Affinage

FOXF2

Forkhead box protein F2 · UniProt Q12947

Length
444 aa
Mass
46.0 kDa
Annotated
2026-06-09
78 papers in source corpus 44 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FOXF2 is a forkhead-family transcriptional activator that operates predominantly in mesenchymal and mural cell populations to coordinate epithelial-mesenchymal signaling during organ development and tissue homeostasis (PMID:8626802, PMID:16439479). It transactivates target promoters through two functionally redundant C-terminal activation domains and engages the basal transcription machinery via direct in vitro binding to TBP and TFIIB, with TFIIB overexpression potentiating its activation in an activation-domain-dependent manner (PMID:9722567). In development, FOXF2 acts as a downstream effector of Hedgehog signaling: SHH/GLI induce Foxf2 in cranial neural crest mesenchyme to drive proliferation (PMID:28506991), and in palatal, lingual, gut, cochlear, and eye mesenchyme Foxf2 controls morphogenesis by tuning TGFβ/SMAD, BMP, Wnt, and HGF signaling and extracellular-matrix composition, with genome-wide ChIP-seq defining direct targets including Fgf18, Hgf, Tgfb2, and Tgfb3 (PMID:12812790, PMID:16439479, PMID:27180663, PMID:30561639, PMID:32040930, PMID:36227576); a homozygous forkhead-domain missense variant that destabilizes FOXF2 protein links it to cochlear/developmental defects (PMID:30561639). In the brain vasculature FOXF2 is expressed in pericytes and endothelial cells, where it maintains blood-brain barrier integrity—through pericyte-endothelial crosstalk and TGFβ-Smad signaling (PMID:26120030) and through endothelial transcriptional activation of Tie2 and other lineage genes, loss of which produces BBB leakage and worsened stroke outcomes rescuable by pharmacological Tie2 activation (PMID:41398477). In cancer, FOXF2 functions context-dependently as tumor suppressor or promoter by directly binding diverse promoters—repressing TWIST1, FOXC2, and FOXQ1 to restrain EMT and metastasis (PMID:25848863, PMID:26210254, PMID:30807702), inhibiting the CDK2-RB-E2F cell-cycle cascade (PMID:27425595, PMID:27377963), and suppressing Wnt/β-catenin signaling via transactivation of the E3 ligase IRF2BPL (PMID:29374064)—while recruiting coactivators (NCoA3, SMARCC1) or corepressors (NCoR1, HDAC3) to switch the same target promoters between activation and repression (PMID:30807702, PMID:35660418, PMID:39828125).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 High

    Established FOXF2 as a sequence-specific transcriptional activator, answering whether it acts directly on DNA and where its activating capacity resides.

    Evidence Cotransfection reporter assays, deletion mapping, and DNaseI footprinting on the CC10 and SPB promoters

    PMID:8626802

    Open questions at the time
    • Did not identify physiological target genes
    • No in vivo validation of promoter occupancy
  2. 1998 High

    Defined the molecular basis of FOXF2 transactivation by mapping two redundant activation domains and showing direct contact with the basal machinery.

    Evidence Deletion mutagenesis, in vitro binding assays to TBP and TFIIB, and reporter potentiation

    PMID:9722567 PMID:9799607

    Open questions at the time
    • Interactions shown in vitro, not in a cellular complex
    • No structural model of the FOXF2-TBP/TFIIB interface
  3. 2003 High

    Demonstrated an essential, tissue-restricted developmental role by showing Foxf2 is required for palatogenesis and craniofacial mesenchyme function.

    Evidence Foxf2 knockout mice with cleft palate and abnormal tongue, morphological analysis

    PMID:12812790

    Open questions at the time
    • Did not define the transcriptional targets driving the palatal defect
    • Lung/GI morphology unaffected, leaving organ-specificity unexplained
  4. 2006 High

    Placed Foxf2 in a signaling hierarchy as a Hedgehog effector that links mesenchymal Hedgehog input to epithelial Bmp and Wnt signaling and ECM production.

    Evidence Compound Foxf1/Foxf2 mutant mice with β-catenin localization and gene expression analysis in gut

    PMID:16439479

    Open questions at the time
    • Redundancy with Foxf1 complicates Foxf2-specific assignment
    • Direct vs indirect regulation of Bmp4/Wnt5a not resolved
  5. 2013 High

    Refined the developmental role into a paracrine Wnt-restraining function in fibroblasts and connected it to stem-cell and tumor-suppressive control in intestine.

    Evidence Foxf2 heterozygous and transgenic mice, Lgr5-eGFP reporter, BrdU, IHC, qPCR linking Foxf2 to Sfrp1

    PMID:23376422

    Open questions at the time
    • Whether Sfrp1 is a direct Foxf2 target not established
    • Mechanism of pericrypt signaling incompletely defined
  6. 2015 Medium

    Identified FOXF2 as a direct transcriptional repressor of EMT drivers and established it within reciprocal miRNA feedback loops, defining its context-dependent role in cancer cell plasticity.

    Evidence RNAi/overexpression, reporter assays, direct miRNA target validation, EMT and metastasis assays in breast and lung cancer cells, plus methylation/SP1 promoter analysis

    PMID:25798833 PMID:25848863 PMID:26070560 PMID:26210254

    Open questions at the time
    • Opposite EMT effects in breast vs lung cancer not mechanistically reconciled
    • Direct ChIP occupancy of some target promoters not fully detailed
  7. 2016 High

    Connected FOXF2 to cell-cycle control by showing direct repression of p21Cip1 and modulation of the CDK-RB-E2F cascade, explaining its proliferation phenotypes.

    Evidence Promoter reporter assays, ChIP, RNAi, orthotopic tumor models, and cell-cycle analysis in rhabdomyosarcoma and breast cancer subtypes

    PMID:27377963 PMID:27425595

    Open questions at the time
    • Cell-cycle function impaired specifically in BLBC cells for unclear reasons
    • Redundancy with FoxF1 in RMS leaves Foxf2-only contribution uncertain
  8. 2015 High

    Defined Foxf2 as a pericyte-specific factor required for blood-brain barrier integrity, tying its mesenchymal/mural identity to vascular function.

