Transcription factor AP-2-alpha (AP-2alpha) is a nuclear, sequence-specific DNA-binding transcription factor of the AP-2 family. It binds GCC(N3)GGC elements as a homodimer or as a heterodimer with AP-2beta or AP-2gamma, using a basic DNA-binding region next to a C-terminal helix-span-helix dimerization domain. An N-terminal proline-rich transactivation domain recruits the CITED2 and p300/CBP coactivators. The same domain is inhibited by KCTD1/KCTD15, and SUMOylation dampens activity. AP-2alpha activates most of its targets, but it represses others in a promoter-specific way (for example C/EBPalpha, MYC and SOD2), partly by recruiting corepressors such as NPM1. It is one of the earliest regulators of the embryonic ectoderm. It is expressed in non-neural ectoderm and at the neural plate border during gastrulation, and then in premigratory and migratory neural crest. In frog it initiates the neural plate border upstream of PAX3 and later acts again within the crest as a crest specifier. In chick it opens chromatin at border enhancers with AP-2gamma and then at crest specification enhancers with AP-2beta. Loss of AP-2alpha, or of AP-2alpha together with AP-2gamma, disrupts crest induction or development in frog and zebrafish. Mouse mutants have cranial neural tube closure failure, craniofacial, body wall, eye, ear and limb malformations. Heterozygous mutations in human TFAP2A cause branchio-oculo-facial syndrome. AP-2alpha also acts in epidermal keratinocytes, lens and retinal development, and dental mesenchymal cells, and it is often dysregulated in cancers. A single AP-2 gene in amphioxus is expressed in non-neural ectoderm but not at the neural plate border, so the ectodermal role is ancestral in chordates and deployment in the neural crest is a vertebrate co-option.
Definition: The formation of the neural plate border, the region of ectoderm at the boundary between the neural plate and the non-neural ectoderm that is competent to give rise to neural crest, preplacodal ectoderm, dorsal neural tube and epidermis.
Justification: GO has no term for the neural plate border. GO:0014029 neural crest formation is defined as forming this ectodermal region but is placed under epithelial to mesenchymal transition, so border specifiers end up annotated to an EMT term. The border is conserved in chordates without neural crest (amphioxus, tunicates), so it cannot be a part of neural crest formation. See projects/NEURAL_CREST_FORMATION_OBSOLETION.md.
Parent term: ectoderm development
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:20066163 AP-2alpha Inhibits c-MYC Induced Oxidative Stress and Apopto... | ACCEPT | Summary: AP-2alpha binds AP-2 sites upstream of c-myc (ChIP) and lowers endogenous c-MYC mRNA and protein in HaCaT keratinocytes. Reason: Direct, DNA-binding-dependent repression of a Pol II gene. AP-2alpha is a bifunctional TF: it activates most targets and represses some in a promoter-specific way. Repression of MYC in epidermal cells is a well-supported example. Supporting Evidence: PMID:20066163 Chromatin immunoprecipitation assays demonstrated that AP-2 proteins bound to a cluster of AP-2 binding sites located within a 2 kb upstream regulatory region of c-myc |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:33000225 KCTD1 mutants in scalpβearβnipple syndrome and APβ2Ξ± P59A in... | ACCEPT | Summary: Hu et al. 2020 studied AP-2alpha/KCTD1 interaction mutants and their effect on Wnt/beta-catenin reporter activity. UniProt cites this paper for AP-2alpha as a repressor of MYC and a negative regulator of canonical Wnt signalling. Reason: Repression of Pol II transcription by AP-2alpha is well established (see the C/EBPalpha, Mn-SOD and c-myc rows). This paper is consistent with that, and the curator read the full text, so the row is accepted. Supporting Evidence: PMID:33000225 wild-type AP-2Ξ± and mutant P60A and P61R protein appeared to demonstrate strong fluorescence in the nucleus and co-localized with KCTD1 protein. file:human/TFAP2A/TFAP2A-uniprot.txt Is involved in the negative regulation of Wnt canonical signaling, and is a transcriptional repressor of MYC (PubMed:33000225). |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:8321221 An alternatively spliced mRNA from the AP-2 gene encodes a n... | ACCEPT | Summary: Buettner et al. 1993 cloned AP-2B, an alternatively spliced TFAP2A product that lacks the dimerization domain. AP-2B acts as a dominant-negative inhibitor of AP-2 transactivation. Reason: This is a real negative regulatory output of the TFAP2A gene, but it belongs to a minor splice isoform (UniProt isoform 4, AP-2B) that interferes with AP-2 activity. It is not repression of target promoters by full-length AP-2alpha. Accepted for consistency with the other GO:0000122 rows, because negative regulation of Pol II transcription is a genuine output of the gene. Note that this row reflects the isoform 4 dominant-negative mechanism. Supporting Evidence: PMID:8321221 Both transient and stable transfection experiments show that AP-2B inhibits AP-2 transactivator function |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:9520389 Derepression of the C/EBPalpha gene during adipogenesis: ide... | ACCEPT | Summary: AP-2alpha was purified as CUP, the preadipocyte factor that binds repressive elements of the C/EBPalpha gene. Expressing it inhibited C/EBPalpha promoter-reporter transcription. Reason: Sequence-specific repression of a Pol II gene by AP-2alpha, identified biochemically. Supporting Evidence: PMID:9520389 Consistent with a repressive role of AP-2alpha/CUP, an AP-2alpha1 expression vector, cotransfected with a C/EBPalpha promoter-reporter construct into 3T3-L1 adipocytes, inhibited reporter gene transcription. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:11278550 A family of AP-2 proteins down-regulate manganese superoxide... | ACCEPT | Summary: AP-2alpha represses the Mn-SOD (SOD2) promoter in a DNA-binding-dependent way. A non-binding dominant negative relieves the repression in AP-2-rich SV40-transformed fibroblasts. Reason: Loss-of-function (dominant negative) evidence for repression of an endogenous Pol II gene. Consistent with promoter-specific repressor activity. Supporting Evidence: PMID:11278550 Repression of Mn-SOD by AP-2 was dependent on DNA binding |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based assignment of chromatin location for a sequence-specific DNA-binding TF. Reason: AP-2alpha occupies promoters and enhancers in chromatin (ChIP at CDKN1A, MYC, HYAL1, NR4A1; genome-wide CUT&RUN in chick crest), so chromatin location is appropriate. Supporting Evidence: PMID:21084835 Maximal expression of CDKN1A requires TFAP2A which binds to two regions of the promoter PMID:31848212 Consistent with the pioneer function of TFAP2A, regions occupied by the transcription factor showed enriched chromatin accessibility and H3K27ac signal |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:12586840 Physical and functional interactions among AP-2 transcriptio... | ACCEPT | Summary: TFAP2A binds AP-2 cis-regulatory sites and is coactivated by CITED2/p300 (Braganca et al. 2003; UniProt notes chromatin association at the PITX2 P1 promoter). Reason: Correct but general. The more specific Pol II cis-regulatory binding term (GO:0000978) is also carried. Supporting Evidence: PMID:12586840 interactions among TFAP2A, CITED2, and p300/CBP are necessary for TFAP2A-mediated transcriptional activation file:human/TFAP2A/TFAP2A-uniprot.txt Associates with chromatin to the PITX2 P1 promoter region. |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:18718911 Epigenetic regulation of HYAL-1 