FOXC2 is a nuclear forkhead transcriptional regulator that recognizes regulatory DNA and controls gene expression in endothelial and mesenchymal contexts. Human FOXC2 occupies promoter-associated chromatin and activates transcription; phosphorylation modulates its recruitment to subsets of chromatin sites in human lymphatic endothelial cells. It also binds NFAT1 (NFATC2) and acts as a transcription corepressor in transfected human cells: DNA strengthens the protein interaction, while recognition of a cognate forkhead motif is dispensable in that system. In mouse endothelial models, Foxc2-dependent integrin expression supports adhesion, migration and vessel sprouting. Human FOXC2 variants disrupt lymphatic development and function. Mouse genetics links Foxc2 and NFATc1 to collecting-vessel maturation and valves; human lymphatic endothelial chromatin and enhancer experiments support their transcriptional cooperation. Mouse genetics also implicates Foxc2 in mesodermal and somite development.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: Human FOXC2 can repress NFAT1-driven transcription through a directly established corepressor mechanism. Reason: The original mouse/Ensembl IEA context is preserved. Its current donor study 18579532 reports downregulated probes while developing an Itgb3 activation mechanism; it does not establish direct DNA-bound repression. Independent human evidence in 42023653 establishes full-length FOXC2-dependent repression of NFAT1-driven reporters and target RNAs in transfected HEK293T cells, weakened by interaction-interface mutations. Purified human domains bind directly; DNA enhances this binding, and the cellular reporter effect requires the NFAT element but not FOXC2 recognition of a cognate forkhead element. This supports the gene-level negative-regulation claim and a corepressor mechanism, without reconstructing the older transfer or establishing native immune-cell or lymphatic-valve physiology. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: Human FOXC2 can repress NFAT1-driven transcription through a directly established corepressor mechanism. Reason: The original mouse ISS context is preserved. Its current donor study 18579532 reports downregulated probes while developing an Itgb3 activation mechanism; it does not establish direct DNA-bound repression. Independent human evidence in 42023653 establishes full-length FOXC2-dependent repression of NFAT1-driven reporters and target RNAs in transfected HEK293T cells, weakened by interaction-interface mutations. Purified human domains bind directly; DNA enhances this binding, and the cellular reporter effect requires the NFAT element but not FOXC2 recognition of a cognate forkhead element. This supports the gene-level negative-regulation claim and a corepressor mechanism, without reconstructing the older transfer or establishing native immune-cell or lymphatic-valve physiology. |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: Chromatin association is supported by endogenous human promoter occupancy and phosphorylation-sensitive recruitment in human lymphatic endothelial cells. Reason: The original TFClass ISA is a family/domain classification. Endogenous human FOXC2 ChIP at the PAI-1 promoter in 16456100 independently supports chromatin association. In 23878394, anti-Myc ChIP-chip and ChIP-qPCR compare overexpressed human FOXC2 with an eight-site phosphorylation-deficient mutant in primary human lymphatic endothelial cells, restricting analysis to sites previously occupied by endogenous FOXC2. Mutant recruitment decreases selectively, while nuclear localization and extract binding to naked DNA are retained. These assays support the compartment and regulated recruitment without resolving the unrecovered 25609649 fractionation row or attributing kinase activity to FOXC2. |
| GO:0000976 transcription cis-regulatory region binding | IEA GO_REF:0000107 | TOO GENERAL | Summary: The electronic cis-regulatory DNA-binding assertion is broader than the retained Pol II cis-region binding term. Reason: The original mouse/Ensembl orthology context is preserved. Mouse Itgb3 promoter occupancy and cis-element experiments in 18579532 and separate human FOXC2 binding in 16081467 support the capacity. GO:0000978 is a verified descendant of GO:0000976, so the broad electronic term is redundant at the level of functional coverage. The current mouse record is corroboration, not a reconstruction of every historical Ensembl inference. |
| GO:0000976 transcription cis-regulatory region binding | ISS GO_REF:0000024 | TOO GENERAL | Summary: Conserved cis-regulatory DNA recognition is represented more specifically by the retained Pol II cis-region binding annotation. Reason: The original ISS transfer from mouse Q61850 is compatible with the actual mouse Itgb3 promoter ChIP and binding-site experiments in 18579532, and independent full-length human FOXC2 DNA binding in 16081467. GO:0000976 is an ancestor of the retained GO:0000978 annotation. The broad source assertion is sound but adds no separate binding specificity; its mouse source and ISS evidence remain intact. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:20956529 Transcription elongation regulator 1 is a co-integrator of t... | TOO GENERAL | Summary: The broader Pol II regulatory-region binding term is entailed by retained cis-regulatory binding; the original extended assay remains unresolved. Reason: Retained GO:0000978 is an is_a descendant of GO:0000977, so this broader term adds no distinct molecular specificity. Independent human FOXC2 EMSA/reporter evidence in 16081467 and endogenous promoter ChIP in 16456100 support the gene-level binding and activation capacities. In the original 20956529 source, FOXC2 activates the DRE reporter, whereas inspected ChIP concerns FOXM1; its exact FOXC2 binding assay and complete two-part conjunction were not independently recovered. The TOO_GENERAL judgment concerns term breadth, not verification of that assay. Preserve the original IDA citation and both part_of atoms unchanged. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inherited Pol II cis-regulatory DNA recognition fits the established FOXC2 transcription-factor mechanism. Reason: The authentic PTHR11829 tree/MSA and original IBD record place human FOXC2 PTN002483621 below positive ancestral node PTN000930906. The exact official 501-aa target sequence is reproduced. This inherited DNA-recognition activity agrees with human full-length FOXC2 EMSA/reporter evidence and human promoter ChIP, while those assays have different experimental scopes. Target self-donor evidence is valid descendant grounding and is not circular. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:20956529 Transcription elongation regulator 1 is a co-integrator of t... | ACCEPT | Summary: Pol II cis-regulatory DNA recognition is established independently, while this original IDA assay attribution remains unresolved. Reason: Human FOXC2 sequence-specific EMSA and reporter experiments in 16081467, together with endogenous human promoter ChIP in 16456100, establish this gene-level cis-regulatory recognition activity and agree with the accepted IBA annotation. The inspected 20956529 experiments show FOXC2 reporter activation, while occupancy and DNA-competition experiments concern FOXM1 or DACH1. Acceptance of the term does not convert those assays into a verified FOXC2 binding experiment or replace the original IDA reference; its precise source attribution remains unverified. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: FOXC2 has a conserved Pol II DNA-binding transcription-factor activity. Reason: The positive PTN000930906 IBD lies on the independently verified human FOXC2 target path. Direct human FOXC2 DNA-binding/reporter experiments and endogenous human promoter ChIP support the biological activity. The original WITH/FROM entries, including target grounding and the current additional rat identifier relative to the older IBD source string, remain unchanged; neither donor count nor target self-reference invalidates the inference. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: The orthology-based Pol II transcription-factor annotation agrees with target-specific human evidence. Reason: Full-length human FOXC2 binds a forkhead recognition element in COS-7 lysate EMSA and activates a reporter in HeLa in 16081467. Endogenous human HMEC-1 promoter occupancy in 16456100 independently supports chromatin action. These target-specific data support the original mouse-derived electronic classification without claiming that every donor experiment or an entire historical pipeline was reconstructed. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: The TFClass assignment captures FOXC2’s defining DNA-binding transcription-factor activity. Reason: The original TFClass 3.3.1 family assignment is a manually evaluated domain/phylogenetic inference, not a new FOXC2 assay. Its Pol II transcription-factor classification is supported independently by full-length human DNA binding and reporter activation and by endogenous human promoter ChIP. Preserve the ISA and TFClass provenance. |
| GO:0001216 DNA-binding transcription activator activity | IDA PMID:9169153 Isolation of the mouse (MFH-1) and human (FKHL 14) mesenchym... | TOO GENERAL | Summary: The original general activator assertion is sound but less specific than the retained Pol II activator activity. Reason: The authentic 9169153 abstract explicitly reports both mouse MFH-1 and human FKHL14 as transcriptional activators, so it is not a wrong-species source. Its full Methods were not recovered. Independent full-length human FOXC2 reporter evidence and the retained GO:0001228 annotation provide the more specific functional coverage; this does not claim that the old assay’s promoter or construct details were inspected. |
| GO:0001216 DNA-binding transcription activator activity | IEA GO_REF:0000107 | TOO GENERAL | Summary: The general transcription-activator term is represented by the retained Pol II-specific activator activity. Reason: The mouse-derived electronic assertion is consistent with the human/mouse activation reported in the 9169153 abstract and with full-length human reporter experiments in 16081467. GO:0001228 is a verified descendant of GO:0001216 and already captures the supported activity. The original 9169153 full assay details remain unavailable; independent corroboration is identified separately. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:20956529 Transcription elongation regulator 1 is a co-integrator of t... | ACCEPT | Summary: FOXC2 activates a Pol II reporter, consistent with its independently established DNA-binding transcription-factor activity. Reason: The repeated DRE/E4-TATA reporter in 20956529 is activated by expressed FOXC2 in 293T cells. This is an actual FOXC2 transcription experiment, distinct from the paper’s FOXM1 ChIP. Full-length human FOXC2 binding and reporter activity are independently established in 16081467. Retain activator activity while keeping the unverified precise binding conjunction in raw2 separate; no FOXC2-specific occupancy assay or independently resolved plasmid species is inferred from the 20956529 host cells. |
| GO:0001756 somitogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Conserved participation in somitogenesis is retained as a developmental outcome. Reason: The current mouse donor is the 11562355 IGI annotation. Compound Foxc1/Foxc2-null embryos fail to form segmented epithelial somites, whereas the examined individual-null and less severe compound genotypes retain somite formation. This supports redundant developmental participation by the transcription factors. The original human IEA remains a transfer, not a human embryonic perturbation assay or proof that FOXC2 alone is indispensable. Supporting Evidence: |