    Evidence Embryonic and adult conditional Foxf2 knockout mice with EM, BBB permeability assays, and TGFβ-Smad pathway analysis

    PMID:26120030

    Open questions at the time
    • Direct transcriptional targets in pericytes not identified at this stage
    • Pericyte-intrinsic vs endothelial contributions not separated
  9. 2018 High

    Revealed Foxf2 as a direct regulator of TGFβ/SMAD signaling, ECM-modifying genes, and Wnt pathway via transactivation of the E3 ligase IRF2BPL, broadening its mechanistic repertoire across fibrosis and cancer.

    Evidence Co-IP with Smad6, ChIP and reporter assays on COL5A2 and IRF2BPL promoters, ubiquitination readouts, and in vivo fibrosis/xenograft models

    PMID:29374064 PMID:29409810 PMID:32022446 PMID:32424142

    Open questions at the time
    • GSK-3β-independent β-catenin degradation mechanism incompletely mapped
    • Whether SMAD/FOXF2 cooperation is direct on all shared targets unclear
  10. 2019 High

    Established that FOXF2 selects gene programs by recruiting opposing coregulators, explaining how the same factor activates or represses identical promoters in different contexts, and linked a human variant to cochlear development.

    Evidence ChIP and co-IP showing NCoR1/HDAC3 vs NCoA3 recruitment to FOXQ1 and WNT2B/FZD1 promoters, plus human FOXF2 variant with reduced protein half-life and KO cochlear phenotyping

    PMID:30561639 PMID:30807702 PMID:31222004

    Open questions at the time
    • What dictates coactivator vs corepressor choice between cell types not resolved
    • Osteomimicry transactivation mechanism not fully elaborated
  11. 2020 High

    Provided genome-wide direct target maps in palatal and stromal cells, anchoring Foxf2's developmental and fibrotic roles to defined target sets including Fgf18 and ECM/cell-cycle genes.

    Evidence ChIP-seq combined with RNA-seq in palatal mesenchyme and endometrial stromal cells with ChIP-PCR validation

    PMID:32040930 PMID:33176855

    Open questions at the time
    • Functional priority among the many direct targets not ranked
    • Cofactor requirements at genomic sites not defined
  12. 2022 High

    Extended Foxf2's stromal role to immune microenvironment control and bone formation, and resolved its vascular function through GWAS-linked enhancer analysis defining its mural-cell regulation.

    Evidence Stromal/osteoprogenitor-specific Foxf2 mouse models, RNA-seq, immune profiling (Cxcl5), Wnt2b identification, and enhancer reporter/mutagenesis of stroke-associated SNPs

    PMID:35660418 PMID:35668101 PMID:35994645 PMID:36369237

    Open questions at the time
    • Direct vs indirect regulation of Cxcl5 and Wnt2b not fully distinguished
    • Upstream regulators of the FOXF2 enhancer in vivo incompletely characterized
  13. 2025 High

    Defined FOXF2 as a pioneer/chromatin-remodeling factor and an endothelial-intrinsic regulator of Tie2 signaling, unifying its developmental, vascular, and cancer chromatin-level activities.

    Evidence EC-specific conditional KO with chromatin sequencing, proteomics, pharmacological Tie2 rescue, iPSC-EC validation, plus ChIP-seq/ATAC-seq and SMARCC1 co-IP in breast cancer

    PMID:39828125 PMID:41398477

    Open questions at the time
    • Whether pioneer-factor activity operates in non-cancer developmental contexts not directly tested
    • Mechanism coupling Tie2 transcription to BBB structure incompletely defined
  14. 2026 Medium

    Demonstrated FOXF2 is required for postnatal pericyte maturation and identified an injury-induced FOXF2+ ependymal population that repairs the BBB via exosomal DLL4-NOTCH signaling.

    Evidence Pericyte-specific and GFAP-Cre conditional KO/overexpression, ATAC-seq, single-cell transcriptomics, and exosomal DLL4 quantification

    PMID:41680210 PMID:41875155

    Open questions at the time
    • Direct FOXF2 targets controlling ANGPTL4 and DLL4 not pinpointed
    • Generality of the ependymal repair mechanism beyond injury models untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what molecular switch determines whether FOXF2 recruits activating or repressive coregulators on shared target promoters across cell types and disease contexts.
  • No defined upstream signal or post-translational modification governs the coactivator/corepressor choice
  • Lack of structural data on FOXF2-coregulator complexes
  • Context-dependent tumor suppressor vs promoter behavior not predictable from sequence alone

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 4 GO:0140223 general transcription initiation factor activity 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 5 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 2 R-HSA-4839726 Chromatin organization 2
Partners
HDAC3NCOA3NCOR1SMAD6SMARCC1SP1TBPTFIIB

