience 125 19074032
2010 Direct transcriptional regulation of neuropilin-2 by COUP-TFII modulates multiple steps in murine lymphatic vessel development. The Journal of clinical investigation 120 20364082
2013 Atrial identity is determined by a COUP-TFII regulatory network. Developmental cell 112 23725765
2013 MicroRNA-302 increases reprogramming efficiency via repression of NR2F2. Stem cells (Dayton, Ohio) 110 23136034
2000 HNF4 and COUP-TFII interact to modulate transcription of the cholesterol 7alpha-hydroxylase gene (CYP7A1). Journal of lipid research 110 10627496
2005 COUP-TFII is essential for radial and anteroposterior patterning of the stomach. Development (Cambridge, England) 107 15829524
2010 COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis. Proceedings of the National Academy of Sciences of the United States of America 102 20133706
2016 Dysregulation of miRNAs-COUP-TFII-FOXM1-CENPF axis contributes to the metastasis of prostate cancer. Nature communications 98 27108958
2008 Essential roles of COUP-TFII in Leydig cell differentiation and male fertility. PloS one 97 18818749
2010 Expression of COUP-TFII nuclear receptor in restricted GABAergic neuronal populations in the adult rat hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 94 20130170
2014 MicroRNA-194 reciprocally stimulates osteogenesis and inhibits adipogenesis via regulating COUP-TFII expression. Cell death & disease 89 25412310
2012 Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which leads to masculinization disorders in rodents. PloS one 74 22615892
2018 Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children. American journal of human genetics 70 29478779
2012 COUP-TFII is a major regulator of cell cycle and Notch signaling pathways. Molecular endocrinology (Baltimore, Md.) 70 22734039
2007 Deletion of the orphan nuclear receptor COUP-TFII in uterus leads to placental deficiency. Proceedings of the National Academy of Sciences of the United States of America 70 17404209
2013 COUP-TFII orchestrates venous and lymphatic endothelial identity by homo- or hetero-dimerisation with PROX1. Journal of cell science 68 23345397
2010 Suppression of ERalpha activity by COUP-TFII is essential for successful implantation and decidualization. Molecular endocrinology (Baltimore, Md.) 68 20219888
2018 LncRNA NR2F2-AS1 promotes tumourigenesis through modulating BMI1 expression by targeting miR-320b in non-small cell lung cancer. Journal of cellular and molecular medicine 65 30592135
2004 The nuclear orphan receptor COUP-TFII is required for limb and skeletal muscle development. Molecular and cellular biology 63 15572686
2016 Angiopoietin receptor Tie2 is required for vein specification and maintenance via regulating COUP-TFII. eLife 60 28005008
2017 Elimination of the male reproductive tract in the female embryo is promoted by COUP-TFII in mice. Science (New York, N.Y.) 59 28818950
2013 BRG1 promotes COUP-TFII expression and venous specification during embryonic vascular development. Development (Cambridge, England) 58 23406903
2019 COUP-TFII in Health and Disease. Cells 57 31906104
2015 Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure. Nature communications 57 26356605
2012 COUP-TFII controls amygdala patterning by regulating neuropilin expression. Development (Cambridge, England) 56 22492355
2017 NR2F2 inhibits Smad7 expression and promotes TGF-β-dependent epithelial-mesenchymal transition of CRC via transactivation of miR-21. Biochemical and biophysical research communications 51 28192117
2017 The Transcription Factors COUP-TFI and COUP-TFII have Distinct Roles in Arealisation and GABAergic Interneuron Specification in the Early Human Fetal Telencephalon. Cerebral cortex (New York, N.Y. : 1991) 51 28922831
2014 The nuclear receptor NR2F2 activates star expression and steroidogenesis in mouse MA-10 and MLTC-1 Leydig cells. Biology of reproduction 51 24899578
2015 miR-30-HNF4γ and miR-194-NR2F2 regulatory networks contribute to the upregulation of metaplasia markers in the stomach. Gut 49 25800782
2017 Coup-TF1 and Coup-TF2 control subtype and laminar identity of MGE-derived neocortical interneurons. Development (Cambridge, England) 48 28694260
2016 miR-27b inhibits gastric cancer metastasis by targeting NR2F2. Protein & cell 46 27844448
2015 Venous Endothelial Marker COUP-TFII Regulates the Distinct Pathologic Potentials of Adult Arteries and Veins. Scientific reports 45 26537113
