Affinage

FOXC2

Forkhead box protein C2 · UniProt Q99958

Length
501 aa
Mass
53.7 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FOXC2 is a forkhead/winged-helix transcription factor that functions as a master regulator of vascular development, lymphatic valve morphogenesis, adipocyte metabolism, and epithelial-mesenchymal transition. Its DNA-binding domain uses helix H3 for base-specific contacts while wing 1 and terminal regions engage the phosphate backbone, enabling direct transcriptional activation of targets including DLL4, ITGB3, CXCL12, RSPO3, p120-catenin, Wnt4, and mtTFA/Tfam (PMID:30722065, PMID:16678147, PMID:37154714, PMID:21270254). FOXC2 transcriptional output is tuned by multiple post-translational modifications: proline-directed phosphorylation at eight sites controls chromatin recruitment in a rheostat-like manner, CK2 phosphorylation at S124 sequesters FOXC2 in the cytoplasm, p38-mediated phosphorylation at S367 governs protein stability and EMT/metastasis via ZEB1, and SUMOylation at synergy control motifs inhibits activity while SENP3-mediated de-SUMOylation potentiates it (PMID:23878394, PMID:25486430, PMID:27292262, PMID:22493429, PMID:25216525). Loss-of-function mutations in FOXC2 cause lymphedema-distichiasis syndrome through haploinsufficiency, reflecting its essential role in lymphatic development where it cooperates with PROX1 to transduce shear-stress signals through calcineurin/NFAT and connexin37 and restrains ERK-driven lymphatic endothelial proliferation (PMID:11078474, PMID:22306086, PMID:27214551).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 High

    Establishing that FOXC2 (MFH-1) is a transcriptional activator essential for mesenchymal morphogenesis resolved its basic molecular function and demonstrated that its loss causes lethal aortic arch and skeletal defects in mice.

    Evidence Transactivation assays of mouse/human MFH-1 protein; targeted gene knockout in mice with phenotypic analysis

    PMID:9169153 PMID:9409679

    Open questions at the time
    • Precise DNA target sequences were unknown
    • Mechanism of transactivation domain function uncharacterized
    • Redundancy with FOXC1 not yet tested
  2. 2000 High

    Identification of truncating FOXC2 mutations as the cause of lymphedema-distichiasis syndrome established FOXC2 haploinsufficiency as the genetic basis for a human lymphatic disorder, connecting FOXC2 transcriptional function to lymphatic vascular development.

    Evidence Mutation sequencing, genetic linkage, and FISH mapping in affected families

    PMID:11078474 PMID:11371511

    Open questions at the time
    • Molecular targets of FOXC2 in lymphatic endothelium unknown
    • Whether different mutation positions produce variable phenotypes was unclear
    • Animal model of lymphedema-distichiasis not yet generated
  3. 2001 High

    Demonstrating that FOXC2 alters PKA holoenzyme composition in adipocytes and that Foxc1/Foxc2 act upstream of Notch/Delta signaling in cardiovascular and somite patterning placed FOXC2 at two major signaling nodes—metabolic regulation and vascular specification.

    Evidence Transgenic FOXC2 overexpression in adipocytes with PKA analysis; compound Foxc1;Foxc2 knockout mice with Notch pathway gene expression

    PMID:11551504 PMID:11562355

    Open questions at the time
    • Direct FOXC2 transcriptional targets in adipocytes not identified
    • Whether FOXC2 directly binds Notch pathway gene promoters was untested
    • Lymphatic-specific roles of Foxc2 vs. Foxc1 not separated
  4. 2006 High

    Showing that Foxc2 directly activates the DLL4 promoter via a Foxc-binding element and that compound Foxc mutants lack arterial markers resolved how FOXC2 instructs arterial cell identity upstream of Notch signaling.

    Evidence Direct Dll4 promoter activation assay; compound knockout mice with arteriovenous malformation phenotype and gene expression

    PMID:16678147 PMID:16839542

    Open questions at the time
    • Genome-wide set of direct FOXC2 targets in endothelium unknown
    • Post-translational regulation of FOXC2 in vascular cells not yet explored
    • How FOXC2 distinguishes arterial from venous programs mechanistically unclear
  5. 2007 High

    Discovery that EMT master regulators (Snail, Twist, Goosecoid) induce FOXC2, and that FOXC2 is required for lung metastasis, established FOXC2 as a critical effector of EMT and metastatic colonization beyond its developmental roles.