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 FOXF2 (FREAC-2) functions as a transcriptional activator; its activation domains were mapped to the C-terminal side of the forkhead domain. DNaseI footprinting verified that FREAC-2 binds to predicted sites in the CC10 and SPB promoters. Both FREAC-1 and FREAC-2 transactivated the SPB promoter, while CC10 was only activated by FREAC-1. Cotransfection reporter assays, deletion mapping, DNaseI footprinting The Journal of biological chemistry High 8626802
1998 FOXF2 (FREAC-2) contains two functionally redundant C-terminal activation domains (AD1: 23 C-terminal amino acids; AD2: three synergistic subdomains in the central region). FREAC-2 interacts in vitro with TBP (binding mapped to the N-terminal repeat of TBP core domain) and TFIIB (binding near the cleft between TFIIB's two globular domains). The TBP-binding region on FREAC-2 maps to 21 amino acids at the C-terminal end of the forkhead domain. Nuclear localization depends on sequences from both ends of the forkhead domain. Overexpression of TFIIB potentiates FREAC-2-mediated activation in an activation-domain-dependent manner. Deletion mutagenesis, in vitro binding assays, cotransfection reporter assays, nuclear localization mapping The Journal of biological chemistry High 9722567
1998 The human FOXF2 (FREAC-2/FKHL6) gene consists of two exons separated by a 3.6 kb intron; exon 1 encodes the forkhead DNA-binding domain and AD2, exon 2 encodes AD1. A 2 kb CpG island is centered around the 5' end of the gene. The gene was localized to chromosomal position 6p25.3 by FISH and radiation hybrid mapping. Genomic sequencing, FISH, radiation hybrid mapping Genomics Medium 9799607
2003 Foxf2 knockout mice die shortly after birth with cleft palate and abnormal tongue, demonstrating that Foxf2 is required for palatogenesis. GI tract and lungs of Foxf2-deficient newborn mice were normal in morphology and function, placing the critical developmental role of Foxf2 in craniofacial/palatal mesenchyme. Gene targeting (Foxf2 knockout mice), morphological analysis Developmental biology High 12812790
2006 Foxf1 and Foxf2 act in splanchnic mesoderm as downstream effectors of hedgehog signaling (activated by epithelial Indian and sonic hedgehog). In Foxf mutants, mesenchymal Bmp4 expression is reduced and Wnt5a is increased, leading to canonical Wnt pathway activation (nuclear β-catenin) in epithelial cells, epithelial over-proliferation, and resistance to apoptosis. Extracellular matrix (especially collagens) is severely reduced in Foxf mutant intestine, causing epithelial depolarization. Thus Foxf proteins link hedgehog to Bmp and Wnt signaling in gut mesenchyme. Genetic compound Foxf1/Foxf2 mutant mice, β-catenin localization, gene expression analysis, histology Development (Cambridge, England) High 16439479
2009 FOXF2 knockdown in primary prostate stromal cells (PrSC) modulates expression of genes including WASF2, BAMBI, CXCL12 (upregulated by FOXF2) and MT1E, MT1F, PDGFA, ITGB1, PSG7 (downregulated by FOXF2). Pathway analysis reveals FOXF2 regulates PPAR signaling, PDGF signaling, and ECM signaling pathways. FOXF2-upregulated genes are anti-correlated with TGFβ3-induced gene expression, suggesting an opposing role to TGFβ3 in prostate stroma. siRNA knockdown, microarray expression profiling, pathway analysis, RT-PCR validation The Prostate Medium 19562724
2009 In vivo overexpression of Foxf2 specifically in adipose tissue results in significantly lower IRS1 mRNA and protein levels in adipocytes and decreased insulin-mediated glucose uptake, without altering the ratio of serine vs. tyrosine phosphorylation of IRS1. Foxf2-overexpressing mice show enhanced insulin secretion in response to intravenous glucose load, identifying Foxf2 as a regulator of glucose homeostasis. Adipose-specific transgenic Foxf2 overexpression in mice, glucose tolerance tests, insulin secretion assays, IRS1 protein/mRNA quantification American journal of physiology. Endocrinology and metabolism Medium 20009030
2011 Heterozygous Foxf2(W174R) mice exhibit thinning of iris stroma, hyperplasia of trabecular meshwork, small or absent Schlemm's canal, and reduced iridocorneal angle. Homozygous Foxf2(W174R) E18.5 mice show absence of ciliary body projections, demonstrating a critical role for Foxf2 in anterior segment and eye development. ENU mutagenesis screen, mouse re-derivation (Foxf2 W174R), histological and morphological analysis of eye PloS one Medium 22022403
2013 FOXF2 is confirmed as a direct functional target of miR-182-5p in prostate cancer, validated by 3'UTR luciferase assay and Western blot. miR-182-5p knockdown increased FOXF2 expression and decreased prostate cancer cell proliferation, migration, and invasion, identifying FOXF2 as a tumor-suppressive target of miR-182-5p in this context. 3'UTR luciferase assay, Western blot, miRNA inhibitor knockdown, in vivo tumor growth assay PloS one Medium 23383207
2013 Foxf2 in intestinal fibroblasts inhibits paracrine Wnt signaling to epithelial cells. Foxf2 heterozygous mice showed stabilized epithelial β-catenin, increased Lgr5+ stem cell numbers, increased crypt cell proliferation, and elevated Myc expression; Foxf2 transgenic mice had fewer adenomas. Foxf2 expression in fibroblasts positively correlates with Sfrp1 (an extracellular Wnt inhibitor) levels, providing a mechanistic link. Foxf2 knockout and transgenic mice, Lgr5-eGFP reporter, BrdU incorporation, immunohistochemistry, qPCR, immunoblot Gastroenterology High 23376422
2015 FOXF2 directly binds the TWIST1 promoter and negatively regulates its transcription in basal-like breast cancer (BLBC) cells. FOXF2 deficiency induces EMT and enhances metastatic ability of BLBC cells in vitro and in vivo through upregulation of TWIST1. RNAi knockdown, overexpression, in vitro and in vivo metastasis assays, RT-qPCR, immunoblot, immunofluorescence, immunohistochemistry Breast cancer research : BCR Medium 25848863
2015 The miR-200 family and miR-183~96~182 cluster directly target FOXF2 (confirmed by direct targeting assays). FOXF2 expression induces EMT, migration, invasion, and metastasis in lung cancer cells, and FOXF2 transcriptionally represses E-cadherin and miR-200 independently of Zeb1, forming a double-negative feedback loop with these miRNAs. miRNA overexpression/inhibition, direct target validation (luciferase assay implied), EMT assays, migration/invasion assays, mouse metastasis models Oncogene Medium 25798833