hyaluronidase expression. id... | ACCEPT | Summary: ChIP shows AP-2 occupying the HYAL-1 minimal promoter, which contains overlapping SP1/EGR1/AP-2 sites, in HYAL-1-expressing bladder/prostate cancer cells. Reason: Direct promoter occupancy. Correct, if general. Supporting Evidence: PMID:18718911 The chromatin immunoprecipitation assay identified that Egr-1, AP-2, and NFkappaB bind to the promoter in HYAL-1-expressing cells |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:31146003 Androgen upregulates NR4A1 via the TFAP2A and ETS signaling ... | ACCEPT | Summary: TFAP2A binds the NR4A1 promoter and downregulates it in HeLa cells. Reason: Promoter binding was shown directly. Acceptable general cis-regulatory binding term. Supporting Evidence: PMID:31146003 all six transcription factors were confirmed to interact directly with the NR4A1 promoter |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of Pol II regulatory region sequence-specific DNA binding for the AP-2 family node, with human TFAP2A/B/C and mouse paralogs as experimental donors. Reason: This is the defining activity of the AP-2 family (GCC(N3)GGC recognition by the basic region plus HSH dimer), conserved to the single amphioxus AP-2. TFAP2A appears among its own donors, which reflects its experimental grounding, not circularity. Supporting Evidence: PMID:1998122 AP-2 required a dimerization domain and an adjacent region of net basic charge to achieve a sequence-specific protein:DNA interaction. PMID:7555706 AP-2 beta binds specifically to a series of well-characterized AP-2 binding sites, consensus to the sequence G/CCCN3GGC, and transactivates transcription from a reporter plasmid under the control of an AP-2-dependent promoter. file:human/TFAP2A/TFAP2A-deep-research-falcon.md It binds regulatory DNA as a homodimer or, in appropriate cellular settings, a heterodimer with another TFAP2 protein, and changes target-gene transcription. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:21084835 Dual association by TFAP2A during activation of the p21cip/C... | ACCEPT | Summary: TFAP2A binds a proximal AP-2 site and an upstream region of the CDKN1A (p21) promoter (ChIP), needed for maximal drug-induced p21 expression. Reason: Direct sequence-specific binding to Pol II cis-regulatory elements is the core molecular activity of AP-2alpha. Supporting Evidence: PMID:21084835 Maximal expression of CDKN1A requires TFAP2A which binds to two regions of the promoter |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:7555706 Cloning and characterization of a second AP-2 transcription ... | ACCEPT | Summary: Moser et al. 1995 showed AP-2 family binding to well-characterised G/CCCN3GGC sites in the context of cloning AP-2beta. Reason: Direct sequence-specific binding to Pol II cis-regulatory elements is the core molecular activity of AP-2alpha. Supporting Evidence: PMID:7555706 AP-2 beta binds specifically to a series of well-characterized AP-2 binding sites, consensus to the sequence G/CCCN3GGC, and transactivates transcription from a reporter plasmid under the control of an AP-2-dependent promoter. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:7559606 Transcription factor AP-2 regulates human insulin-like growt... | ACCEPT | Summary: Human AP-2 binds proximal GCCNNNGGC-like sites in the IGFBP5 promoter (EMSA), and these sites are needed for transactivation. Reason: Direct sequence-specific binding to Pol II cis-regulatory elements is the core molecular activity of AP-2alpha. Supporting Evidence: PMID:7559606 Both sequences bound specifically to human AP-2 in vitro by gel shift mobility assay. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:9520389 Derepression of the C/EBPalpha gene during adipogenesis: ide... | ACCEPT | Summary: AP-2alpha/CUP binds the repressive elements of the C/EBPalpha promoter. Reason: Direct sequence-specific binding to Pol II cis-regulatory elements is the core molecular activity of AP-2alpha. Supporting Evidence: PMID:9520389 Consistent with a repressive role of AP-2alpha/CUP, an AP-2alpha1 expression vector, cotransfected with a C/EBPalpha promoter-reporter construct into 3T3-L1 adipocytes, inhibited reporter gene transcription. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:12586840 Physical and functional interactions among AP-2 transcriptio... | ACCEPT | Summary: TFAP2A transcriptional activity on AP-2 reporters depends on CITED2 and p300/CBP coactivators. Reason: Correct. The more informative activator/repressor child terms (GO:0001228, GO:0001227) are also carried, and this parent stays valid. Supporting Evidence: PMID:12586840 interactions among TFAP2A, CITED2, and p300/CBP are necessary for TFAP2A-mediated transcriptional activation |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:21084835 Dual association by TFAP2A during activation of the p21cip/C... | ACCEPT | Summary: TFAP2A binds and is needed for maximal activation of the CDKN1A promoter. Reason: Correct. The more informative activator/repressor child terms (GO:0001228, GO:0001227) are also carried, and this parent stays valid. Supporting Evidence: PMID:21084835 Maximal expression of CDKN1A requires TFAP2A which binds to two regions of the promoter |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:7555706 Cloning and characterization of a second AP-2 transcription ... | ACCEPT | Summary: AP-2 factors bind AP-2 sites and transactivate AP-2-dependent reporters. Reason: Correct. The more informative activator/repressor child terms (GO:0001228, GO:0001227) are also carried, and this parent stays valid. Supporting Evidence: PMID:7555706 AP-2 beta binds specifically to a series of well-characterized AP-2 binding sites, consensus to the sequence G/CCCN3GGC, and transactivates transcription from a reporter plasmid under the control of an AP-2-dependent promoter. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass assignment of AP-2alpha (class 1.3.1, AP-2 family) as a Pol II DNA-binding transcription factor. Reason: Consistent with all direct evidence. Supporting Evidence: file:human/TFAP2A/TFAP2A-uniprot.txt AP-2 factors bind to the consensus sequence 5'-GCCNNNGGC-3' and activate genes involved in a large spectrum of important biological functions including proper eye, face, body wall, limb and neural tube development. |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IDA PMID:11278550 A family of AP-2 proteins down-regulate manganese superoxide... | ACCEPT | Summary: DNA-binding-dependent repression of the Mn-SOD promoter by AP-2alpha. Reason: Sequence-specific repression has been shown on several promoters, so AP-2alpha is a context-dependent repressor as well as an activator. Repression can work through recruited corepressors (NPM1) and is opposed by coactivators. Supporting Evidence: PMID:11278550 Repression of Mn-SOD by AP-2 was dependent on DNA binding |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IDA PMID:20066163 AP-2alpha Inhibits c-MYC Induced Oxidative Stress and Apopto... | ACCEPT | Summary: AP-2alpha binds upstream AP-2 sites of c-myc and represses c-MYC expression. Reason: Sequence-specific repression has been shown on several promoters, so AP-2alpha is a context-dependent repressor as well as an activator. Repression can work through recruited corepressors (NPM1) and is opposed by coactivators. Supporting Evidence: PMID:20066163 Chromatin immunoprecipitation assays demonstrated that AP-2 proteins bound to a cluster of AP-2 binding sites located within a 2 kb upstream regulatory region of c-myc |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IDA PMID:9520389 Derepression of the C/EBPalpha gene during adipogenesis: ide... | ACCEPT | Summary: AP-2alpha (CUP) binds and represses the C/EBPalpha promoter in preadipocytes. Reason: Sequence-specific repression has been shown on several promoters, so AP-2alpha is a context-dependent repressor as well as an activator. Repression can work through recruited corepressors (NPM1) and is opposed by coactivators. Supporting Evidence: PMID:9520389 Consistent with a repressive role of AP-2alpha/CUP, an AP-2alpha1 expression vector, cotransfected with a C/EBPalpha promoter-reporter construct into 3T3-L1 adipocytes, inhibited reporter gene transcription. |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IMP PMID:31146003 Androgen upregulates NR4A1 via the TFAP2A and ETS signaling ... | ACCEPT | Summary: TFAP2A binds the NR4A1 promoter and its overexpression downregulates NR4A1 expression. Reason: Binding plus repression of the reporter supports the repressor term. The context is PCOS granulosa/HeLa cells, but the molecular activity is general. Supporting Evidence: PMID:31146003 TFAP2A downregulated NR4A1 expression PMID:31146003 all six transcription factors were confirmed to interact directly with the NR4A1 promoter |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT assignment of Pol II-specific activator activity to the AP-2 family node. Reason: Activation is the main mode of action of all AP-2 proteins (N-terminal PY-motif transactivation domain plus CITED2/p300 coactivation). It is the core MF of TFAP2A. Supporting Evidence: PMID:12586840 interactions among TFAP2A, CITED2, and p300/CBP are necessary for TFAP2A-mediated transcriptional activation PMID:7555706 AP-2 beta binds specifically to a series of well-characterized AP-2 binding sites, consensus to the sequence G/CCCN3GGC, and transactivates transcription from a reporter plasmid under the control of an AP-2-dependent promoter. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:11278550 A family of AP-2 proteins down-regulate manganese superoxide... | ACCEPT | Summary: In the same study that found Mn-SOD repression, AP-2 transactivated the AP-2-responsive c-erbB-3 promoter. Reason: Direct reporter evidence for activator activity on a canonical AP-2 target. Supporting Evidence: PMID:11278550 another AP-2-responsive gene, c-erbB-3, was transactivated by AP-2 |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:20808827 Expression of human frataxin is regulated by transcription f... | ACCEPT | Summary: TFAP2 binds the FXN promoter directly (ChIP/EMSA), and its binding sites enhance FXN promoter-reporter activity. Overexpression raises frataxin mRNA and protein. Reason: Binding plus activation through identified sites supports the activator term. Supporting Evidence: PMID:20808827 We found that the transcription factors SRF and TFAP2 bind directly to FXN promoter sequences. |
| GO:0001501 skeletal system development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT inference of skeletal system development from mouse Tfap2a and zebrafish tfap2a. Reason: Tfap2a-null mice lack or deform many head and trunk bones. The cranial skeleton is crest-derived, so this is a downstream output of the crest role, not a separate core function. Kept as non-core. Supporting Evidence: PMID:8622766 Skeletal defects occur in the head and trunk region, where many bones are deformed or absent. |
| GO:0001822 kidney development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT inference of kidney development for the AP-2alpha clade. Reason: AP-2alpha is expressed in meso-metanephric tissue, and BOFS includes renal anomalies, but in mammals the kidney role belongs mainly to TFAP2B. Legitimate, non-core. Supporting Evidence: PMID:1989904 Additional expression of AP-2 occurs in limb bud mesenchyme and in meso-metanephric regions. PMID:21204207 Major features include cutaneous and ocular abnormalities, characteristic facies, renal, ectodermal, and temporal bone anomalies. |
| GO:0001822 kidney development | IMP PMID:21204207 Genotype-phenotype analysis of the branchio-oculo-facial syn... | KEEP AS NON CORE | Summary: Renal anomalies are a minor feature of TFAP2A-mutant branchio-oculo-facial syndrome. Reason: Human genetic phenotype evidence. Variable and secondary in BOFS, so non-core. Supporting Evidence: PMID:21204207 Major features include cutaneous and ocular abnormalities, characteristic facies, renal, ectodermal, and temporal bone anomalies. |
| GO:0003404 optic vesicle morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tfap2a IMP (optic vesicle morphogenesis). Reason: AP-2alpha is needed for lens vesicle and optic morphogenesis in mouse, and coloboma/ocular anomalies occur in BOFS. A real, tissue-specific developmental role outside the crest core. Supporting Evidence: file:human/TFAP2A/TFAP2A-uniprot.txt AP-2-alpha is the only AP-2 protein required for early morphogenesis of the lens vesicle. PMID:21204207 Major features include cutaneous and ocular abnormalities, characteristic facies, renal, ectodermal, and temporal bone anomalies. |
| GO:0003409 optic cup structural organization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tfap2a IMP (optic cup structural organization). Reason: Same eye-morphogenesis role as the optic vesicle row. Non-core. Supporting Evidence: PMID:21204207 Major features include cutaneous and ocular abnormalities, characteristic facies, renal, ectodermal, and temporal bone anomalies. |
| GO:0003677 DNA binding | IDA PMID:16236267 Proteomic analysis of SUMO4 substrates in HEK293 cells under... | ACCEPT | Summary: The SUMO4 substrate study reports that SUMO4 conjugation represses AP-2alpha transcriptional activity. DNA binding of AP-2alpha is well established. Reason: True but very general. The more specific sequence-specific and cis-regulatory binding terms are carried elsewhere. The parent term is not wrong, and the curator read the full text. Supporting Evidence: PMID:16236267 SUMO4 sumoylation represses AP-1 and AP-2alpha transcriptional activity PMID:1998122 AP-2 required a dimerization domain and an adjacent region of net basic charge to achieve a sequence-specific protein:DNA interaction. |
| GO:0003682 chromatin binding | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse Tfap2a IDA (ChIP occupancy of target promoters). Reason: AP-2alpha occupies target chromatin and behaves as a pioneer factor that raises accessibility at border and crest enhancers. Chromatin binding is the closest available MF for that behaviour. Supporting Evidence: PMID:31848212 Consistent with the pioneer function of TFAP2A, regions occupied by the transcription factor showed enriched chromatin accessibility and H3K27ac signal |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro mapping (TF_AP-2 domain) to DNA-binding transcription factor activity. Reason: Correct, general IEA. Supporting Evidence: file:human/TFAP2A/TFAP2A-uniprot.txt AP-2 factors bind to the consensus sequence 5'-GCCNNNGGC-3' and activate genes involved in a large spectrum of important biological functions including proper eye, face, body wall, limb and neural tube development. |
| GO:0005515 protein binding | IPI PMID:10987820 Tau promoter confers neuronal specificity and binds Sp1 and ... | REMOVE | Summary: IPI with MAPT (tau) from a study of the MAPT promoter, which showed that an 80-bp tau promoter fragment binds Sp1 and AP-2. Reason: The cached abstract describes AP-2 binding to the tau gene promoter (protein-DNA), not to the tau protein. Generic protein binding is uninformative in any case, and the promoter binding is already covered by the cis-regulatory binding rows. Removing it does not dispute the reported binding. Supporting Evidence: PMID:10987820 this 80-bp fragment binds both Sp1 and AP-2 proteins |