    Evidence RNAi knockdown and overexpression in mouse mammary carcinoma cells; in vivo lung metastasis assay

    PMID:17537911

    Open questions at the time
    • Direct transcriptional targets mediating FOXC2-driven EMT not identified
    • How FOXC2 nuclear vs. cytoplasmic localization affects EMT unresolved
    • Post-translational modifications controlling FOXC2 in cancer context unknown
  6. 2008 High

    Identification of integrin β3 as a direct FOXC2 transcriptional target in endothelial cells, with functional validation by neutralizing antibody rescue, provided the first mechanistic link between FOXC2 and integrin-mediated angiogenesis.

    Evidence Promoter binding assay; ITGB3 antibody rescue of FOXC2-driven migration; Foxc2 heterozygous mice with impaired microvessel outgrowth

    PMID:18579532

    Open questions at the time
    • Full repertoire of FOXC2-regulated integrins unknown
    • Signaling downstream of ITGB3 in FOXC2-driven angiogenesis not characterized
  7. 2009 High

    Showing that FOXC2 subcellular localization (cytoplasmic vs. nuclear) determines whether it promotes epithelial maintenance or mesenchymal transition revealed a binary switch model for FOXC2 function, and that FOXC2 directly represses p120-catenin explained how it destabilizes adherens junctions.

    Evidence RNAi and overexpression with subcellular fractionation in epithelial vs. fibroblast cells; EMSA confirming direct FOXC2 binding to p120-catenin promoter

    PMID:19935708 PMID:20460685

    Open questions at the time
    • Kinase controlling cytoplasmic retention unknown
    • Full mechanism of p120-catenin repression (cofactors, chromatin remodeling) not explored
  8. 2012 High

    Discovery that FOXC2, PROX1, and shear stress cooperatively induce connexin37 and calcineurin/NFAT signaling for lymphatic valve formation, combined with demonstration that SUMOylation at synergy control motifs inhibits FOXC2 transcriptional activity, established the mechanotransduction pathway and a key post-translational regulatory mechanism.

    Evidence Shear stress assays in LECs with genetic mouse models; in vitro SUMOylation reconstitution with purified components and SENP2 reversal; mutagenesis

    PMID:22306086 PMID:22493429

    Open questions at the time
    • Identity of the kinase(s) driving FOXC2 phosphorylation in shear response unknown
    • Whether SUMOylation regulates FOXC2 specifically in lymphatic cells untested
    • Structural basis for SUMOylation effects on DNA binding unclear
  9. 2013 High

    Genome-wide ChIP-seq mapping of FOXC2 in LECs combined with phosphosite mutagenesis showed that phosphorylation at eight proline-directed sites controls chromatin recruitment in a site-selective, rheostat-like manner, and SENP3-mediated de-SUMOylation was shown to potentiate FOXC2 transcriptional activity toward EMT targets like N-cadherin.

    Evidence ChIP-seq in LECs; mass spectrometry phosphosite mapping; phosphorylation-deficient mutants failing to remodel vasculature in vivo; SENP3 knockdown/overexpression with EMT readouts

    PMID:23878394 PMID:25216525

    Open questions at the time
    • Identity of the proline-directed kinase(s) not determined
    • Interplay between phosphorylation and SUMOylation on same FOXC2 molecule unknown
    • Whether SENP3 regulation of FOXC2 operates in lymphatic endothelium not tested
  10. 2014 High

    Identification of CK2 as the kinase phosphorylating FOXC2 at S124 to enforce cytoplasmic retention in epithelial cells resolved the localization switch: loss of CK2β in breast cancer permits nuclear FOXC2 accumulation and mesenchymal gene activation.

    Evidence In vitro CK2 kinase assay; S124L/S124D mutagenesis with localization and migration phenotypes; CK2 knockdown/overexpression

    PMID:25486430

    Open questions at the time
    • Whether CK2-FOXC2 axis operates in lymphatic endothelium unknown
    • Other kinases contributing to cytoplasmic retention not excluded
    • Crystal structure of phospho-S124 FOXC2 not determined
  11. 2015 High

    Mapping p38 phosphorylation of FOXC2 at S367 as essential for protein stability, EMT induction, and selective metastasis promotion (without affecting primary tumor growth), and identifying Cdk5 as a FOXC2 kinase in lymphatic endothelium, defined two context-specific phosphorylation events governing FOXC2 in cancer and lymphatic development.