2015 FOXF2 directly targets FOXC2 promoter to negatively regulate FOXC2 transcription in BLBC cells. FOXC2 mediates the FOXF2-regulated EMT phenotype, aggressive behavior, and multiple chemotherapy drug resistance of BLBC cells. Transcriptional reporter assay, RT-qPCR, Western blot, functional EMT/drug resistance assays Cancer letters Medium 26210254
2015 The CpG island of the FOXF2 proximal promoter is methylated in a breast cancer subtype-specific manner, contributing to its silencing. SP1 directly binds to the proximal FOXF2 promoter and drives its transcription; this binding is abrogated by DNA methylation. DNMT1, DNMT3A, and DNMT3B contribute to FOXF2 promoter methylation in different breast cancer cells. Methylation analysis, ChIP assay (SP1 binding), luciferase reporter assay, siRNA knockdown of DNMTs The Journal of biological chemistry Medium 26070560
2015 Foxf2 is specifically expressed in brain pericytes. Foxf2-/- embryos develop intracranial hemorrhage, perivascular edema, thinning of vascular basal lamina, increased luminal endothelial caveolae, and leaky BBB. Foxf2-/- brain pericytes are more numerous and proliferate faster, with reduced Pdgfrβ expression. Tgfβ-Smad2/3 signaling is attenuated, while phosphorylation of Smad1/5 and p38 is enhanced. Tgfβ pathway components (Tgfβ2, Tgfβr2, Alk5, integrins αVβ8) are reduced. Adult inactivation of Foxf2 also results in BBB breakdown and increased trans-endothelial vesicular transport. Foxf2 knockout mice (embryonic and adult conditional), electron microscopy, BBB permeability assays, immunohistochemistry, Western blot, phosphorylation analysis Developmental cell High 26120030
2016 FoxF1 and FoxF2 directly bind to and repress transcriptional activity of the p21Cip1 promoter through the -556/-545 bp region in rhabdomyosarcoma cells. Depletion of either FoxF1 or FoxF2 increased p21Cip1 and p27Kip1 protein levels, delayed G1-S progression, reduced phosphorylated Rb, and decreased CDK2, CDK4/6, Cyclin D1, and Cyclin E2. Knockdown of p21Cip1 rescued cell cycle progression in FoxF-deficient tumor cells. Depletion of both FoxF1 and FoxF2 completely abrogated RMS tumor growth in orthotopic mouse models. Promoter reporter assays, ChIP, RNAi knockdown, overexpression, orthotopic mouse tumor models, cell cycle analysis Oncogene High 27425595
2016 Foxf2 in palatal shelf mesenchyme is required for palatal closure. Foxf2-/- maxillary explants cultured in vitro (without tongue/mandible) fail to close. Foxf2-/- palatal shelves show reduced proliferation, decreased collagen content, reduced Smad2/3 phosphorylation (attenuated TGFβ signaling), increased p38 phosphorylation, reduced TGFβ2 protein (without mRNA change), and reduced expression of fibronectin splice-isoform, Tgfbr3 (betaglycan), and integrins αV and β1. In vitro maxillary explant culture, Foxf2 KO mice, phospho-Smad2/3 and p38 analysis, protein and mRNA quantification Developmental biology High 27180663
2016 In luminal and HER2-positive breast cancer cells, FOXF2 inhibits the CDK2-RB-E2F cascade and maintains stringency of DNA replication; its loss triggers dysregulation of DNA replication and activates p53 checkpoint pathway. In basal-like breast cancer cells, the cell-cycle function of FOXF2 is impaired but FOXF2 is still required for EMT and mobility. FOXF2 is epigenetically silenced in luminal-type and HER2-positive breast cancers. Ectopic expression, in vitro and in vivo tumor assays, gene expression profiling, cell cycle analysis Cellular signalling Medium 27377963
2017 Foxf2 is upregulated during TGFβ-induced EMT in NMuMG cells. Foxf2 is essential for disruption of cell junctions and downregulation of epithelial markers (including E-cadherin) during TGFβ-induced EMT by promoting transcription of Zeb1 and Zeb2 and repressing Id2 and miR-200 family members. Foxf2 is also required for TGFβ-mediated apoptosis through transcriptional activation of the proapoptotic BH3-only protein Noxa and by repressing EGFR ligands betacellulin and amphiregulin. Gene expression profiling, functional EMT assays, RNAi knockdown, promoter/transcription analysis, NMuMG cell model Breast cancer research : BCR Medium 30285803
2017 Sonic hedgehog (SHH) signaling induces Foxf2 expression in cranial neural crest cell (cNCC) mesenchyme through GLI transcription factors; a functional GLI-binding site was identified downstream of Foxf2. Either SHH ligand addition or FOXF2 overexpression is sufficient to induce cNCC proliferation. Reduced Foxf2 and Gli1 expression parallels reduced proliferation in cleft lip pathogenesis. Mouse gene expression profiling, GLI binding site identification, SHH ligand treatment, FOXF2 overexpression, proliferation assays in cNCC, human SNP analysis Development (Cambridge, England) Medium 28506991
2017 MAZ (Myc-associated zinc finger protein) transcriptionally activates FOXF2 expression in basal-like breast cancer cells, and FOXF2 mediates MAZ-regulated suppression of aggressiveness and promotion of proliferation. RT-qPCR, Western blot, functional assays, promoter analysis Cancer letters Low 28577976
2018 FOXF2 suppresses Wnt signaling in gastric cancer by inducing β-catenin protein ubiquitination and degradation independently of GSK-3β. Mechanistically, FOXF2 directly binds the promoter of E3 ligase IRF2BPL and induces its transcriptional expression; IRF2BPL then interacts with β-catenin to increase its ubiquitination and degradation. Ectopic expression, KD, luciferase reporter assay (promoter binding), Co-IP (IRF2BPL–β-catenin interaction), xenograft tumor models, cell cycle and apoptosis analysis Cancer research High 29374064
2018 FOXF2 controls TGF-β/SMAD signaling in BLBC cells through transrepression of TGF-β-coding genes. FOXF2-deficient BLBC cells acquire a myofibroblast/CAF-like phenotype and increase autocrine TGF-β signaling. TGF-β in turn silences FOXF2 through upregulation of miR-182-5p and direct transrepression by SMAD3. miR-182-5p and FOXF2 form a reciprocal repression loop; FOXF2 directly transrepresses MIR182 expression. Gene knockdown/overexpression, functional metastasis assays, pathway analysis, reporter assays Cell death and differentiation Medium 32424142