| GO:0005515 protein binding | IPI PMID:11447109 Myosin VI isoform localized to clathrin-coated vesicles with... | REMOVE | Summary: IPI with MYO6 (myosin VI) from Buss et al. 2001. The study is about clathrin-mediated endocytosis. Reason: The cached full text shows the "AP-2" in this paper is the clathrin adaptor protein complex AP-2 (alpha-adaptin ear-domain pull-downs, clathrin-coated vesicles), not transcription factor AP-2alpha. The interaction does not involve TFAP2A, so this is name confusion. Even if it did, generic protein binding is uninformative. Supporting Evidence: PMID:11447109 Myosin VI, precipitated from whole cytosol, was present in a protein complex containing adaptor protein (AP)-2 and clathrin, and enriched in purified clathrin-coated vesicles. |
| GO:0005515 protein binding | IPI PMID:11694877 Cardiac malformations, adrenal agenesis, neural crest defect... | MODIFY | Summary: CITED2 binds and coactivates all TFAP2 isoforms. Transactivation by TFAP2 fails in Cited2-/- fibroblasts and is restored by CITED2. Reason: The interaction is functional coactivation, so the informative MF is transcription coactivator binding. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:11694877 CITED2 interacts with and co-activates all isoforms of transcription factor AP-2 (TFAP2) |
| GO:0005515 protein binding | IPI PMID:12072434 Transcription factor AP-2 interacts with the SUMO-conjugatin... | REMOVE | Summary: UBC9 (UBE2I) two-hybrid and in vivo interaction. AP-2 is SUMOylated at K10, which lowers its transactivation potential. Reason: The interaction shows that AP-2alpha is a SUMOylation substrate. That is a property of the substrate, not a molecular function, and generic protein binding is uninformative. The removal does not dispute the interaction. Supporting Evidence: PMID:12072434 sumolation of AP-2 decreases its transcription activation potential |
| GO:0005515 protein binding | IPI PMID:12586840 Physical and functional interactions among AP-2 transcriptio... | MODIFY | Summary: TFAP2A interacts with p300/CBP (through its N-terminal transactivation domain) and with CITED2 (through the dimerization domain). Both are needed for coactivation. Reason: Both partners recorded for this paper (EP300, CITED2) are transcription coactivators, so transcription coactivator binding is the informative replacement. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:12586840 N-terminal residues of TFAP2A, containing the transactivation domain, are both necessary and sufficient for interaction with p300 PMID:12586840 interactions among TFAP2A, CITED2, and p300/CBP are necessary for TFAP2A-mediated transcriptional activation |
| GO:0005515 protein binding | IPI PMID:12586840 Physical and functional interactions among AP-2 transcriptio... | MODIFY | Summary: Second IPI row from Braganca et al. 2003 (CITED2 or EP300 partner). Reason: As for the other row from this paper: the partner is a coactivator, so this becomes transcription coactivator binding. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:12586840 interactions among TFAP2A, CITED2, and p300/CBP are necessary for TFAP2A-mediated transcriptional activation |
| GO:0005515 protein binding | IPI PMID:17318229 Nucleophosmin acts as a novel AP2alpha-binding transcription... | MODIFY | Summary: NPM1 forms a complex with AP-2alpha on retinoic-acid-responsive promoters and acts as its corepressor. Reason: The partner works as a transcription corepressor recruited by AP-2alpha, so transcription corepressor binding is the informative MF. Proposed replacements: transcription corepressor binding Supporting Evidence: PMID:17318229 This study unveils a hitherto unrecognized transcriptional corepressor function of the NPM protein PMID:17318229 suppression of NPM by RNA interference alleviates the repression of gene expression mediated by retinoic acid and AP2alpha |
| GO:0005515 protein binding | IPI PMID:19115315 The interaction of KCTD1 with transcription factor AP-2alpha... | MODIFY | Summary: KCTD1 binds the AP-2alpha N-terminus (yeast two-hybrid, GST pull-down, co-IP) and represses AP-2alpha transactivation through its BTB domain. Reason: KCTD1 carries GO:0003714 transcription corepressor activity by IDA from this same paper (QuickGO, Q719H9). The informative MF for AP-2alpha is therefore transcription corepressor binding. The KCTD1/KCTD15 brake on the activation domain also limits crest induction in zebrafish. Proposed replacements: transcription corepressor binding Supporting Evidence: PMID:19115315 our results indicate the novel function of KCTD1 as the transcriptional repressor for AP-2 family, especially for AP-2alpha PMID:23382213 Kctd15 binds specifically to the activation domain of AP-2Ξ± and efficiently inhibits transcriptional activation |
| GO:0005515 protein binding | IPI PMID:24835590 Sumoylation pathway is required to maintain the basal breast... | REMOVE | Summary: UBC9 pull-down/co-IP in a study of SUMOylation in basal breast cancer. Reason: This reflects AP-2alpha being SUMOylated (UBC9 is the E2). Generic protein binding is uninformative. The removal does not dispute the interaction. Supporting Evidence: PMID:24835590 GST pull-down and co-immunoprecipitation confirmed that Ubc9 bound to both TFAP2A and TFAP2C |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interactome detection of an interaction with MKRN3 or GSTO2. Reason: Generic protein binding from a large-scale screen, with no functional context. Uninformative, so it is removed. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interactome detection of an interaction with MKRN3 or GSTO2. Reason: Generic protein binding from a large-scale screen, with no functional context. Uninformative, so it is removed. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... | REMOVE | Summary: High-throughput interactome detection of an interaction with MAX. Reason: Generic protein binding from a large-scale screen, with no functional context. Uninformative, so it is removed. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: High-throughput interactome detection of an interaction with ACOT1. Reason: Generic protein binding from a large-scale screen, with no functional context. Uninformative, so it is removed. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: High-throughput interactome detection of an interaction with GSTO2. Reason: Generic protein binding from a large-scale screen, with no functional context. Uninformative, so it is removed. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput interactome detection of an interaction with ACOT1. Reason: Generic protein binding from a large-scale screen, with no functional context. Uninformative, so it is removed. Removal does not mean the interaction is false. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT nuclear localisation for the AP-2 family. Reason: AP-2alpha is a nuclear transcription factor. Supporting Evidence: file:human/TFAP2A/TFAP2A-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005634 nucleus | IDA PMID:16236267 Proteomic analysis of SUMO4 substrates in HEK293 cells under... | ACCEPT | Summary: Nuclear localisation of AP-2alpha observed experimentally. Reason: Consistent with its function as a DNA-binding transcription factor. Supporting Evidence: PMID:16236267 SUMO4 sumoylation represses AP-1 and AP-2alpha transcriptional activity |
| GO:0005634 nucleus | IDA PMID:19115315 The interaction of KCTD1 with transcription factor AP-2alpha... | ACCEPT | Summary: Nuclear localisation of AP-2alpha observed experimentally. Reason: Consistent with its function as a DNA-binding transcription factor. Supporting Evidence: PMID:19115315 the two proteins were completely co-localized in the nuclei of mammalian cells |