| GO:0001946 lymphangiogenesis | IMP PMID:12114478 Analysis of the phenotypic abnormalities in lymphoedema-dist... | KEEP AS NON CORE | Summary: Human FOXC2-associated lymphatic dysfunction is complemented by experimental collecting-vessel maturation evidence. Reason: The original 12114478 human clinical study reports lymphoedema-distichiasis, normal or increased lymphatic channels and tracer reflux; it does not measure a molecular vessel-formation step. Independent 19398761 mouse Foxc2 loss and calcineurin/NFAT inhibition show defective collecting-vessel maturation and valves. The same paper maps endogenous FOXC2 chromatin occupancy in primary human intestinal lymphatic endothelial cells and tests selected enhancer responses with NFATc1 in transfected 293T cells. These findings support a transcriptional role in lymphatic development while preserving the original human clinical source and its endpoints. NFATc1 cooperation is distinct from the NFAT1/NFATC2 corepression mechanism; no new developmental process annotation is proposed. |
| GO:0003677 DNA binding | IEA GO_REF:0000107 | TOO GENERAL | Summary: Generic DNA binding is subsumed by the retained sequence-specific and cis-regulatory DNA recognition activities. Reason: The original mouse-derived electronic term is biologically correct. Human FOXC2 lysate EMSA, promoter ChIP and purified extended-domain SELEX establish more informative DNA recognition. Verified ontology ancestry places the retained specific binding terms under GO:0003677; the general electronic assertion adds no distinct activity. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | TOO GENERAL | Summary: The broad transcription-factor term is covered by the retained Pol II-specific activity. Reason: The InterPro/mouse electronic classification agrees with FOXC2’s forkhead DNA-binding domain and functional reporter evidence. GO:0000981 is a verified descendant of GO:0003700 and captures the supported Pol II activity. Preserve all original source alternatives and do not turn a domain assignment into an independently measured assay. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: The positive TRIM27 interaction supports the specific class ubiquitin protein ligase binding. Reason: The exact human FOXC2–P14373 pair is positive in the 25416956 IntAct Y2H screen/array/retest records. P14373 is reviewed human TRIM27, whose E3 identity is experimentally supported: 22829933 uses human TRIM27 and compares WT with the CC16/31AA RING mutant in cellular NOD2 ubiquitination assays. GO:0031625 specifically denotes binding an E3 ubiquitin protein ligase, so it refines this measured pair. This does not assign E3 catalysis to FOXC2, establish FOXC2 as a substrate, or demonstrate a native ubiquitination pathway. The three curated records are stages of the same screened pair, not three independent physiological validations. Proposed replacements: ubiquitin protein ligase binding |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: A positive FOXC2–TAX1BP1 Y2H interaction is retained with its screen-specific scope. Reason: Exact 25416956 IntAct records identify human Q86VP1/TAX1BP1 and FOXC2 in yeast screening, array and retest stages. The official partner record establishes an adaptor/autophagy-receptor role, but the pair does not establish a FOXC2 autophagy mechanism, ubiquitin-receptor activity or a supported more specific binding term. Retain the measured association as non-core under the campaign policy. No pair-specific native-cell or orthogonal validation is inferred from validation subsets elsewhere in the study. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: The accession-specific RBPMS interaction is retained without transferring RNA-binding or splice-regulatory activity to FOXC2. Reason: The 25416956 positive Y2H records resolve FOXC2–Q93062/RBPMS and the assay stages. Reviewed RBPMS functions are partly molecule-specific, and the tested construct has not been mapped to a particular natural RBPMS product. Binding an RNA-binding protein does not establish FOXC2 RNA binding, a spliceosome role, or a sequence-specific DNA-binding TF-partner class. The positive association remains non-core with its heterologous screen limit. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: The exact Q96IQ6 interaction is retained while product identity and catalytic specificity remain bounded. Reason: Positive 25416956 IntAct records identify the original Q96IQ6 participant. Official metadata now resolves an unreviewed 246-aa record linked to CNOT7 GeneID 29883; its poly(A)-ribonuclease label is ARBA-derived. It is not an established match to reviewed Q9UIV1 or its natural products. Neither the CCR4-NOT name nor a transferred catalytic label establishes a specific FOXC2 TF-binding or enzyme-binding mechanism. Preserve Q96IQ6 and the positive Y2H association as non-core. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The positive GOLGA2 association is retained without assigning Golgi location or structural function to FOXC2. Reason: Exact 32296183 IntAct records identify human FOXC2 and GOLGA2/GM130 in HuRI Y2H. The reported sufficient-binding region 13–1002 belongs to GOLGA2, not to the 501-aa FOXC2 target. Reviewed GOLGA2 matrix/tether roles do not establish FOXC2 Golgi residency, tethering or a specific structural binding mechanism. Retain the association as non-core; no native encounter, purified affinity or pair-specific MAPPIT/GPCA validation is established. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The exact METTL27 interaction is retained without deriving an enzyme-binding specialization from the partner name. Reason: Positive HuRI IntAct records identify Q8N6F8/METTL27 and FOXC2 with human participants in yeast. The official reviewed 245-aa partner record has no FUNCTION comment establishing a substrate-specific catalytic role. The name alone therefore does not justify a catalytic-class refinement. Retain the accession-specific positive association as non-core, without assigning FOXC2 methyltransferase activity or assuming physiological validation. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The KRTAP3-3 interaction remains a non-core screened association. Reason: Exact HuRI records support the FOXC2–Q9BYR6 Y2H pair. Official metadata identifies a keratin-associated interfilamentous matrix protein, not a keratin filament subunit itself. This does not establish keratin binding, a defined cytoskeletal-component interaction, or a FOXC2 hair-shaft structural function. Keep the positive association with its assay limits; absence of demonstrated physiological encounter is not evidence that the interaction is false. Supporting Evidence: |
| GO:0005634 nucleus | EXP PMID:28179430 Polydom Is an Extracellular Matrix Protein Involved in Lymph... | ACCEPT | Summary: Human lymphatic-endothelial nuclear FOXC2 is supported by corresponding original author experiments. Reason: The 28179430 journal body was inaccessible, but the first author’s official Osaka dissertation lists that exact paper and reports anti-human FOXC2 nuclear staining/intensity in human dermal lymphatic endothelial cells after Ang1/Ang2 treatment. Methods, Figure 35 and the publication list were inspected. This is corresponding original author research, not a byte-identical journal reprint or independent replication. Keep the EXP annotation with this access limit; mouse Polydom-loss phenotypes are separate. Supporting Evidence: |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear localization is supported by verified phylogenetic inheritance and direct target evidence. Reason: The positive nucleus IBD lies on the authentic human FOXC2 target path. Direct human aortic smooth-muscle staining in 11562355 and tagged human FOXC2 localization in 16081467 independently fit a nuclear transcription-factor role. The latter is predominantly, not exclusively, nuclear. Preserve the valid self-donor/descendant grounding and do not infer all-cell or all-condition exclusivity. |
| GO:0005634 nucleus | IC PMID:9169153 Isolation of the mouse (MFH-1) and human (FKHL 14) mesenchym... | ACCEPT | Summary: The curated nuclear inference is biologically consistent with independently established human localization. Reason: The original IC annotation cites 9169153 and transcription-activator activity as its basis. Its full assay details remain unavailable, but direct human nuclear evidence in 11562355 and 16081467 independently supports the location. Retain the source inference without pretending that a nuclear assay was inspected in 9169153 or replacing its original reference. |
| GO:0005634 nucleus | IDA PMID:11562355 The murine winged helix transcription factors, Foxc1 and Fox... | ACCEPT | Summary: The cited source contains direct nuclear staining of human FOXC2. Reason: Original 11562355 Results and Figure 1G-H report nuclear FOXC2 staining in cultured human aortic smooth-muscle cells. This is separate from the paper’s mouse compound-null embryology. Retain the IDA nuclear annotation without claiming independent image-pixel analysis, complete antibody-validation experiments or universal localization. Supporting Evidence: |
| GO:0005634 nucleus | IDA PMID:16081467 The establishment of a predictive mutational model of the fo... | ACCEPT | Summary: Tagged full-length human FOXC2 is predominantly nuclear in the tested cells. Reason: In 16081467, the explicitly human FOXC2 construct was expressed in COS-7 cells. Figure 3 and Methods report over 200 cells in two experiments, with WT approximately 92% nucleus-only, 7% nuclear and cytoplasmic, and 1% cytoplasmic. Disease variants have different effects, which are not natural-product differences. This supports nucleus without asserting exclusive localization or conflating host species with insert identity. Supporting Evidence: |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt nucleus mapping is corroborated by direct human-cell localization, including the cited phosphorylation study. Reason: The official Q99958 record maps SL-0191 to nucleus and cites 23878394 experimentally for localization. Selected original Results and Figure 3A report nuclear Myc-tagged human FOXC2 and its eight-site mutant in primary human lymphatic endothelial cells; both are expressed at similar levels, about 100-fold above endogenous protein. This corroborates earlier human staining and tagged-protein assays. Preserve the IEA mapping provenance and distinguish overexpressed localization from a new endogenous imaging measurement. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Official target-specific immunofluorescence supports nucleoplasmic FOXC2. Reason: Current HPA056302 records identify nucleoplasmic FOXC2 in BJ human fibroblasts and HeLa, with standard Supported ICC/IF, PFA fixation and 1:7 dilution. The 72-aa antigen exactly matches official FOXC2 residues 429–500. These are current assay metadata, not a reconstruction of a historical image version. No enhanced knockdown/GFP validation, independent image-pixel interpretation or universal distribution is claimed. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | TOO GENERAL | Summary: General transcriptional regulation is represented more specifically by the retained Pol II process. Reason: The InterPro inference fits the conserved forkhead transcription factor. GO:0006357 is a verified descendant of GO:0006355 and captures the established Pol II transcriptional regulation. Positive and negative target-specific outcomes do not require retaining an additional generic transcription process as separate functional coverage. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: FOXC2’s conserved transcriptional activity directly regulates Pol II output. Reason: The exact positive PTN000930906 IBD and human target descent are independently verified. Human FOXC2 binding, promoter occupancy and reporter experiments demonstrate that the protein performs transcriptional regulation. Preserve the original donor alternatives, including self-grounding; no donor-count criticism or circularity is warranted. Activating and context-dependent repressive effects are compatible with this unsigned process. |