2018 FOXF2 directly activates VEGFR3 transcription in BLBC cells. FOXF2 deficiency enhances VEGF-C/VEGFR3 signaling, enabling aggressive BLBC cells to form lymphangiogenic mimicry (lymphatic vessel-like structures positive for LYVE-1, podoplanin, and VEGFR3), promoting lymphatic metastasis. Promoter reporter assay (VEGFR3 transcriptional activation by FOXF2), immunohistochemistry, in vitro and in vivo functional assays Cancer letters Medium 29409810
2018 Foxf2 interacts physically with Smad6 (demonstrated by co-immunoprecipitation) and both bind the same promoter region of COL5A2 (demonstrated by ChIP and dual-luciferase reporter assay). Foxf2 promotes COL5A2 transcription, while Smad6 inhibits Foxf2-induced COL5A2 expression. Foxf2 downregulation and Smad6 upregulation decreased fibrosis and COL5A2/COL1A1 expression in a rat IUA model. Co-immunoprecipitation, ChIP, dual-luciferase reporter assay, siRNA knockdown, overexpression, rat IUA in vivo model Journal of cellular and molecular medicine Medium 32022446
2018 Overexpression of Foxf2 in adipose-specific transgenic mice reduces IRS1 mRNA and protein levels and decreases insulin-mediated glucose uptake in adipocytes, without altering IRS1 phosphorylation ratio. FOXF2 is identified as a regulator of adipocyte glucose homeostasis. Adipose-specific transgenic mouse overexpression, metabolic phenotyping, glucose uptake assays Neurogastroenterology and motility Medium 30565344
2018 Knockout of both Foxf1 and Foxf2 (but not either alone) from adult mouse smooth muscle results in delayed liquid gastric emptying and decreased expression of smooth muscle contractile proteins, SRF, and myocardin in stomach muscularis, demonstrating functional redundancy in maintaining gastric function. Smooth muscle-specific conditional double knockout mice (Foxf1 and Foxf2), gastric emptying assay, protein expression analysis Neurogastroenterology and motility Medium 30565344
2019 FOXF2 functions as a master transcription factor that reprograms breast cancer cells into an osteomimetic phenotype (epithelial-to-osteomimicry transition) by pleiotropic transactivation of BMP4/SMAD1 signaling pathway and bone-related genes expressed at early stages of bone differentiation. The BMP antagonist Noggin significantly inhibits FOXF2-driven osteolytic bone metastasis. Transcriptional activation assays, BMP4/SMAD1 pathway analysis, in vivo bone metastasis models, Noggin inhibition Nature communications Medium 31222004
2019 FOXF2 and FOXQ1 exhibit mutual transcriptional repression in BLBC cells, forming a reciprocal negative feedback loop. FOXF2 recruits nuclear receptor corepressor 1 (NCoR1) and histone deacetylase 3 (HDAC3) to the FOXQ1 promoter to inhibit its transcription; FOXQ1 does not exert this mechanism on FOXF2. Transcriptional reporter assays, ChIP, co-immunoprecipitation, functional EMT and chemoresistance assays FASEB journal Medium 30807702
2019 FOXF2 cochlear expression is required for cochlear development. A human homozygous FOXF2 missense variant (p.I109F in the forkhead domain) reduces FOXF2 protein half-life. Foxf2 knockout mice show shortened/malformed cochleae, altered hair cell shape with innervation and planar cell polarity defects, and reduced Eya1 and Pax3 expression in cochleae. Human genome sequencing, in vitro protein stability assay, Foxf2 KO mouse cochlear phenotyping, in situ hybridization, immunohistochemistry Human molecular genetics High 30561639
2019 FOXF2 directly binds to the promoter of H19 lncRNA and activates its transcription in NSCLC cells (demonstrated by ChIP assay). H19 in turn recruits EZH2 to downregulate PTEN, mediating FOXF2-driven proliferation and migration of NSCLC cells. ChIP assay (FOXF2 binding to H19 promoter), Western blot, functional proliferation/migration assays, rescue experiments European review for medical and pharmacological sciences Low 31858547
2020 FOXF2 regulates multiple downstream target genes in human endometrial stromal cells including collagen (COL5A2), vimentin (VIM), and cyclin D2/CDK4 (identified by ChIP-seq). FOXF2 downregulation inhibits TGF-β1-mediated fibrosis including ECM formation, cell proliferation, and Wnt/β-catenin signaling. LncRNA SNHG5 directly regulates FOXF2 expression (demonstrated by RIP, RNA pulldown, FISH). ChIP-seq, ChIP-PCR, RNA immunoprecipitation, RNA pulldown, FISH, qRT-PCR, Western blot, flow cytometry Stem cell research & therapy Medium 33176855
2020 Foxf2 genome-wide binding in developing palatal mesenchyme (ChIP-seq) combined with RNA-seq identified 88 direct target genes. These include Fgf18 (verified by ChIP-PCR), and multiple genes encoding transcription factors and ECM-modifying proteins. Foxf2 loss leads to ectopic Chst2 expression in posterior palatal mesenchyme, increased sulfated keratan sulfate, reduced chondroitin sulfate, altered versican and collagen I expression. Foxf2 thus controls palatal morphogenesis through both Fgf18-Shh signaling and ECM composition. RNA-seq, ChIP-seq, ChIP-PCR, in situ hybridization, immunohistochemistry, Foxf2 KO mice Journal of dental research High 32040930
2022 Foxf2 in prostate stromal fibroblasts transcriptionally downregulates Cxcl5, which reduces immunosuppressive myeloid cell infiltration and enhances T cell cytotoxicity. Increasing prostatic stromal Foxf2 suppresses growth of syngeneic and autochthonous mouse prostate cancers and sensitizes them to immune checkpoint blockade. Conditional Foxf2 overexpression in prostate stroma, syngeneic and autochthonous mouse models, immune profiling, transcriptomic analysis Nature communications Medium 36369237
2022 Foxf2 represses bone formation by regulating Wnt2b. Foxf2 overexpression in MSCs inhibits osteoblastic differentiation; Foxf2 knockdown promotes it. Osteoprogenitor-specific Foxf2 KO mice develop high bone mass due to increased bone formation. RNA-seq and molecular experiments identified Wnt2b as the mediator of Foxf2's anti-osteogenic function. Knockdown of Foxf2 in mouse femurs enhanced bone regeneration in vivo. MSC differentiation assays, osteoprogenitor-specific Foxf2 KO mice, RNA-seq, molecular pathway analysis, in vivo bone regeneration assay Experimental & molecular medicine High 35668101