| GO:0005634 nucleus | IDA PMID:20607706 AP2 transcription factor induces apoptosis in retinoblastoma... | ACCEPT | Summary: Nuclear localisation of AP-2alpha observed experimentally. Reason: Consistent with its function as a DNA-binding transcription factor. Supporting Evidence: PMID:20607706 TFAP2A and TFAP2B, which map to chromosome arm 6p, are expressed in the amacrine and horizontal cells of human retina |
| GO:0005634 nucleus | IDA PMID:33000225 KCTD1 mutants in scalpβearβnipple syndrome and APβ2Ξ± P59A in... | ACCEPT | Summary: Nuclear localisation of AP-2alpha observed experimentally. Reason: Consistent with its function as a DNA-binding transcription factor. Supporting Evidence: PMID:33000225 wild-type AP-2Ξ± and mutant P60A and P61R protein appeared to demonstrate strong fluorescence in the nucleus and co-localized with KCTD1 protein. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated nuclear localisation. Reason: Correct. Supporting Evidence: file:human/TFAP2A/TFAP2A-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005634 nucleus | IMP PMID:12586840 Physical and functional interactions among AP-2 transcriptio... | ACCEPT | Summary: Nuclear localisation of AP-2alpha observed experimentally. Reason: Consistent with its function as a DNA-binding transcription factor. Supporting Evidence: file:human/TFAP2A/TFAP2A-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence shows nucleoplasm. Reason: Consistent with nuclear TF function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864278 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864278) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864307 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864307) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864343 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864343) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864381 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864381) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864412 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864412) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864426 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864426) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864453 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864453) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864690 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864690) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864718 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864718) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864737 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864737) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8864989 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8864989) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8865244 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8865244) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8869542 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8869542) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8869543 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8869543) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8869549 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8869549) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8869568 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8869568) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8869575 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8869575) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8869580 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-8869580) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9768288 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-9768288) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9836270 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-9836270) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9836275 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-9836275) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9907144 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-9907144) placing TFAP2A dimers and complexes in the nucleoplasm. Reason: Nucleoplasm is the correct site of AP-2 dimerisation, cofactor binding and promoter engagement. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro mapping to regulation of DNA-templated transcription. Reason: Correct, general. |
| GO:0007399 nervous system development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT inference of nervous system development for the AP-2alpha clade. Reason: AP-2alpha is needed for cranial ganglia and neural tube closure and is expressed in a column of hindbrain/spinal cord neurons. Correct but broad, and covered more specifically by the crest and cranial ganglion terms. Non-core. Supporting Evidence: PMID:8622766 Analysis of these mice earlier in embryogenesis indicates a failure of cranial neural-tube closure and defects in cranial ganglia development. PMID:1989904 The principle part of this expression occurs in neural crest cells and their major derivatives, including cranial and spinal sensory ganglia and facial mesenchyme. |
| GO:0007605 sensory perception of sound | IMP PMID:21204207 Genotype-phenotype analysis of the branchio-oculo-facial syn... | MARK AS OVER ANNOTATED | Summary: BOFS patients can have conductive or sensorineural deafness and temporal bone anomalies. Reason: The hearing loss comes from malformation of crest- and ectoderm-derived ear structures. AP-2alpha is not involved in the sensory perception of sound itself. The morphogenesis term (inner ear morphogenesis, row kept) captures the defect. A sensory-perception process term is a phenotype-to-process over-reach. Supporting Evidence: PMID:21204207 Major features include cutaneous and ocular abnormalities, characteristic facies, renal, ectodermal, and temporal bone anomalies. |
| GO:0008285 negative regulation of cell population proliferation | IDA PMID:20607706 AP2 transcription factor induces apoptosis in retinoblastoma... | KEEP AS NON CORE | Summary: Transfecting TFAP2A into retinoblastoma cells (which lack the protein) inhibits proliferation and induces apoptosis. Reason: Overexpression in tumour lines. It fits AP-2alpha activating CDKN1A and its growth-suppressive behaviour in some cancers, but it is context-dependent and not a core developmental role. Supporting Evidence: PMID:20607706 Transfection of TFAP2A and TFAP2B expression constructs into retinoblastoma cells induces apoptosis and inhibits proliferation. PMID:21084835 Maximal expression of CDKN1A requires TFAP2A which binds to two regions of the promoter |
| GO:0010628 positive regulation of gene expression | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse Tfap2a IDA (positive regulation of gene expression). Reason: Correct but broad. It restates the activator role recorded more precisely by GO:0045944. Supporting Evidence: file:human/TFAP2A/TFAP2A-uniprot.txt AP-2 factors bind to the consensus sequence 5'-GCCNNNGGC-3' and activate genes involved in a large spectrum of important biological functions including proper eye, face, body wall, limb and neural tube development. |