| GO:0007498 mesoderm development | NAS PMID:8674414 Clustered arrangement of winged helix genes fkh-6 and MFH-1:... | KEEP AS NON CORE | Summary: Mesoderm development is retained with the original nonexperimental and cross-species limits. Reason: The original 8674414 paper maps the human locus and describes mouse MFH-1 mesodermal expression. Its proposed relationship to the amputated mouse mutation was a candidate hypothesis, not a demonstrated causal rescue. Later compound mouse Foxc1/Foxc2 genetics in 11562355 independently supports mesodermal/somite developmental participation. Retain the NAS developmental annotation without turning expression into direct human perturbation evidence or repeating the old mutant-causation hypothesis. |
| GO:0007507 heart development | IMP PMID:21457232 Identification of de novo mutations and rare variants in hyp... | UNDECIDED | Summary: The exact FOXC2 functional evidence for this heart-development IMP annotation remains inaccessible. Reason: The authentic 21457232 abstract describes a candidate-gene study in 53 hypoplastic-left-heart subjects, including rare inherited FOXC2 variants of uncertain significance. The full source was not recovered, so the precise experiment behind the IMP assertion cannot be checked. The presence of NOTCH1 or other genes in the abstract is not evidence of misattribution. Retain the original source fields and defer a directional curation decision. Supporting Evidence: |
| GO:0008286 insulin receptor signaling pathway | IDA PMID:16456100 Foxc2 is a common mediator of insulin and transforming growt... | KEEP AS NON CORE | Summary: FOXC2 participates in an insulin-responsive transcriptional branch rather than receptor or kinase catalysis. Reason: The 16456100 human HMEC-1 ChIP experiments show insulin-enhanced FOXC2 occupancy at the PAI-1 promoter. Reporter and mouse/bovine experiments support the downstream transcriptional branch with their own model limits. FOXC2 supplies transcriptional activity within the response, but the evidence does not assign insulin-receptor binding, proximal receptor signaling or kinase activity. Keep this context-specific process as non-core. Supporting Evidence: |
| GO:0009653 anatomical structure morphogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The inherited morphogenesis role is retained as a broad developmental outcome of transcriptional regulation. Reason: The positive IBD node is on the verified human FOXC2 target path. Mouse mesoderm/somite genetics and human lymphatic disease evidence support morphogenetic roles, while their different species and endpoints remain distinct. This broad developmental process is not a separate molecular activity; no donor-count or self-donor objection is made. |
| GO:0009725 response to hormone | IDA PMID:16456100 Foxc2 is a common mediator of insulin and transforming growt... | KEEP AS NON CORE | Summary: Hormone-responsive promoter regulation is a supported context-dependent FOXC2 function. Reason: Actual human HMEC-1 FOXC2 promoter occupancy changes after insulin or TGF-beta in 16456100. The protein contributes a transcriptional response rather than simply being a measured marker, while separate reporter and organismal experiments have bovine or mouse scope. Retain the broad hormone-response annotation as non-core without assigning receptor activity or universal responsiveness. Supporting Evidence: |
| GO:0010595 positive regulation of endothelial cell migration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: FOXC2-dependent transcription promotes endothelial migration in the mouse donor model. Reason: The original human IEA transfer is preserved. In 18579532, mouse Foxc2 overexpression and heterozygosity alter endothelial migration; Itgb3 promoter experiments and blocking antibody connect the response to a transcriptional mechanism. Scratch closure and Transwell migration are distinct from an in vivo vascular-repair assay. Retain the conserved regulatory participation as non-core without claiming a directly tested human endothelial perturbation. Supporting Evidence: |
| GO:0010595 positive regulation of endothelial cell migration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: FOXC2-dependent transcription promotes endothelial migration in the mouse donor model. Reason: The original human ISS transfer is preserved. In 18579532, mouse Foxc2 overexpression and heterozygosity alter endothelial migration; Itgb3 promoter experiments and blocking antibody connect the response to a transcriptional mechanism. Scratch closure and Transwell migration are distinct from an in vivo vascular-repair assay. Retain the conserved regulatory participation as non-core without claiming a directly tested human endothelial perturbation. Supporting Evidence: |