    Evidence S367E/S367A mutagenesis with orthotopic syngeneic tumor model; Cdk5 substrate identification with endothelial-specific knockout and lymphatic valve phenotype

    PMID:26027726 PMID:27292262

    Open questions at the time
    • Whether Cdk5 phosphorylates the same sites as proline-directed kinases unclear
    • How p38-FOXC2-ZEB1 axis interfaces with CK2-mediated S124 regulation unknown
    • Cdk5-specific phosphosites on FOXC2 not mapped
  12. 2017 High

    Demonstration that TLR4-ERK signaling phosphorylates FOXC2 to activate DLL4 transcription in inflammatory angiogenesis, and that FOXC2 interacts with YAP-TEAD to promote glycolysis, expanded FOXC2's role to innate immune–vascular coupling and metabolic reprogramming.

    Evidence ERK-FOXC2 Co-IP; ChIP of FOXC2 on DLL4 promoter in endothelial cells; LPS in vivo model; FOXC2-YAP-TEAD Co-IP with HK2 expression analysis

    PMID:28433696 PMID:29380370

    Open questions at the time
    • ERK phosphosite(s) on FOXC2 not mapped
    • YAP-TEAD interaction validated only by Co-IP without reciprocal or structural confirmation
    • Whether ERK-FOXC2-DLL4 axis operates in lymphatic endothelium untested
  13. 2019 High

    Crystal structures of the FOXC2 DNA-binding domain revealed how helix H3 makes all base-specific contacts while wing 1 and terminal regions contact the phosphate backbone, providing a structural framework to interpret disease-causing mutations and FOXC2 target selection.

    Evidence X-ray crystallography of FOXC2-DBD bound to two DNA sequences; biochemical binding assays; disease mutation mapping

    PMID:30722065

    Open questions at the time
    • Full-length FOXC2 structure with transactivation domain absent
    • Structural basis for cofactor interaction (e.g., PROX1, YAP) unknown
    • How post-translational modifications alter DNA-binding geometry not resolved
  14. 2020 High

    Establishing that FOXC2 controls lymphatic junctional integrity via ROCK signaling, with ROCK inhibition rescuing valve degeneration in Foxc2 mutant mice, identified a pharmacologically targetable effector downstream of FOXC2 in lymphedema pathogenesis.

    Evidence Shear stress in LECs; FOXC2 knockdown and ROCK inhibition; inducible endothelial-specific Foxc2 knockout mice with postnatal valve analysis

    PMID:32510325

    Open questions at the time
    • Whether FOXC2 directly transcribes ROCK pathway genes or acts indirectly unknown
    • Long-term therapeutic efficacy of ROCK inhibition in lymphedema not assessed
    • FOXC2 cell cycle dependency (PLK1-mediated stability) not integrated with lymphatic function
  15. 2023 High

    ChIP-confirmed direct FOXC2 binding to CXCL12 and RSPO3 regulatory elements in vascular and lymphatic endothelium, with rescue experiments, established a paracrine mechanism by which endothelial FOXC2 sustains intestinal stem cell Wnt signaling and epithelial barrier integrity.

    Evidence EC/LEC-specific conditional Foxc knockout mice; ChIP; CXCL12/RSPO3 rescue in ischemia-reperfusion injury model

    PMID:37154714

    Open questions at the time
    • Whether this paracrine mechanism operates in other organs unknown
    • FOXC2 vs. FOXC1 differential target gene specificity at these loci not resolved
    • Post-translational modifications controlling FOXC2 in intestinal endothelium unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: which proline-directed kinase(s) phosphorylate the eight conserved sites controlling chromatin recruitment, how the multiple post-translational modifications (phosphorylation, SUMOylation) are integrated on individual FOXC2 molecules in different cell types, and whether the structural basis for cofactor interactions (PROX1, YAP-TEAD) can explain target gene selectivity.
  • Identity of proline-directed kinase(s) for the eight conserved sites
  • Full-length FOXC2 structure including transactivation domain
  • Integrated model of how multiple PTMs coordinate context-specific FOXC2 output

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0003677 DNA binding 8
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 2
Pathway
R-HSA-1266738 Developmental Biology 9 R-HSA-74160 Gene expression (Transcription) 9 R-HSA-162582 Signal Transduction 8 R-HSA-392499 Metabolism of proteins 6 R-HSA-1430728 Metabolism 5
Partners
CDK5CSNK2A1ERK2FOXC1MAPK14PROX1SENP3YAP1