2013 COUP-TFII regulates human endometrial stromal genes involved in inflammation. Molecular endocrinology (Baltimore, Md.) 44 24176914
2017 A COUP-TFII Human Embryonic Stem Cell Reporter Line to Identify and Select Atrial Cardiomyocytes. Stem cell reports 43 29173897
2015 MicroRNA-302a stimulates osteoblastic differentiation by repressing COUP-TFII expression. Journal of cellular physiology 42 25215426
2008 Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) regulates growth and patterning of the postnatal mouse cerebellum. Developmental biology 42 19041640
2011 Transcription factor COUP-TFII is indispensable for venous and lymphatic development in zebrafish and Xenopus laevis. Biochemical and biophysical research communications 41 21641336
2014 Suppression of COUP-TFII by proinflammatory cytokines contributes to the pathogenesis of endometriosis. The Journal of clinical endocrinology and metabolism 40 24423359
2013 Expression and functional pathway analysis of nuclear receptor NR2F2 in ovarian cancer. The Journal of clinical endocrinology and metabolism 40 23690307
2012 Multiple roles of COUP-TFII in cancer initiation and progression. Journal of molecular endocrinology 40 22966133
2013 Sonic hedgehog (Shh) regulates the expression of angiogenic growth factors in oxygen-glucose-deprived astrocytes by mediating the nuclear receptor NR2F2. Molecular neurobiology 39 23378030
2012 COUP-TFII is essential for metanephric mesenchyme formation and kidney precursor cell survival. Development (Cambridge, England) 39 22669823
2002 Expression of COUP-TFII in metabolic tissues during development. Mechanisms of development 39 12385758
2016 MicroRNA-382 inhibits prostate cancer cell proliferation and metastasis through targeting COUP-TFII. Oncology reports 38 27748848
2011 COUP-TFII expressing interneurons in human fetal forebrain. Cerebral cortex (New York, N.Y. : 1991) 38 22178710
2016 MiR-382 inhibits cell growth and invasion by targeting NR2F2 in colorectal cancer. Molecular carcinogenesis 37 26800338
2015 The COUP-TFII/Neuropilin-2 is a molecular switch steering diencephalon-derived GABAergic neurons in the developing mouse brain. Proceedings of the National Academy of Sciences of the United States of America 37 26305926
2014 The role of the orphan nuclear receptor COUP-TFII in tumorigenesis. Acta pharmacologica Sinica 37 25283503
2021 NR2F2 controls malignant squamous cell carcinoma state by promoting stemness and invasion and repressing differentiation. Nature cancer 35 35122061
2022 Nr2f2 Overexpression Aggravates Ferroptosis and Mitochondrial Dysfunction by Regulating the PGC-1α Signaling in Diabetes-Induced Heart Failure Mice. Mediators of inflammation 33 36081650
2016 De novo frameshift mutation in COUP-TFII (NR2F2) in human congenital diaphragmatic hernia. American journal of medical genetics. Part A 33 27363585
2013 COUP-TFII in pancreatic adenocarcinoma: clinical implication for patient survival and tumor progression. International journal of cancer 33 24122412
2014 COUP-TFII regulates metastasis of colorectal adenocarcinoma cells by modulating Snail1. British journal of cancer 32 25032732
2010 Involvement of transcription factor NR2F2 in human trophoblast differentiation. PloS one 32 20195529
2019 Oncogenic KRAS signaling activates mTORC1 through COUP-TFII-mediated lactate production. EMBO reports 31 30988000
2019 Cooperativity of co-factor NR2F2 with Pioneer Factors GATA3, FOXA1 in promoting ERα function. Theranostics 31 31588232
2015 Molecular and Electrophysiological Characterization of GABAergic Interneurons Expressing the Transcription Factor COUP-TFII in the Adult Human Temporal Cortex. Cerebral cortex (New York, N.Y. : 1991) 31 25787832
2020 Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment. Science advances 30 32494682
2017 A novel NR2F2 loss-of-function mutation predisposes to congenital heart defect. European journal of medical genetics 30 29222010
2014 The critical roles of COUP-TFII in tumor progression and metastasis. Cell & bioscience 30 25328664
2004 Interaction of the glucocorticoid receptor and the chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII): implications for the actions of glucocorticoids on glucose, lipoprotein, and xenobiotic metabolism. Annals of the New York Academy of Sciences 30 15265774
2021 Orphan nuclear receptor COUP-TFII enhances myofibroblast glycolysis leading to kidney fibrosis. EMBO reports 29 34031962