| GO:0016604 nuclear body | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA supports a nuclear-body pool without identifying a separate body-specific molecular function. Reason: Current HPA056302 ICC/IF records identify nuclear bodies as well as nucleoplasm in BJ and HeLa. Standard Supported ICC is retained with the independent antigen match and disclosed validation limits. No named body subtype, dynamic assembly mechanism or special FOXC2 activity in that body has been established from the inspected metadata. Retain this localization as non-core rather than treating it as false or using it to create a new functional core. |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The verified inherited differentiation role is retained with developmental context. Reason: The human target inherits the positive PTN000930906 annotation in the authentic PAINT tree. The transcription-factor mechanism and mouse mesoderm/somite developmental evidence support differentiation-related participation. This broad outcome does not define a separate catalytic activity or imply every cell lineage is controlled by FOXC2; the original phylogenetic assertion remains intact. |
| GO:0031490 chromatin DNA binding | IDA PMID:16456100 Foxc2 is a common mediator of insulin and transforming growt... | ACCEPT | Summary: Endogenous human FOXC2 occupies promoter-associated chromatin DNA. Reason: The actual 16456100 Methods/Results report anti-FOXC2 ChIP at the endogenous PAI-1 promoter in human HMEC-1 cells, enhanced after insulin or TGF-beta stimulation. This directly supports chromatin DNA binding as part of the transcriptional mechanism. Nearby FBE and IRE sites occur within some sonicated fragments, so their individual occupancy is not separately resolved. Bovine/mouse reporter experiments are kept distinct from the human ChIP. Supporting Evidence: |
| GO:0033630 positive regulation of cell adhesion mediated by integrin | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: FOXC2 promotes integrin-dependent endothelial adhesion through gene regulation in the donor model. Reason: The original human IEA fields and mouse donor are retained. Actual 18579532 mouse experiments couple Foxc2-dependent Itgb3 transcription to increased adhesion on vitronectin, with beta3-integrin blockade reducing the response. FOXC2 contributes transcriptional work; it is not the extracellular adhesive ligand or integrin itself. Human 293T use was for adenovirus production, not proof of the same human endothelial functional assay. Supporting Evidence: |
| GO:0033630 positive regulation of cell adhesion mediated by integrin | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: FOXC2 promotes integrin-dependent endothelial adhesion through gene regulation in the donor model. Reason: The original human ISS fields and mouse donor are retained. Actual 18579532 mouse experiments couple Foxc2-dependent Itgb3 transcription to increased adhesion on vitronectin, with beta3-integrin blockade reducing the response. FOXC2 contributes transcriptional work; it is not the extracellular adhesive ligand or integrin itself. Human 293T use was for adenovirus production, not proof of the same human endothelial functional assay. Supporting Evidence: |
| GO:0035470 positive regulation of vascular wound healing | IEA GO_REF:0000107 | MODIFY | Summary: The inspected donor experiments support endothelial migration more directly than restoration of damaged vasculature. Reason: Preserve the original human IEA transfer and Q61850 donor. Its current exact mouse source 18579532 measures cultured endothelial scratch closure, Transwell migration and ex vivo aortic-ring sprouting. GO:0035470 specifically describes blood-vessel formation contributing to restoration of damaged vasculature; that integrated repair endpoint is not established by the inspected experiments. Propose GO:0010595 for the positive measured migration outcome. This is an endpoint correction, not a claim that migration is an ontology child of vascular wound healing, and it does not negate the original positive assay results. Proposed replacements: positive regulation of endothelial cell migration Supporting Evidence: |
| GO:0035470 positive regulation of vascular wound healing | ISS GO_REF:0000024 | MODIFY | Summary: The inspected donor experiments support endothelial migration more directly than restoration of damaged vasculature. Reason: Preserve the original human ISS transfer and Q61850 donor. Its current exact mouse source 18579532 measures cultured endothelial scratch closure, Transwell migration and ex vivo aortic-ring sprouting. GO:0035470 specifically describes blood-vessel formation contributing to restoration of damaged vasculature; that integrated repair endpoint is not established by the inspected experiments. Propose GO:0010595 for the positive measured migration outcome. This is an endpoint correction, not a claim that migration is an ontology child of vascular wound healing, and it does not negate the original positive assay results. Proposed replacements: positive regulation of endothelial cell migration Supporting Evidence: |
| GO:0042802 identical protein binding | IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... | UNDECIDED | Summary: The exact FOXC2 self-association entry remains unverified at the original table level. Reason: The full 25609649 cache explains SFB-tagged human TF purification from HEK293T soluble and chromatin-released fractions, but the exact FOXC2 self-pair, fraction and validation row were not recovered from its supplements. The retained IntAct response has no matching self-pair; that absence does not refute the curator. A general TAP-MS protocol cannot establish the exact association or a stoichiometric homodimer. Preserve the original IPI/Q99958 assertion as unresolved. Supporting Evidence: |