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 FOXC2 (MFH-1) protein acts as a positive transcriptional transactivator, as demonstrated by transcriptional activity assays of the mouse and human MFH-1 proteins, and is essential for aortic arch patterning and skeletogenesis in vivo as shown by targeted gene knockout in mice. Transcriptional activity assay; targeted gene knockout in mice with phenotypic analysis Development (Cambridge, England) High 9169153 9409679
2000 Loss-of-function mutations (nonsense and frameshift) in FOXC2, a forkhead/winged-helix transcription factor, cause lymphedema-distichiasis syndrome via FOXC2 haploinsufficiency, establishing FOXC2 as required for lymphatic development. Mutation identification by sequencing; genetic linkage; FISH mapping American journal of human genetics High 11078474
2001 FOXC2 overexpression in adipocytes increases sensitivity of the beta-adrenergic-cAMP-PKA signaling pathway by altering adipocyte PKA holoenzyme composition, leading to a lean, insulin-sensitive phenotype and counteracting obesity and hypertriglyceridemia. Transgenic mouse overexpression; gene expression profiling; PKA holoenzyme composition analysis Cell High 11551504
2001 Foxc1 and Foxc2 have dose-dependent, cooperative roles in cardiovascular development and somitogenesis; compound Foxc1;Foxc2 homozygous knockout mice show complete absence of segmented paraxial mesoderm and profound defects in branchial arches and blood vessel remodeling, with loss of Notch pathway target gene expression (Mesp1, Mesp2, Hes5, Notch1, Dll1, Lfng, ephrinB2), placing Foxc1/2 upstream of the Notch/Delta/Mesp regulatory loop. Compound knockout mouse genetics; gene expression analysis; epistasis Genes & development High 11562355
2001 Truncating mutations throughout FOXC2 that disrupt the DNA-binding domain and/or C-terminal alpha-helices essential for transcription activation cause multiple lymphedema syndromes, demonstrating these domains are functionally required. Mutation sequencing in 86 lymphedema families; domain-function correlation Human molecular genetics Medium 11371511
2004 FoxC2 inhibits white adipocyte differentiation (adipogenesis) by blocking the ability of PPARgamma to promote expression of a subset of adipogenic genes (C/EBPalpha, adiponectin, perilipin) without affecting PPARgamma DNA binding or transactivation from a PPARgamma response element directly. Overexpression in 3T3-L1 preadipocytes and Swiss fibroblasts; PPARgamma overexpression rescue experiments; reporter assays The Journal of biological chemistry High 15277530
2006 Foxc1 and Foxc2 directly activate the Dll4 promoter via a Foxc-binding site to induce arterial cell specification upstream of Notch signaling; compound Foxc1;Foxc2 mutant embryos lack arterial markers and display arteriovenous malformations and defects in lymphatic sprouting due to reduced VEGF-C. Compound knockout mouse genetics; in vitro overexpression; direct promoter activation assay (Dll4 promoter with Foxc-binding site); gene expression analysis Developmental biology High 16678147
2006 Foxc1 and Foxc2 are required for cardiac outflow tract morphogenesis; compound mutants show downregulation of Tbx1 and Fgf8/10 in the second heart field and extensive neural crest cell apoptosis during migration, placing Foxc genes upstream of the Tbx1-FGF cascade. Compound knockout mouse genetics; gene expression analysis; cell proliferation and apoptosis assays Developmental biology High 16839542
2007 FOXC2 expression is induced by EMT-inducing signals (TGF-beta1, Snail, Twist, Goosecoid) and is required for the mesenchymal component of EMT; knockdown impairs lung metastasis of mammary carcinoma cells, and overexpression enhances metastatic ability in mouse models. Loss-of-function (RNAi) and gain-of-function (overexpression) in mouse mammary carcinoma cells; in vivo lung metastasis assay; gene expression profiling Proceedings of the National Academy of Sciences of the United States of America High 17537911
2008 Foxc2 directly regulates angiogenesis by binding to multiple Forkhead-binding elements within the Itgb3 (integrin beta3) promoter to drive Itgb3 expression; Foxc2 overexpression enhances endothelial cell migration and adhesion, an effect blocked by Itgb3 neutralizing antibody; Foxc2 heterozygous mutant mice show reduced Itgb3 expression and impaired microvessel outgrowth. Gene expression profiling; promoter binding assay; Itgb3 neutralizing antibody rescue; aortic ring ex vivo sprouting assay; Foxc2 heterozygous mouse model The Journal of biological chemistry High 18579532
2009 FOXC2 subcellular localization determines its function: cytoplasmic FOXC2 in normal epithelial cells promotes epithelial redifferentiation, while nuclear FOXC2 promotes mesenchymal/EMT phenotype; silencing FOXC2 in epithelial cells causes EMT and increased migration, whereas in fibroblasts it causes increased epithelial marker expression; overexpression in renal epithelial cells drives de novo nuclear localization and mesenchymal phenotype. RNAi knockdown; overexpression; subcellular fractionation/immunofluorescence; kidney ischemia-reperfusion in vivo model Oncogene Medium 19935708