| GO:0010842 retina layer formation | IEP PMID:20607706 AP2 transcription factor induces apoptosis in retinoblastoma... | MARK AS OVER ANNOTATED | Summary: TFAP2A and TFAP2B are expressed in amacrine and horizontal cells of human retina. Reason: An expression pattern (IEP) does not show a role in forming retinal layers. A retinal requirement for Tfap2a/b exists in mouse but was not tested here. The authors only propose a differentiation link. Supporting Evidence: PMID:20607706 TFAP2A and TFAP2B, which map to chromosome arm 6p, are expressed in the amacrine and horizontal cells of human retina PMID:20607706 We propose that inability to differentiate along the amacrine/horizontal cell lineages may underlie retinoblastoma tumor formation. |
| GO:0021559 trigeminal nerve development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tfap2a IMP (cranial ganglia defects in nulls). Reason: The trigeminal ganglion is built from crest and placode cells, both AP-2alpha-expressing lineages. A legitimate downstream output, non-core. Supporting Evidence: PMID:8622766 Analysis of these mice earlier in embryogenesis indicates a failure of cranial neural-tube closure and defects in cranial ganglia development. PMID:8622765 AP-2(-/-) mice died perinatally with cranio-abdominoschisis and severe dismorphogenesis of the face, skull, sensory organs and cranial ganglia. |
| GO:0021623 oculomotor nerve formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tfap2a IMP (Zhang et al. 1996). Reason: The oculomotor nerve is a CNS motor nerve and not a crest derivative. The defect in nulls probably follows from the exencephaly/midbrain malformation, not a direct nerve-specific role. Kept as non-core, deferring to the mouse curators who read the full text. Supporting Evidence: PMID:8622766 Analysis of these mice earlier in embryogenesis indicates a failure of cranial neural-tube closure and defects in cranial ganglia development. |
| GO:0030501 positive regulation of bone mineralization | IDA PMID:19578371 BCOR regulates mesenchymal stem cell function by epigenetic ... | KEEP AS NON CORE | Summary: In dental mesenchymal stem cells, overexpressing AP-2alpha raises ALP activity and mineralization, and knockdown in BCOR-mutant MSCs reduces them. Reason: Gain- and loss-of-function evidence in human MSCs that AP-2alpha promotes osteo/dentinogenic mineralization. A real but tissue-specific role, downstream of BCOR repression. Non-core. Supporting Evidence: PMID:19578371 Gain- and loss-of-function assays suggest that AP-2alpha is a key factor that mediates the increased osteo-dentinogenic capacity of MSCs. PMID:19578371 over-expression of AP-2Ξ± significantly enhanced ALP activity and mineralization upon induction. |
| GO:0035115 embryonic forelimb morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tfap2a IMP (limb defects in nulls/chimeras). Reason: AP-2alpha is expressed in limb bud mesenchyme and mouse mutants have limb defects. A legitimate developmental role outside the crest, non-core. Supporting Evidence: PMID:1989904 Additional expression of AP-2 occurs in limb bud mesenchyme and in meso-metanephric regions. |
| GO:0042127 regulation of cell population proliferation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT inference of regulation of cell population proliferation for the AP-2 family. Reason: AP-2 factors affect proliferation in many contexts (e.g. CDKN1A activation, crest progenitor survival), with signs that differ by cell type. The broad regulation term fits that, as a non-core role. Supporting Evidence: PMID:21084835 Maximal expression of CDKN1A requires TFAP2A which binds to two regions of the promoter PMID:20607706 Transfection of TFAP2A and TFAP2B expression constructs into retinoblastoma cells induces apoptosis and inhibits proliferation. |
| GO:0042472 inner ear morphogenesis | IMP PMID:21204207 Genotype-phenotype analysis of the branchio-oculo-facial syn... | KEEP AS NON CORE | Summary: BOFS patients have malformed pinnae and temporal bone anomalies. Mouse crest-specific Tfap2a deletion causes middle ear defects. Reason: Ear morphogenesis depends on crest and ectoderm derivatives in which AP-2alpha acts. Legitimate, non-core. Supporting Evidence: PMID:21204207 Major features include cutaneous and ocular abnormalities, characteristic facies, renal, ectodermal, and temporal bone anomalies. PMID:14975722 Neural crest-specific disruption of tcfap2a results in frequent perinatal lethality associated with neural tube closure defects and cleft secondary palate. |
| GO:0042802 identical protein binding | IPI PMID:1998122 Characterization of a dimerization motif in AP-2 and its fun... | MODIFY | Summary: Williams and Tjian 1991 mapped the helix-span-helix dimerization domain, which forms AP-2 homodimers needed for DNA binding. Reason: Identical protein binding is better captured as protein homodimerization activity, which is the actual, functionally required activity (DNA binding needs the dimer). AP-2alpha also heterodimerizes with TFAP2B/C; that partner switch drives border versus crest specification. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:1998122 This helix-span-helix (HSH) domain was unable to bind DNA when separated from the basic region, but was still capable of dimerization. file:human/TFAP2A/TFAP2A-uniprot.txt Binds DNA as a dimer. Can form homodimers or heterodimers with other AP-2 family members. |
| GO:0043066 negative regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT inference of negative regulation of apoptosis for the AP-2alpha clade. Reason: Loss of Tfap2a increases apoptosis of cranial crest and neural fold cells in mouse and zebrafish, so AP-2alpha supports progenitor survival. Real but secondary to its fate-specification role, and pro-apoptotic effects are reported in some tumour cells. Supporting Evidence: PMID:8622765 AP-2(-/-) mice died perinatally with cranio-abdominoschisis and severe dismorphogenesis of the face, skull, sensory organs and cranial ganglia. |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:20066163 AP-2alpha Inhibits c-MYC Induced Oxidative Stress and Apopto... | KEEP AS NON CORE | Summary: Co-expressing AP-2alpha suppresses c-MYC-induced apoptosis in HaCaT keratinocytes. Reason: Context-dependent, and mediated through repression of c-myc. Kept as non-core. Supporting Evidence: PMID:20066163 over expression of c-MYC was associated with accumulation of reactive oxygen species (ROS) and apoptosis in human keratinocytes, both of which were significantly inhibited by co-expression of AP-2 |
| GO:0043525 positive regulation of neuron apoptotic process | IDA PMID:20607706 AP2 transcription factor induces apoptosis in retinoblastoma... | MARK AS OVER ANNOTATED | Summary: Forced TFAP2A expression induces apoptosis in retinoblastoma cell lines. Reason: Retinoblastoma lines are tumour cells, not neurons, and the result comes from overexpression in cells that normally lack the protein. "Neuron apoptotic process" overstates both the cell type and the physiological role. It also conflicts with the anti-apoptotic role seen in development. Supporting Evidence: PMID:20607706 Transfection of TFAP2A and TFAP2B expression constructs into retinoblastoma cells induces apoptosis and inhibits proliferation. |
| GO:0043565 sequence-specific DNA binding | IDA PMID:12586840 Physical and functional interactions among AP-2 transcriptio... | ACCEPT | Summary: TFAP2A binds AP-2 consensus DNA (Braganca et al. 2003; UniProt DNA-binding evidence). Reason: Core activity. Supporting Evidence: file:human/TFAP2A/TFAP2A-uniprot.txt AP-2 factors bind to the consensus sequence 5'-GCCNNNGGC-3' and activate genes involved in a large spectrum of important biological functions including proper eye, face, body wall, limb and neural tube development. |