2022 FOXF2 oppositely regulates stemness in luminal versus basal-like breast cancer cells through the Wnt/β-catenin pathway. In luminal cells, FOXF2 recruits NCoA3 to the WNT2B and FZD1 promoters to activate their transcription; in BLBC cells, FOXF2 recruits NCoR1 to the same promoters to repress transcription. ChIP (promoter occupancy), transcriptional reporter assays, stemness functional assays, co-immunoprecipitation (coactivator/corepressor recruitment) The Journal of biological chemistry Medium 35660418
2022 Stroke-associated SNPs in the intergenic region between FOXF2 and FOXQ1 are located within a functional transcriptional enhancer for FOXF2. This enhancer contains binding sites for ETS1, RBPJ, and CTCF. SNP rs74564934 (adjacent to ETS1 binding site) decreases enhancer function, as does mutation of RBPJ sites. Foxf2 is expressed in vascular mural pericytes in zebrafish and has a conserved function in vascular stabilization. Enhancer reporter assays in human cells and zebrafish, mutagenesis of enhancer binding sites, GWAS SNP functional testing Proceedings of the National Academy of Sciences of the United States of America Medium 35994645
2022 The Foxf1/Foxf2 transcription factors in CNCC-derived mandibular mesenchyme control myoblast migration into the tongue primordium and regulate intrinsic tongue muscle assembly and lingual tendon formation. ChIP-seq identified Hgf, Tgfb2, and Tgfb3 as direct target genes of Foxf2 in the embryonic tongue. Foxf1/Foxf2 mediate SHH signaling-driven myoblast migration by activating HGF and TGFβ signaling pathways. CNCC-specific conditional double KO mice (Smo and Foxf1/Foxf2), ChIP-seq, genetic epistasis analysis Development (Cambridge, England) High 36227576
2024 FOXF2 directly binds the MSI2 promoter and promotes its transcriptional expression (demonstrated by luciferase and ChIP assays). FOXF2 knockdown inhibited MSI2 protein translation while enhancing NUMB protein expression, suppressing pancreatic cancer development in vivo. MSI2 silencing reversed the proliferative effects of FOXF2 overexpression. Luciferase reporter assay, ChIP assay, xenograft mouse models, flow cytometry, Western blot Oncology reports Medium 38847273
2024 FOXF2 promotes transcription of RNF144A (an E3 ubiquitin ligase), which in turn causes ubiquitination and degradation of FTO (an m6A demethylase) in esophageal squamous cell carcinoma. Overexpression of FTO abolishes the effects of FOXF2 on TAM M2 polarization. FOXF2 inhibits both ESCC cell proliferation and M2 polarization of tumor-associated macrophages through this RNF144A-FTO axis. Gene overexpression/silencing, macrophage polarization assays, Western blot (ubiquitination/degradation), transcriptional reporter assays International immunopharmacology Medium 39447407
2025 Foxf2 maintains endothelial cell function in the brain through transcriptional activation of Tie2 and other endothelial lineage-specific genes (identified by RNA and chromatin sequencing). EC-specific Foxf2 deletion in adult mice caused BBB leakage (worsened after experimental stroke), impaired functional hyperemia, reduced NO production, increased infarct size through disrupted Tie2 signaling. Pharmacological activation of Tie2 with AKB-9778 rescued these effects. Proteomic analyses of Foxf2-deficient mouse and human iPSC-derived ECs revealed downregulation of multiple Tie2 signaling proteins. EC-specific conditional Foxf2 KO mice, RNA-seq, chromatin sequencing, proteomics, BBB permeability assays, stroke model, pharmacological Tie2 rescue (AKB-9778), iPSC-derived ECs Nature neuroscience High 41398477
2025 ERα represses FOXF2 transcription in ER+ breast cancer by facilitating H3K27me3 deposition at its genomic locus; endocrine therapy de-represses FOXF2 by loss of H3K27me3. FOXF2 acts as a pioneer factor to globally activate enhancers of EMT/epithelial-osteogenic transition genes and super-enhancers of NCOA3 and SP1 by recruiting SMARCC1, which mediates chromatin architecture reorganization. BRD4 inhibition significantly inhibits FOXF2-orchestrated endocrine resistance and bone metastasis. ChIP-seq (H3K27me3, enhancer analysis), ATAC-seq (chromatin accessibility), co-immunoprecipitation (SMARCC1 recruitment), BRD4 inhibitor treatment, functional resistance/metastasis assays Cancer letters Medium 39828125
2026 Foxf2 expression in pericytes increases postnatally and is required for pericyte maturation and function during postnatal lung development. Pdgfrb-CreER-mediated Foxf2 deletion leads to pericyte hyperplasia, impaired migration, and reduced expression of angiogenic factors including ANGPTL4. FOXF2 maintains chromatin accessibility at pro-angiogenic loci. Loss of FOXF2 disrupts pericyte-endothelial crosstalk, impairing angiogenesis and alveolarization. Pdgfrb-CreER conditional Foxf2 KO, ATAC-seq (chromatin accessibility), RNA-seq, functional angiogenesis and alveolarization assays, neonatal hyperoxic injury model Nature communications Medium 41680210
2026 A distinct subpopulation of GFAP+ FOXF2+ ependymal cells expands in the SVZ after neural injury. Conditional deletion of Foxf2 in GFAP+ cells impairs endothelial junction integrity and increases BBB permeability; overexpression enhances vascular repair and functional recovery. GFAP+ FOXF2+ ependymal cells secrete exosomal DLL4, which activates NOTCH pathway signaling to restore BBB function. Single-cell transcriptomics, Foxf2 conditional KO (GFAP-Cre), AAV-mediated Foxf2 overexpression, immunohistochemistry, BBB permeability assays, exosome DLL4 quantification Proceedings of the National Academy of Sciences of the United States of America Medium 41875155
2022 LSD1 directly binds the 687-887-bp region of the FOXF2 promoter and upregulates H3K4me2 methylation, facilitating FOXF2 transcriptional activation. LSD1 interacts with Ku80 (identified by immunoprecipitation-mass spectrometry), and Ku80 expression negatively correlates with FOXF2 expression in colon cancer. FOXF2 activation downstream of LSD1-Ku80 downregulates Wnt/β-catenin signaling pathway proteins. Immunoprecipitation-mass spectrometry, ChIP-PCR, Western blot, functional proliferation/migration assays American journal of cancer research Low 36119820