2009 Pax3 and Foxc2 exhibit reciprocal transcriptional repression in the somite dermomyotome, and the Pax3:Foxc2 ratio determines myogenic versus vascular smooth muscle cell fate in multipotent progenitors. Genetic approaches (compound mouse mutants); somite explant manipulation; epistasis analysis Developmental cell High 20059958
2009 Foxc2 stimulates osteoblast differentiation by activating canonical Wnt-beta-catenin/TCF-LEF signaling, and this effect is partially mediated by protein kinase A (PKA), as the PKA inhibitor H-89 suppresses Foxc2-mediated TCF/LEF transcriptional activity. Electroporation overexpression in cranial suture mesenchymal cells; siRNA knockdown; reporter (TCF/LEF luciferase) assay; pharmacological inhibition (H-89) Biochemical and biophysical research communications Medium 19540201
2010 Foxc2 directly binds to the p120-catenin promoter between positions +267 and +282 (confirmed by EMSA) and transcriptionally represses p120-catenin expression in NSCLC cells; FOXC2 silencing restores p120-catenin and subsequently E-cadherin levels. Serial deletion promoter analysis; EMSA (electromobility shift assay); RNAi silencing; reporter assay Molecular cancer research : MCR High 20460685
2011 FOXC2 expression in adipocytes induces mitochondriogenesis, elongated mitochondrial morphology, increased aerobic metabolic capacity, and specifically trans-activates the nuclear-encoded mitochondrial transcription factor A (mtTFA/Tfam) gene promoter—a function unique among tested forkhead genes. Quantitative RT-PCR; promoter assay (trans-activation); electron microscopy; oxygen consumption and palmitate oxidation measurements Diabetes High 21270254
2011 Foxc2 promotes osteoblastogenesis by directly binding to a Forkhead-binding element in the integrin beta1 promoter and up-regulating integrin beta1 expression, with downstream activation of Akt and ERK phosphorylation. Promoter binding assay (direct binding to Forkhead element); siRNA knockdown; overexpression in MC3T3-E1 and primary calvarial cells; ex vivo organ culture Bone Medium 21640215
2012 PROX1, FOXC2, and flow (shear stress) coordinately control expression of connexin37 (gap junction protein) and activation of calcineurin/NFAT signaling to mediate lymphatic valve formation; FOXC2 mediates mechanosensory responses to shear stress in lymphatic endothelial cells. In vitro shear stress experiments; genetic mouse models; gene expression analysis; functional valve morphogenesis assays Developmental cell High 22306086
2012 SUMOylation of FOXC2 occurs primarily at one consensus synergy control motif (with minor contribution of a second site) and negatively regulates FOXC2 transcriptional activity; SUMOylation can be reconstituted in vitro with purified components and reversed by SUMO protease SENP2; SUMOylation-deficient FOXC2 mutants show higher transcriptional activity. In vitro SUMOylation reconstitution with purified components; SENP2 protease reversal; mutagenesis of synergy control motifs; transcriptional activity assay; detection of endogenous SUMO2/3-modified FOXC1 The Journal of biological chemistry High 22493429
2013 FOXC2 is phosphorylated on eight evolutionarily conserved proline-directed serine/threonine residues; phosphorylation regulates FOXC2 chromatin recruitment in a site-selective (rheostat-like) manner in lymphatic endothelial cells; phosphorylation-deficient FOXC2 mutant fails to induce vascular remodeling in vivo. Genome-wide ChIP-seq in lymphatic endothelial cells; phosphorylation-deficient mutagenesis; in vivo vascular remodeling assay; mass spectrometry Molecular and cellular biology High 23878394
2013 SENP3 de-SUMOylates FOXC2, potentiating its transcriptional activity; de-SUMOylated FOXC2 transcriptionally activates N-cadherin expression, promoting EMT in gastric cancer; reactive oxygen species-induced de-SUMOylation of FOXC2 is blocked by silencing SENP3. Biochemical SUMO assay; SENP3 overexpression/knockdown; target gene expression analysis; nude mouse model Oncotarget High 25216525
2013 Egr-1 in adipocytes suppresses FOXC2 expression, thereby promoting energy storage in white adipose tissue; Egr-1 null mice show elevated FOXC2 expression and its target genes, leading to increased energy expenditure and protection from diet-induced obesity. Egr-1 null mouse model; gene expression analysis in WAT; correlation of Egr-1 and FOXC2 expression Scientific reports Medium 23502673
2013 BSTA promotes mTORC2-mediated phosphorylation of Akt1 at Ser473, which suppresses FOXC2 expression to stimulate adipocyte differentiation; the mTORC2-BSTA-Akt1-FoxC2 signaling axis is required for adipogenesis. BSTA gene-trap murine ES cells; co-immunoprecipitation (BSTA-Akt1 complex); phosphorylation assays; FOXC2 expression analysis Science signaling High 23300339