| GO:0043565 sequence-specific DNA binding | IMP PMID:1998122 Characterization of a dimerization motif in AP-2 and its fun... | ACCEPT | Summary: Mutating the dimerization or basic region abolishes sequence-specific DNA binding. Reason: Core activity, mapped to domains. Supporting Evidence: PMID:1998122 AP-2 required a dimerization domain and an adjacent region of net basic charge to achieve a sequence-specific protein:DNA interaction. |
| GO:0045595 regulation of cell differentiation | IDA PMID:20607706 AP2 transcription factor induces apoptosis in retinoblastoma... | MARK AS OVER ANNOTATED | Summary: The authors propose that loss of TFAP2A/B blocks amacrine/horizontal differentiation and contributes to retinoblastoma. Reason: The cached abstract presents this as a hypothesis, not an experimental finding. Regulation of cell differentiation is very broad. AP-2alpha does control differentiation in several lineages (crest, epidermis), but this row overstates what the paper shows. Supporting Evidence: PMID:20607706 We propose that inability to differentiate along the amacrine/horizontal cell lineages may underlie retinoblastoma tumor formation. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:20607706 AP2 transcription factor induces apoptosis in retinoblastoma... | ACCEPT | Summary: Repression row from the retinoblastoma study. The repressor activity of AP-2alpha is well supported elsewhere. Reason: The cached abstract does not show the repression data, but repression by AP-2alpha is well established and the curator read the full text. Accepted by deference. It is the broad parent of GO:0000122. Supporting Evidence: PMID:9520389 Consistent with a repressive role of AP-2alpha/CUP, an AP-2alpha1 expression vector, cotransfected with a C/EBPalpha promoter-reporter construct into 3T3-L1 adipocytes, inhibited reporter gene transcription. |
| GO:0045892 negative regulation of DNA-templated transcription | IMP PMID:31146003 Androgen upregulates NR4A1 via the TFAP2A and ETS signaling ... | ACCEPT | Summary: TFAP2A represses NR4A1. Reason: Consistent with the repressor activity. Supporting Evidence: PMID:31146003 TFAP2A downregulated NR4A1 expression |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:12586840 Physical and functional interactions among AP-2 transcriptio... | ACCEPT | Summary: CITED2/p300-dependent transcriptional activation by TFAP2A. Reason: Correct. GO:0045944 is the more specific term. Supporting Evidence: PMID:12586840 interactions among TFAP2A, CITED2, and p300/CBP are necessary for TFAP2A-mediated transcriptional activation |
| GO:0045893 positive regulation of DNA-templated transcription | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse Tfap2a. Reason: Correct, general. Supporting Evidence: file:human/TFAP2A/TFAP2A-uniprot.txt AP-2 factors bind to the consensus sequence 5'-GCCNNNGGC-3' and activate genes involved in a large spectrum of important biological functions including proper eye, face, body wall, limb and neural tube development. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of positive regulation of Pol II transcription for the AP-2 family node, from fly, worm and vertebrate donors. Reason: Activation is the ancestral activity of the family (Drosophila TFAP-2 and C. elegans paralogs are among the donors). Core. Supporting Evidence: PMID:12586840 interactions among TFAP2A, CITED2, and p300/CBP are necessary for TFAP2A-mediated transcriptional activation PMID:7555706 AP-2 beta binds specifically to a series of well-characterized AP-2 binding sites, consensus to the sequence G/CCCN3GGC, and transactivates transcription from a reporter plasmid under the control of an AP-2-dependent promoter. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:11278550 A family of AP-2 proteins down-regulate manganese superoxide... | ACCEPT | Summary: AP-2alpha activates transcription of an AP-2 site-containing Pol II promoter. Reason: Core biological consequence of its activator activity. Supporting Evidence: PMID:11278550 another AP-2-responsive gene, c-erbB-3, was transactivated by AP-2 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:20808827 Expression of human frataxin is regulated by transcription f... | ACCEPT | Summary: AP-2alpha activates transcription of an AP-2 site-containing Pol II promoter. Reason: Core biological consequence of its activator activity. Supporting Evidence: PMID:20808827 We found that the transcription factors SRF and TFAP2 bind directly to FXN promoter sequences. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:7555706 Cloning and characterization of a second AP-2 transcription ... | ACCEPT | Summary: AP-2alpha activates transcription of an AP-2 site-containing Pol II promoter. Reason: Core biological consequence of its activator activity. Supporting Evidence: PMID:7555706 AP-2 beta binds specifically to a series of well-characterized AP-2 binding sites, consensus to the sequence G/CCCN3GGC, and transactivates transcription from a reporter plasmid under the control of an AP-2-dependent promoter. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:7559606 Transcription factor AP-2 regulates human insulin-like growt... | ACCEPT | Summary: AP-2alpha activates transcription of an AP-2 site-containing Pol II promoter. Reason: Core biological consequence of its activator activity. Supporting Evidence: PMID:7559606 Cotransfection with AP-2 significantly elevated IGFBP-5 promoter activity. |
| GO:0048701 embryonic cranial skeleton morphogenesis | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse Tfap2a IMP: nulls have severe dysmorphogenesis of face and skull. Reason: The craniofacial skeleton is the main crest output of AP-2alpha in mouse, and human BOFS (cleft lip/palate, facial dysmorphism) shows the same function. This is the conserved downstream developmental role. Supporting Evidence: PMID:8622765 AP-2(-/-) mice died perinatally with cranio-abdominoschisis and severe dismorphogenesis of the face, skull, sensory organs and cranial ganglia. PMID:18423521 We conclude BOFS is caused by mutations involving TFAP2A. |
| GO:0060021 roof of mouth development | IMP PMID:21204207 Genotype-phenotype analysis of the branchio-oculo-facial syn... | KEEP AS NON CORE | Summary: Cleft lip/palate is the most frequent BOFS feature. Crest-specific Tfap2a deletion causes cleft secondary palate in mouse. Reason: Real developmental role that follows from the crest function. Non-core relative to crest/border specification. Supporting Evidence: PMID:21204207 are evidence for BOFS as a neurocristopathy PMID:14975722 Neural crest-specific disruption of tcfap2a results in frequent perinatal lethality associated with neural tube closure defects and cleft secondary palate. |
| GO:0060349 bone morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tfap2a IMP (deformed or absent bones). Reason: Downstream skeletal output. Non-core. Supporting Evidence: PMID:8622766 Skeletal defects occur in the head and trunk region, where many bones are deformed or absent. |
| GO:0061029 eyelid development in camera-type eye | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tfap2a IMP (eyelid defects). Reason: Surface-ectoderm-derived structure, consistent with the ancestral ectodermal role. Non-core. Supporting Evidence: PMID:21204207 Major features include cutaneous and ocular abnormalities, characteristic facies, renal, ectodermal, and temporal bone anomalies. |
| GO:0070172 positive regulation of tooth mineralization | IDA PMID:19578371 BCOR regulates mesenchymal stem cell function by epigenetic ... | KEEP AS NON CORE | Summary: AP-2alpha promotes osteo/dentinogenic mineralization of dental apical papilla MSCs, explaining radiculomegaly in BCOR-mutant OFCD. Reason: Gain- and loss-of-function in human dental MSCs. Real but tissue-specific. Non-core. Supporting Evidence: PMID:19578371 Gain- and loss-of-function assays suggest that AP-2alpha is a key factor that mediates the increased osteo-dentinogenic capacity of MSCs. |