Source papers

Stage 0 corpus · 78 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Foxf1 and Foxf2 control murine gut development by limiting mesenchymal Wnt signaling and promoting extracellular matrix production. Development (Cambridge, England) 200 16439479
2013 MicroRNA-182-5p promotes cell invasion and proliferation by down regulating FOXF2, RECK and MTSS1 genes in human prostate cancer. PloS one 131 23383207
2015 Foxf2 Is Required for Brain Pericyte Differentiation and Development and Maintenance of the Blood-Brain Barrier. Developmental cell 118 26120030
2015 The miR-200 family and the miR-183~96~182 cluster target Foxf2 to inhibit invasion and metastasis in lung cancers. Oncogene 115 25798833
2000 Forkhead transcription factor FoxF2 is expressed in mesodermal tissues involved in epithelio-mesenchymal interactions. Developmental dynamics : an official publication of the American Association of Anatomists 92 10822266
1996 Differential activation of lung-specific genes by two forkhead proteins, FREAC-1 and FREAC-2. The Journal of biological chemistry 92 8626802
2015 FOXF2 suppresses the FOXC2-mediated epithelial-mesenchymal transition and multidrug resistance of basal-like breast cancer. Cancer letters 76 26210254
2003 Forkhead transcription factor Foxf2 (LUN)-deficient mice exhibit abnormal development of secondary palate. Developmental biology 73 12812790
2018 LncRNA ADAMTS9-AS2 regulates ovarian cancer progression by targeting miR-182-5p/FOXF2 signaling pathway. International journal of biological macromolecules 72 30268751
2017 Sonic hedgehog regulation of Foxf2 promotes cranial neural crest mesenchyme proliferation and is disrupted in cleft lip morphogenesis. Development (Cambridge, England) 61 28506991
2018 Forkhead Box F2 Suppresses Gastric Cancer through a Novel FOXF2-IRF2BPL-β-Catenin Signaling Axis. Cancer research 59 29374064
2020 si-SNHG5-FOXF2 inhibits TGF-β1-induced fibrosis in human primary endometrial stromal cells by the Wnt/β-catenin signalling pathway. Stem cell research & therapy 58 33176855
2016 FoxF1 and FoxF2 transcription factors synergistically promote rhabdomyosarcoma carcinogenesis by repressing transcription of p21Cip1 CDK inhibitor. Oncogene 57 27425595
2015 FOXF2 deficiency promotes epithelial-mesenchymal transition and metastasis of basal-like breast cancer. Breast cancer research : BCR 56 25848863
1998 The human forkhead protein FREAC-2 contains two functionally redundant activation domains and interacts with TBP and TFIIB. The Journal of biological chemistry 53 9722567
2013 Foxf2 in intestinal fibroblasts reduces numbers of Lgr5(+) stem cells and adenoma formation by inhibiting Wnt signaling. Gastroenterology 52 23376422
2019 FOXF2 reprograms breast cancer cells into bone metastasis seeds. Nature communications 49 31222004
2015 DNA Methylation Affects the SP1-regulated Transcription of FOXF2 in Breast Cancer Cells. The Journal of biological chemistry 49 26070560
2017 Dual function of MAZ mediated by FOXF2 in basal-like breast cancer: Promotion of proliferation and suppression of progression. Cancer letters 40 28577976
2019 Genes CEP55, FOXD3, FOXF2, GNAO1, GRIA4, and KCNA5 as potential diagnostic biomarkers in colorectal cancer. BMC medical genomics 38 30987631
2020 FOXF2 deficiency accelerates the visceral metastasis of basal-like breast cancer by unrestrictedly increasing TGF-β and miR-182-5p. Cell death and differentiation 36 32424142
2017 MicroRNA-182 promotes proliferation and metastasis by targeting FOXF2 in triple-negative breast cancer. Oncology letters 35 29085483
2016 Foxf2 is required for secondary palate development and Tgfβ signaling in palatal shelf mesenchyme. Developmental biology 32 27180663
2016 The dual role of FOXF2 in regulation of DNA replication and the epithelial-mesenchymal transition in breast cancer progression. Cellular signalling 30 27377963
2022 Stromal FOXF2 suppresses prostate cancer progression and metastasis by enhancing antitumor immunity. Nature communications 28 36369237
2018 FOXF2 deficiency permits basal-like breast cancer cells to form lymphangiogenic mimicry by enhancing the response of VEGF-C/VEGFR3 signaling pathway. Cancer letters 28 29409810
2009 The FOXF2 pathway in the human prostate stroma. The Prostate 28 19562724
2020 Foxf2 and Smad6 co-regulation of collagen 5A2 transcription is involved in the pathogenesis of intrauterine adhesion. Journal of cellular and molecular medicine 27 32022446
2018 Foxf2 plays a dual role during transforming growth factor beta-induced epithelial to mesenchymal transition by promoting apoptosis yet enabling cell junction dissolution and migration. Breast cancer research : BCR 24 30285803
2019 Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 30807702
2015 MicroRNA-519a promotes proliferation and inhibits apoptosis of hepatocellular carcinoma cells by targeting FOXF2. FEBS open bio 23 26693396
2017 MicroRNA-182 targets FOXF2 to promote the development of triple-negative breast cancer. Neoplasma 22 28043147
2019 FOXF2 aggravates the progression of non-small cell lung cancer through targeting lncRNA H19 to downregulate PTEN. European review for medical and pharmacological sciences 21 31858547
2021 lncRNA MCM3AP-AS1 inhibits the progression of colorectal cancer via the miR-19a-3p/FOXF2 axis. The journal of gene medicine 19 33450091
2020 FOXF2 acts as a crucial molecule in tumours and embryonic development. Cell death & disease 18 32503970
2022 FOXF2 oppositely regulates stemness in luminal and basal-like breast cancer cells through the Wnt/beta-catenin pathway. The Journal of biological chemistry 17 35660418
2021 CircGDI2 Regulates the Proliferation, Migration, Invasion and Apoptosis of OSCC via miR-454-3p/FOXF2 Axis. Cancer management and research 17 33603482
2019 FOXF2 is required for cochlear development in humans and mice. Human molecular genetics 17 30561639
2021 The regulatory roles and mechanisms of the transcription factor FOXF2 in human diseases. PeerJ 15 33717680
2018 FOXF2 inhibits proliferation, migration, and invasion of Hela cells by regulating Wnt signaling pathway. Bioscience reports 15 30249755