2014 Casein kinase 2 (CK2) associates with Foxc2 and phosphorylates it at serine 124 in vitro; CK2-mediated phosphorylation at S124 maintains Foxc2 in the cytoplasm of normal epithelial cells; mutation of S124 to leucine causes constitutive nuclear Foxc2 localization and mesenchymal gene expression, while S124D phosphomimetic causes constitutive cytoplasmic localization; loss of CK2beta in breast cancer correlates with nuclear FOXC2. In vitro kinase assay (CK2 phosphorylation of Foxc2); mutagenesis (S124L, S124D); subcellular localization imaging; CK2 knockdown/overexpression; cell migration assays Oncogene High 25486430
2014 FOXC2 acts as a transcriptional repressor of p120-catenin (CTNND1) downstream of PKCalpha, leading to destabilization of E-cadherin at adherens junctions; ChIP confirmed direct FOXC2 binding to the p120-catenin promoter; inhibition of PKCalpha or FOXC2 rescues p120-catenin and E-cadherin, reducing tumor cell migration. Chromatin immunoprecipitation (ChIP); luciferase promoter reporter assay; Western blot; transwell migration/invasion assays; RNAi BMC cancer High 29216867
2015 Cyclin-dependent kinase 5 (Cdk5) phosphorylates Foxc2 in lymphatic endothelial cells; Cdk5 is an essential regulator of lymphatic vessel development and valve formation, mechanistically linked through Foxc2 as its key substrate. Endothelial-specific Cdk5 knockdown; identification of Foxc2 as Cdk5 substrate; lymphatic vessel and valve phenotype analysis Nature communications High 26027726
2015 p38 kinase phosphorylates FOXC2 at serine 367 (S367) to regulate its protein stability and function; the phosphomimetic FOXC2(S367E) mutant is refractory to p38 inhibition while FOXC2(S367A) non-phosphorylatable mutant fails to elicit EMT or upregulate ZEB1; p38-FOXC2 signaling selectively promotes metastasis without affecting primary tumor growth; ZEB1 is a downstream transcriptional target of FOXC2. Site-directed mutagenesis (S367E, S367A); orthotopic syngeneic mouse tumor model; p38 inhibitor (SB203580) treatment; gene expression analysis; in vitro EMT assays Oncogene High 27292262
2015 Notch signaling acts upstream of Foxc2 in hemogenic endothelial cells to promote definitive hematopoiesis; Foxc2 is required for proper development of definitive hematopoiesis downstream of Notch, as shown in zebrafish, mouse embryos, and mouse ES cell differentiation assays. Mouse ES cell differentiation; zebrafish loss-of-function; mouse embryo Foxc2 analysis; epistasis with Notch induction Blood High 25587036
2016 FOXC1 and FOXC2 regulate ERK signaling in lymphatic endothelial cells; LEC-specific deletion of Foxc1 or Foxc2 causes increased LEC proliferation and enlarged, abnormal lymphatic vessels associated with ERK hyperactivation; pharmacological ERK inhibition rescues the enlarged lymphatic vessel phenotype in FOXC-deficient embryos. LEC-specific conditional knockout mice; ERK signaling analysis; pharmacological ERK inhibition in utero; gene expression of Ras regulators The Journal of clinical investigation High 27214551
2016 p38MAPK signaling is a druggable upstream regulator of FOXC2, and FOXC2 elevated by p38 promotes an AR-negative stem-like prostate cancer phenotype resistant to androgen deprivation therapy; p38 inhibition restores epithelial attributes and reduces circulating tumor cells in vivo. p38 inhibitor (SB203580) treatment; FOXC2 expression analysis; in vivo tumor model with circulating tumor cell analysis; RNAi Oncogene Medium 26804168
2016 FOXC2 disease mutations outside the forkhead domain cause either loss or gain of FOXC2 transcriptional activity, as measured by transactivation assay using FOXC1/C2 response element reporter; a frameshift truncated mutant protein localizes to nuclear aggregates while all mutants retain nuclear localization. Luciferase reporter transactivation assay; subcellular localization by immunofluorescence; mutagenesis analysis Oncotarget Medium 27276711
2017 FOXC2 interacts with YAP and TEAD to activate YAP signaling, which in turn positively regulates Hexokinase 2 (HK2) expression and promotes glycolysis in nasopharyngeal carcinoma cells. Co-immunoprecipitation (FOXC2-YAP-TEAD complex); gene expression analysis; HK2 expression and glycolysis assays; in vitro and in vivo tumor assays Experimental cell research Medium 28433696
2017 TLR4 signaling in lung endothelial cells induces ERK phosphorylation, which causes ERK-FOXC2 protein interaction, ERK-dependent FOXC2 serine/threonine phosphorylation, and subsequent FOXC2 transcriptional activation of DLL4 (master regulator of sprouting angiogenesis); FOXC2 directly binds the DLL4 promoter in vivo; this TLR4-ERK-FOXC2-DLL4 axis regulates inflammatory angiogenesis. ERK-FOXC2 co-immunoprecipitation; FOXC2 phosphorylation assay; ChIP (FOXC2 binding to DLL4 promoter); FOXC2 siRNA and ERK dominant negative; in vivo LPS mouse model; retinal angiogenesis assay The Journal of physiology High 29380370