| GO:0071281 cellular response to iron ion | IDA PMID:20808827 Expression of human frataxin is regulated by transcription f... | MARK AS OVER ANNOTATED | Summary: Iron depletion (DFO) lowers TFAP2 mRNA levels in HEK293 and SH-SY5Y cells. Reason: This is a change in TFAP2 transcript level after an iron chelator, i.e. expression evidence. AP-2alpha has no known role in sensing or responding to iron, and the authors only suggest the change "might" affect frataxin. Supporting Evidence: PMID:20808827 TFAP2 mRNA levels were significantly decreased by iron depletion in both HEK293 and SH SY5Y cells |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: Methyl-SELEX profiling of human TF specificities, including TFAP2 family members binding their GCC(N3)GGC motifs. Reason: Sequence-specific dsDNA binding is the core activity. Supporting Evidence: PMID:28473536 Impact of cytosine methylation on DNA binding specificities of human transcription factors |
| GO:2000378 negative regulation of reactive oxygen species metabolic process | IDA PMID:20066163 AP-2alpha Inhibits c-MYC Induced Oxidative Stress and Apopto... | MARK AS OVER ANNOTATED | Summary: AP-2alpha co-expression reduces c-MYC-induced ROS accumulation in keratinocytes. Reason: The effect is indirect: AP-2alpha represses c-myc and so blunts MYC-driven ROS. It does not regulate ROS metabolism itself. The repression of MYC is already captured. Supporting Evidence: PMID:20066163 over expression of c-MYC was associated with accumulation of reactive oxygen species (ROS) and apoptosis in human keratinocytes, both of which were significantly inhibited by co-expression of AP-2 |
| NTR neural plate border formation | ISS PMID:21169220 Reiterative AP2a activity controls sequential steps in the n... | NEW | Summary: AP-2alpha acts at two steps of crest formation. At the neural plate border it is the earliest border specifier: it is induced by Wnt, activates pax3, and alone can impose a border-like pattern on neuralized ectoderm. Within the crest it then acts as a crest specifier, sufficient to induce Slug/Sox9, and as a pioneer factor that opens border (with TFAP2C) and then crest (with TFAP2B) enhancers. Reason: Human TFAP2A has no neural crest process term. Frog, chick, zebrafish and mouse data show that AP-2alpha is a DNA-binding TF that acts first at the neural plate border: induced by Wnt, it activates pax3 and alone imposes a border-like pattern on neuralized ectoderm; with TFAP2C it opens border enhancers. That border-initiating step is captured by the proposed term 'neural plate border formation' (NTR), which replaces GO:0014029 (proposed for obsoletion: its text describes the border region but it is placed under epithelial to mesenchymal transition; projects/NEURAL_CREST_FORMATION_OBSOLETION.md). The later crest-specifier role is a separate NEW row at GO:0014036. ISS because the experiments are on vertebrate orthologs. Supporting Evidence: PMID:21169220 As the earliest known NB specifier, AP2a mediates Wnt signals to initiate the NB and activate pax3; as a NC specifier, AP2a regulates further NC development independent of and downstream of NB patterning. PMID:21169220 AP2a initiates NB patterning and is sufficient to elicit a NB-like pattern in neuralized ectoderm. PMID:12511599 Ectopic expression of AP2alpha is sufficient to activate high-level expression of NC-specific genes such as Slug and Sox9 PMID:12511599 Loss-of-function experiments with antisense AP2alpha morpholino oligonucleotides result in severe reduction in the NC territory. PMID:31848212 According to this model, TFAP2A/C heterodimers mediate neural plate border induction, whereas TFAP2A/B heterodimers promote neural crest specification. PMID:17258188 simultaneous inhibition of tfap2a and tfap2c utterly prevents neural crest induction, supporting a conserved role for Tfap2-type activity in neural crest induction PMID:21204207 are evidence for BOFS as a neurocristopathy |
| GO:0014036 neural crest cell fate specification | ISS PMID:12511599 Induction of neural crest in Xenopus by transcription factor... | NEW | Summary: After initiating the border, AP-2alpha acts within the prospective crest as a crest specifier, sufficient to activate Slug and Sox9 and, with TFAP2B, occupying crest specification enhancers. Reason: Crest-intrinsic role, distinct from the border role. In frog, AP2alpha gain of function activates Slug and Sox9 and its knockdown reduces the crest territory; it regulates crest development independently of and downstream of border patterning. In chick, TFAP2A/B heterodimers promote crest specification. Comparator (QuickGO, 2026-10-05): zebrafish tfap2a carries GO:0014036 by IMP (PMID:14534133). ISS because the experiments are on vertebrate orthologs. Supporting Evidence: PMID:21169220 As the earliest known NB specifier, AP2a mediates Wnt signals to initiate the NB and activate pax3; as a NC specifier, AP2a regulates further NC development independent of and downstream of NB patterning. PMID:12511599 Ectopic expression of AP2alpha is sufficient to activate high-level expression of NC-specific genes such as Slug and Sox9 PMID:31848212 According to this model, TFAP2A/C heterodimers mediate neural plate border induction, whereas TFAP2A/B heterodimers promote neural crest specification. |
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Download this section (compressed HTML)Q: GO has no neural plate border formation/specification term. AP-2alpha is the clearest case for one: it initiates the border (upstream of pax3) before crest specification. The project proposes one (neural plate border formation), with AP-2alpha, Pax3/7, Zic1, Msx1 and AP-2gamma under it, and the obsoletion of GO:0014029. Is AP-2alpha the right exemplar to cite in the GO request?
Q: AP-2alpha spans both the border and the specifier layers and now carries both the proposed border term and GO:0014036 (two NEW rows), as zebrafish tfap2a carries GO:0014036 by IMP. Once GO:0014029 is obsoleted these two are no longer ancestor and descendant. Do curators accept a gene carrying both layers?
Q: Pioneer factor activity (opening closed chromatin at border and crest enhancers) has no GO molecular function term. Is a term needed, or is chromatin binding plus transcription activator activity enough?
Q: Epidermis/non-neural ectoderm development is the ancestral AP-2 role (amphioxus) but is not annotated to human TFAP2A, possibly because of TFAP2C redundancy in mammals. Should a TFAP2A epidermis development annotation rest on combined Tfap2a/Tfap2c mouse epidermal knockouts?
Q: Several UniProt-cited interactions (MYO6; RALBP1/EPN1/NUMB) may involve the clathrin adaptor complex AP-2 rather than transcription factor AP-2alpha. Should these be audited across TFAP2A records?
Experiment: Test whether amphioxus AP-2, expressed in Xenopus neuralized ectoderm, can impose a border-like pattern (pax3 activation) and induce snail2/sox9 as Xenopus AP2a does. This separates protein-level from cis-regulatory evolution of the AP-2 border role.
Experiment: Profile TFAP2A/TFAP2C and TFAP2A/TFAP2B heterodimer occupancy (CUT&RUN) in human pluripotent stem cell-derived neural plate border and cranial neural crest, to test whether the chick partner switch holds in human.
Experiment: Map AP-2 binding at the lamprey and amphioxus orthologous enhancers of pax3/7, msx and soxE, to ask whether border/crest AP-2 inputs are vertebrate-specific cis-regulatory additions.
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