2017 MiR-200c inhibits metastasis of breast tumor via the downregulation of Foxf2. Genetics and molecular research : GMR 15 28829888
2011 Foxf2: a novel locus for anterior segment dysgenesis adjacent to the Foxc1 gene. PloS one 15 22022403
2017 FOXF2 deficiency promotes hepatocellular carcinoma metastasis by inducing mesenchymal-epithelial transition. Cancer biomarkers : section A of Disease markers 14 28582850
1998 The two-exon gene of the human forkhead transcription factor FREAC-2 (FKHL6) is located at 6p25.3. Genomics 14 9799607
2022 miRNA-182-5p promotes human bladder cancer proliferation and migration through the FOXF2/SHH axis. Neoplasma 13 35068163
2022 Foxf2 represses bone formation via Wnt2b/β-catenin signaling. Experimental & molecular medicine 13 35668101
2020 MicroRNA-96-5p promotes proliferation, invasion and EMT of oral carcinoma cells by directly targeting FOXF2. Biology open 12 32014885
2009 Mutation analysis of FOXF2 in patients with disorders of sex development (DSD) in combination with cleft palate. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 12 19276632
2022 Stroke-associated intergenic variants modulate a human FOXF2 transcriptional enhancer. Proceedings of the National Academy of Sciences of the United States of America 11 35994645
2018 Gastroparesis is associated with decreased FOXF1 and FOXF2 in humans, and loss of FOXF1 and FOXF2 results in gastroparesis in mice. Neurogastroenterology and motility 11 30565344
2022 Alcohol-induced inhibition of bone formation and neovascularization contributes to the failure of fracture healing via the miR-19a-3p/FOXF2 axis. Bone & joint research 10 35730670
2022 The transcription factors Foxf1 and Foxf2 integrate the SHH, HGF and TGFβ signaling pathways to drive tongue organogenesis. Development (Cambridge, England) 10 36227576
2015 Novel evidence of association with nonsyndromic cleft lip with or without cleft palate was shown for single nucleotide polymorphisms in FOXF2 gene in an Asian population. Birth defects research. Part A, Clinical and molecular teratology 10 26278207
2022 MiRNA-301b-3p induces proliferation and inhibits apoptosis in AML cells by targeting FOXF2 and regulating Wnt/β-catenin axis. Molecular and cellular probes 9 35259424
2021 A Methylome and Transcriptome Analysis of Normal Human Scar Cells Reveals a Role for FOXF2 in Scar Maintenance. The Journal of investigative dermatology 9 34687743
2020 Genome-wide Identification of Foxf2 Target Genes in Palate Development. Journal of dental research 9 32040930
2019 MiR-182 promotes cell proliferation, migration and invasion by targeting FoxF2 in endometrial carcinoma cells. International journal of clinical and experimental pathology 9 31933939
2018 miR-130b participates in wear particle-induced inflammation and osteolysis via FOXF2/NF-κB pathway. Immunopharmacology and immunotoxicology 8 30488739
2022 FOXF2 Regulates PRUNE2 Transcription in the Pathogenesis of Colorectal Cancer. Technology in cancer research & treatment 7 35929169
2018 FOXF2 differentially regulates expression of metabolic genes in non-cancerous and cancerous breast epithelial cells. Trends in diabetes and metabolism 7 30294731
2009 Overexpression of Foxf2 in adipose tissue is associated with lower levels of IRS1 and decreased glucose uptake in vivo. American journal of physiology. Endocrinology and metabolism 7 20009030
2025 Breast Cancer Subtype-Specific Organotropism Is Dictated by FOXF2-Regulated Metastatic Dormancy and Recovery. Cancer research 6 39589789
2019 Disruption of FOXF2 as a Likely Cause of Absent Uvula in an Egyptian Family. Journal of dental research 6 30917284
2017 The controversial role of forkhead box F2 (FOXF2) transcription factor in breast cancer. PRAS open 6 29046905
2017 Overexpression of miR-96 promotes cell proliferation by targeting FOXF2 in prostate cancer. International journal of clinical and experimental pathology 4 31966604
2024 Transcription factor FOXF2 promotes the development and progression of pancreatic cancer by targeting MSI2. Oncology reports 3 38847273
2024 FOXF2 suppressed esophageal squamous cell carcinoma by reducing M2 TAMs via modulating RNF144A-FTO axis. International immunopharmacology 3 39447407
2022 LSD1 regulates the FOXF2-mediated Wnt/β-catenin signaling pathway by interacting with Ku80 to promote colon cancer progression. American journal of cancer research 3 36119820
2017 Association of FOXF2 gene polymorphisms with ischemic stroke in Chinese Han population. Oncotarget 3 29163794
2010 Identification and gastrointestinal expression of Xenopus laevis FoxF2. The International journal of developmental biology 3 20336609
2025 FOXF2 expression triggered by endocrine therapy orchestrates therapeutic resistance through reorganization of chromatin architecture in breast cancer. Cancer letters 2 39828125
2025 The stroke risk gene Foxf2 maintains brain endothelial cell function via Tie2 signaling. Nature neuroscience 2 41398477
2026 Progressive mural cell deficiencies across the lifespan in a foxf2 model of cerebral small vessel disease. eLife 1 41789880
2026 GFAP+ FOXF2+ ependymal cells promote blood-brain barrier repair via DLL4-NOTCH signaling after neural injury. Proceedings of the National Academy of Sciences of the United States of America 1 41875155
2024 Role of the Forkhead box family protein FOXF2 in the progression of solid tumor: systematic review. Journal of cancer research and clinical oncology 1 39724282
2026 FOXF2 regulates pericyte-endothelial signaling required for vascular homeostasis after neonatal hyperoxic lung injury. Nature communications 0 41680210
2026 Astrocyte-specific FoxF2 modulates immune and myelin repair: Evidence from multiple sclerosis lesions and an animal model. Journal of neuroimmunology 0 41785663
2024 FOXF2 may inhibit esophageal squamous cell carcinoma growth and metastasis by regulating the EZR-ERBB2 axis. Translational cancer research 0 39816549

Missed literature

Know a paper Affinage missed for FOXF2? Flag it for the maintainers and the community.

No submissions yet.