| GO:0043565 sequence-specific DNA binding | IDA PMID:16081467 The establishment of a predictive mutational model of the fo... | TOO GENERAL | Summary: Directly measured sequence-specific DNA recognition is retained as evidence, while the broad term is subsumed by Pol II cis-regulatory binding. Reason: The inspected 16081467 Methods explicitly use full-length human FOXC2, and COS-7 lysate EMSA demonstrates sequence-specific forkhead-element recognition, with reporter activation tested separately in HeLa. This positive binding evidence remains valid. GO:0000978 is an is_a descendant of GO:0043565, so the broader term adds no distinct specificity regardless of evidence code. These are cell-extract assays, not purified-protein equilibrium measurements; disease variants and host species do not define natural FOXC2 products. Supporting Evidence: |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000002 | TOO GENERAL | Summary: The broad sequence-specific DNA recognition term is subsumed by retained Pol II cis-regulatory binding. Reason: The InterPro-derived recognition capacity is correct, but retained GO:0000978 is an is_a descendant of GO:0043565. The broad term therefore adds no distinct molecular specificity in either the IEA or IDA context. Human FOXC2 EMSA and purified-domain sequence selection remain positive supporting experiments with their original source and construct limits. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:16081467 The establishment of a predictive mutational model of the fo... | TOO GENERAL | Summary: The general positive-transcription process is represented by the retained Pol II-specific process. Reason: The original 16081467 full-length human construct activates a reporter in HeLa; binding was tested separately in COS-7 lysates. GO:0045944 is a verified descendant of GO:0045893 and is already retained for the target. This breadth disposition does not change the original evidence code or citation and does not claim that every original assay or construct was independently reconstructed. Supporting Evidence: |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:9169153 Isolation of the mouse (MFH-1) and human (FKHL 14) mesenchym... | TOO GENERAL | Summary: The general positive-transcription process is represented by the retained Pol II-specific process. Reason: The authentic 9169153 abstract explicitly reports human and mouse activation, although its full assay details remain unavailable. GO:0045944 is a verified descendant of GO:0045893 and is already retained for the target. This breadth disposition does not change the original evidence code or citation and does not claim that every original assay or construct was independently reconstructed. |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000107 | TOO GENERAL | Summary: The general positive-transcription process is represented by the retained Pol II-specific process. Reason: The original mouse-derived electronic assertion is supported by donor activation evidence and separate human functional studies. GO:0045944 is a verified descendant of GO:0045893 and is already retained for the target. This breadth disposition does not change the original evidence code or citation and does not claim that every original assay or construct was independently reconstructed. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:20956529 Transcription elongation regulator 1 is a co-integrator of t... | ACCEPT | Summary: The original FOXC2 reporter experiment directly supports positive Pol II transcriptional regulation. Reason: FOXC2 expression increases the DRE/E4-TATA reporter in 293T cells in 20956529. That positive transcriptional endpoint is supported even though the same paper does not independently establish FOXC2 ChIP at the element. The supplied expression plasmid’s insert species/sequence is not independently resolved, and human full-length activity in 16081467 provides separate corroboration. Preserve the original IDA assertion without borrowing FOXM1 occupancy evidence. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: FOXC2-dependent promoter activation supports the conserved positive Pol II transcription process. Reason: The original mouse ISS transfer is preserved. Current mouse source records include Cxcr4 and Itgb3 regulation; selected 18187037 and 18579532 experiments support positive promoter regulation. Independent full-length human FOXC2 reporter evidence in 16081467 corroborates the capacity. The current donor set contains reverse transfers as well as primary records; the conclusion rests on the inspected primary grounding, not on counting those records. |
| GO:0090050 positive regulation of cell migration involved in sprouting angiogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: FOXC2 regulates a migration-dependent sprouting response in the mouse endothelial model. Reason: The original human IEA and mouse donor remain intact. In 18579532, Foxc2-dependent Itgb3 transcription is linked to endothelial migration and ex vivo aortic-ring microvessel outgrowth, with beta3-integrin blockade and heterozygous tissue giving complementary evidence. This supports regulatory participation in the sprouting context, not a direct human in vivo angiogenesis experiment or a structural vessel-building activity. Supporting Evidence: |
| GO:0090050 positive regulation of cell migration involved in sprouting angiogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: FOXC2 regulates a migration-dependent sprouting response in the mouse endothelial model. Reason: The original human ISS and mouse donor remain intact. In 18579532, Foxc2-dependent Itgb3 transcription is linked to endothelial migration and ex vivo aortic-ring microvessel outgrowth, with beta3-integrin blockade and heterozygous tissue giving complementary evidence. This supports regulatory participation in the sprouting context, not a direct human in vivo angiogenesis experiment or a structural vessel-building activity. Supporting Evidence: |