2017 Foxc2 coordinates white adipose tissue inflammation and browning through the leptin-JAK2/STAT3 pathway; STAT3 physically interacts with PRDM16 to form a complex that promotes WAT browning; CREB is required for Foxc2-mediated inflammation regulation; Foxc2-mediated suppression of JAK2/STAT3 and promotion of STAT3-PRDM16 complex were confirmed by ChIP and Co-IP. Co-immunoprecipitation (STAT3-PRDM16 complex); ChIP (CREB on leptin and Foxc2 promoters); LPS-induced inflammatory model; ob/ob mouse comparison; Foxc2 overexpression in HFD-obese mice International journal of obesity (2005) Medium 28925407
2019 Crystal structures of the FOXC2 DNA-binding domain (DBD) in complex with two different DNA sites reveal the winged-helix fold mechanism: helix H3 makes all base-specific contacts, while the N-terminus, wing 1, and C-terminus of FOXC2-DBD make additional contacts with DNA phosphate groups; structural analysis provides molecular basis for disease-causing mutations. X-ray crystallography (two crystal structures); biochemical binding assays; bioinformatics analysis; mutagenesis of disease-causing mutations Nucleic acids research High 30722065
2019 H19 lncRNA directly binds Foxc2 protein (confirmed by RNA immunoprecipitation and RNA pulldown); H19 and Foxc2 synergistically promote osteogenic differentiation of BMSCs; Foxc2 directly binds the Wnt4 promoter (confirmed by ChIP) and promotes its transcription, activating the Wnt-beta-catenin pathway. RNA immunoprecipitation; RNA pulldown; ChIP (Foxc2 binding to Wnt4 promoter); osteogenic differentiation assays; qRT-PCR and Western blot Journal of cellular physiology Medium 30633332
2020 FOXC2 exhibits cell cycle-dependent expression with protein levels accumulating in G2 and rapidly decreasing during mitosis; PLK1 kinase activity is required for FOXC2 protein stability; FOXC2 knockdown delays mitotic entry in CSC-enriched TNBC cells; FOXC2-expressing cells are sensitive to PLK1 inhibition. Cell cycle synchronization; FOXC2 protein level analysis through cell cycle; PLK1 inhibitor treatment; RNAi knockdown; mitotic entry assays Scientific reports Medium 27064522
2020 FOXC2 shear stimulation specifically increases ROCK activation and disrupts cell junctions in lymphatic endothelial cells; FOXC2 deletion increases focal adherens and disrupts junctional integrity via ROCK; ROCK inhibition rescues junctional integrity changes induced by FOXC2 inactivation in vitro and ameliorates valve degeneration in Foxc2 mutant mice in vivo. Shear stress experiments on human LECs; FOXC2 knockdown; ROCK inhibition; inducible endothelial-specific Foxc2 knockout mice; postnatal valve analysis eLife High 32510325
2021 Inactivation of mechanosensitive transcription factor Foxc2 in adult lymphatic endothelium compromises gut epithelial barrier, promotes dysbiosis and bacterial translocation, and skews lymphatic endothelial subtype specialization toward pro-fibrotic identities; commensal microbiota depletion corrected intestinal lymphatic dysfunction, revealing a cross-talk between lymphatic vascular function and commensal microbiota. Inducible adult-specific Foxc2 knockout mice; single-cell RNA sequencing; antibiotic microbiota depletion; intestinal lymphatic function assays; cytokine and metabolite profiling Science advances High 34272244
2022 Exosomal circKIF18A from M2 microglia binds to FOXC2 protein, maintains its stability and promotes its nuclear translocation in brain endothelial cells; nuclear FOXC2 then directly binds the promoters of ITGB3, CXCR4, and DLL4 to upregulate their expression and activate PI3K/AKT signaling, promoting GBM angiogenesis. Co-culture with microglial exosomes; circKIF18A-FOXC2 interaction assay; FOXC2 nuclear translocation imaging; ChIP (FOXC2 binding to ITGB3, CXCR4, DLL4 promoters); in vitro angiogenesis assays; in vivo tumorigenicity Oncogene Medium 35637250
2023 FOXC1 and FOXC2 directly bind to regulatory elements of the CXCL12 (in blood endothelial cells) and RSPO3 (in lymphatic endothelial cells) loci, respectively; vascular EC- and LEC-specific deletion of Foxc genes impairs CXCL12 and RSPO3 expression, reducing Wnt signaling in intestinal stem cells and worsening ischemia-reperfusion-induced intestinal damage; exogenous CXCL12 and RSPO3 rescue intestinal damage in respective Foxc mutants. EC/LEC-specific conditional Foxc1/Foxc2 knockout mice; ChIP (FOXC1/2 binding to CXCL12 and RSPO3 loci); Wnt signaling analysis in ISCs; CXCL12/RSPO3 rescue experiments; I/R injury model EMBO reports High 37154714
2023 FOXC2 drives vasculogenic mimicry (VM) in solid tumors by transcriptionally activating endothelial genes in tumor cells; hypoxia stimulates this activity; VM-proficient tumors resistant to anti-angiogenic therapy become sensitized when FOXC2 is suppressed. Loss-of-function in diverse solid tumor cell lines; gene expression profiling; in vitro VM assays; in vivo anti-angiogenic therapy combination experiments Cell reports Medium 37499655