2020 NR2F2 plays a major role in insulin-induced epithelial-mesenchymal transition in breast cancer cells. BMC cancer 29 32631390
2001 COUP-TFI and COUP-TFII regulate expression of the NHE through a nuclear hormone responsive element with enhancer activity. European journal of biochemistry 26 11168401
2014 High NR2F2 transcript level is associated with increased survival and its expression inhibits TGF-β-dependent epithelial-mesenchymal transition in breast cancer. Breast cancer research and treatment 25 25129343
2010 5.78 Mb terminal deletion of chromosome 15q in a girl, evaluation of NR2F2 as candidate gene for congenital heart defects. European journal of medical genetics 25 21172461
2016 NR2F2 regulates chondrogenesis of human mesenchymal stem cells in bioprinted cartilage. Biotechnology and bioengineering 24 27345768
2016 COUP-TFII regulates satellite cell function and muscular dystrophy. The Journal of clinical investigation 24 27617862
2015 Transcription factors COUP-TFI and COUP-TFII are required for the production of granule cells in the mouse olfactory bulb. Development (Cambridge, England) 24 25922524
2019 The Natural History of a Man With Ovotesticular 46,XX DSD Caused by a Novel 3-Mb 15q26.2 Deletion Containing NR2F2 Gene. Journal of the Endocrine Society 23 31687637
2017 Dysregulation of nuclear receptor COUP-TFII impairs skeletal muscle development. Scientific reports 23 28600496
2012 COUP-TFII controls mouse pancreatic β-cell mass through GLP-1-β-catenin signaling pathways. PloS one 23 22292058
2001 Coup-TFII is up-regulated in adenovirus type 12 tumorigenic cells and is a repressor of MHC class I transcription. Virology 23 11352663
2018 COUP-TFII revisited: Its role in metabolic gene regulation. Steroids 22 30481528
2019 NR2F2 loss‑of‑function mutation is responsible for congenital bicuspid aortic valve. International journal of molecular medicine 21 30720060
2017 Endoglin inhibition leads to intussusceptive angiogenesis via activation of factors related to COUP-TFII signaling pathway. PloS one 21 28859090
2005 Dynamic expression of COUP-TFI and COUP-TFII during development and functional maturation of the mouse inner ear. Gene expression patterns : GEP 21 15907456
2021 Fbxo21 regulates the epithelial-to-mesenchymal transition through ubiquitination of Nr2f2 in gastric cancer. Journal of Cancer 20 33531987
2018 Suppression of COUP-TFII upregulates angiogenin and promotes angiogenesis in endometriosis. Human reproduction (Oxford, England) 20 29982401
2016 The orphan nuclear receptor COUP-TFII coordinates hypoxia-independent proangiogenic responses in hepatic stellate cells. Journal of hepatology 20 27866920
2013 Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids. Reproduction (Cambridge, England) 20 23704310
2013 COUP-TFII inhibits NFkappaB activation in endocrine-resistant breast cancer cells. Molecular and cellular endocrinology 20 24141032
2015 Choose your destiny: Make a cell fate decision with COUP-TFII. The Journal of steroid biochemistry and molecular biology 19 26658017
2023 An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma. Nature communications 18 37015919
2020 LncRNA NR2F2-AS1 Silencing Induces Cell Cycle Arrest in G0/G1 Phase via Downregulating Cyclin D1 in Colorectal Cancer. Cancer management and research 18 32210626
2020 Elevated COUP-TFII expression in dopaminergic neurons accelerates the progression of Parkinson's disease through mitochondrial dysfunction. PLoS genetics 18 32579581
2015 Mutation within the hinge region of the transcription factor Nr2f2 attenuates salt-sensitive hypertension. Nature communications 18 25687237
2020 NR2F2-AS1 accelerates cell proliferation through regulating miR-4429/MBD1 axis in cervical cancer. Bioscience reports 17 32469064
2017 Inactivation of the Nuclear Orphan Receptor COUP-TFII by Small Chemicals. ACS chemical biology 17 28059499
2016 Knockdown of COUP-TFII inhibits cell proliferation and induces apoptosis through upregulating BRCA1 in renal cell carcinoma cells. International journal of cancer 17 27193872
2005 Comparative genomic analysis reveals a distant liver enhancer upstream of the COUP-TFII gene. Mammalian genome : official journal of the International Mammalian Genome Society 17 15859353
2019 LncRNA NR2F2-AS1 positively regulates CDK4 to promote cancer cell proliferation in prostate carcinoma. The aging male : the official journal of the International Society for the Study of the Aging Male 16 31566058