| GO:0120163 negative regulation of cold-induced thermogenesis | IMP PMID:11551504 FOXC2 is a winged helix gene that counteracts obesity, hyper... | UNDECIDED | Summary: The negative direction of cold-induced thermogenesis is not resolved by the inspected source endpoints. Reason: The 11551504 transgene uses human adipose-derived FOXC2 cDNA in mice. The inspected cold exposure, lipid mobilization, UCP1 and oxygen-consumption results establish metabolic effects but do not clearly establish the specific negative cold-thermogenesis assertion. WAT oxygen consumption rises, while a significant BAT oxygen-consumption difference was not reported in the inspected text. Preserve IMP and the original source; do not flip the sign from leanness, basal metabolism or another paper’s cold-dependent RNA change. Supporting Evidence: |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | TOO GENERAL | Summary: A sequence-verified FOXC2 DNA-binding domain selects double-stranded DNA motifs. Reason: The authentic 28473536 workbook identifies FOXC2’s 132-aa extended DNA-binding domain, exactly matching official human residues 55–186. The inspected PWM rows and HT-SELEX/methyl-SELEX methods support sequence-specific dsDNA recognition by the purified bacterial-expression construct. This supports the defining DNA-recognition capacity without treating the fragment as a full-length cellular transcription experiment or assigning an affinity constant. GO:0000978 is an is_a descendant of GO:1990837 and is independently retained for the gene, so this broader term is TOO_GENERAL under the same specificity rationale used for GO:0043565. This term-level disposition preserves the positive original HT-SELEX evidence; it does not turn the domain selection assay into a promoter-specific cellular experiment. Supporting Evidence: |
| GO:1990841 promoter-specific chromatin binding | IEA GO_REF:0000107 | ACCEPT | Summary: The electronic promoter-chromatin binding assertion agrees with measured FOXC2 promoter occupancy. Reason: Mouse Cxcr4 promoter evidence in 18187037 is the current exact-term donor grounding; human HMEC-1 FOXC2 ChIP at PAI-1 in 16456100 independently corroborates promoter-associated chromatin action. Preserve the original mouse/Ensembl alternatives and IEA evidence. This does not identify which historical donor record was used or transfer the paper’s separate Foxc1 phenotypes. |
| GO:1990841 promoter-specific chromatin binding | ISS GO_REF:0000024 | ACCEPT | Summary: Promoter-associated chromatin binding is supported by the mouse source and independent human occupancy evidence. Reason: The current mouse Q61850 source is 18187037, whose selected original Results support Foxc2 activation and occupancy at the Cxcr4 promoter. The Foxc1 knockout/migration experiments in that paper are separate. Independent endogenous human FOXC2 PAI-1 promoter ChIP in 16456100 supports the transferred capacity. Retain the original ISS and donor; no human Cxcr4 assay or historical pipeline reconstruction is claimed. |
| GO:0003714 transcription corepressor activity | IDA PMID:42023653 FOXC2 represses NFAT1-dependent transcription through a DNA-... | NEW | Summary: Human FOXC2 acts as an NFAT1-associated transcription corepressor in a defined reconstituted and cellular system. Reason: Purified human FOXC2 DNA-binding domain directly binds the human NFAT1 Rel-homology region; three ternary structures and interface-mutant binding assays establish the contact. DNA enhances complex formation. Full-length FOXC2 represses NFAT1-dependent human IL2-ARRE2 reporter activity and target RNA abundance in transfected HEK293T cells, and interface mutations weaken repression. The NFAT element is required, whereas the cognate FOX element is dispensable. This is a positive, target-specific molecular activity matching GO:0003714, distinct from sequence-specific transcriptional activation; it is not inferred from a phenotype or transferred from another FOX protein. No redundant new TF-binding or biological-process annotation is added. Endogenous immune-cell and lymphatic-valve roles of this NFAT1/NFATC2 mechanism remain unestablished. Supporting Evidence: |
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Download this section (compressed HTML)Q: In which endogenous cell types does FOXC2 repress NFAT1/NFATC2-dependent transcription, and how does that mechanism differ from FOXC2 cooperation with NFATC1 in lymphatic vessels?
Q: How much of Foxc2-dependent endothelial migration is mediated by integrin beta3, and is this target-to-migration relationship conserved in human endothelial cells?
Q: Which cold-challenge endpoint supports a negative effect of FOXC2 on thermogenesis, separately from its effects on basal adipose oxidative metabolism?
Experiment: In a human cell model with confirmed endogenous FOXC2 and NFAT1 expression, measure a small panel of NFAT1-responsive and FOXC2-activated transcripts after FOXC2 depletion and near-endogenous rescue. Pair nascent-transcript measurements with targeted FOXC2/NFAT1 chromatin occupancy and reciprocal association assays under basal and NFAT1-activating conditions. Confirm protein abundance, nuclear localization and cell viability; interpret occupancy and co-association separately from direct physical contact.
Hypothesis: FOXC2-mediated NFAT1 repression depends on cellular context and can be separated experimentally from FOXC2-driven target activation.
Type: Targeted transcription, chromatin-occupancy and protein-association assays
Experiment: Compare matched Foxc2/FOXC2 depletion and rescue in mouse and human endothelial cultures. Measure ITGB3 transcript and surface protein, adhesion and Transwell migration, and test whether ITGB3 re-expression restores the migration endpoint. Include cell-number and viability controls to separate migration from growth. These assays test a defined cellular mechanism and do not establish repair of an injured vessel.
Hypothesis: Integrin beta3 mediates part of the endothelial migration response downstream of Foxc2, with conservation in human cells requiring direct testing.
Type: Targeted cross-species perturbation and rescue with adhesion/migration readouts
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