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proceedings of the National Academy of Sciences of the United States of America 486 17537911
2000 Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. American journal of human genetics 454 11078474
2001 FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 439 11551504
2012 Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation. Developmental cell 333 22306086
2001 The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis. Genes & development 291 11562355
2000 Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract. Development (Cambridge, England) 274 10704385
2006 The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development. Developmental biology 224 16678147
1997 Essential roles of the winged helix transcription factor MFH-1 in aortic arch patterning and skeletogenesis. Development (Cambridge, England) 207 9409679
2017 Antisense lncRNA FOXC2-AS1 promotes doxorubicin resistance in osteosarcoma by increasing the expression of FOXC2. Cancer letters 171 28323030
2001 Truncating mutations in FOXC2 cause multiple lymphedema syndromes. Human molecular genetics 171 11371511
2007 Mutations in FOXC2 are strongly associated with primary valve failure in veins of the lower limb. Circulation 146 17372167
2006 Forkhead transcription factors, Foxc1 and Foxc2, are required for the morphogenesis of the cardiac outflow tract. Developmental biology 128 16839542
2003 Reduced expression of FOXC2 and brown adipogenic genes in human subjects with insulin resistance. Obesity research 119 14569043
2012 MiR-520h-mediated FOXC2 regulation is critical for inhibition of lung cancer progression by resveratrol. Oncogene 109 22410781
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