EYA1 is a transcriptional coactivator and an aspartate-based protein tyrosine phosphatase of the haloacid dehalogenase superfamily. An N-terminal activation region is coupled to the conserved C-terminal Eya domain, which mediates phosphatase chemistry and SIX-family interactions. SIX homeodomain partners supply sequence-specific DNA recognition and promote EYA1 nuclear accumulation; human SIX1 association and conserved Eya1βSix1/Six2/Six4/Six5 cooperation connect this partnership to developmental transcription. EYA1 occurs in both nuclear and cytoplasmic compartments and contributes to formation of the inner ear, kidney and branchial structures, with conserved roles in craniofacial and hypaxial-muscle development. Pathogenic EYA1 variants cause branchio-oto-renal, branchio-otic and otofaciocervical syndromes. In the DNA-damage response, EYA1 promotes removal of the Tyr142 phosphate from histone H2AX, altering the histone state toward repair-factor engagement and cell survival. Endogenous human EYA1 is SUMO-modified; in mouse Eya1 reporter systems, SUMOylation restrains coactivation and Akt-dependent phosphorylation enhances activity in part by reducing SUMOylation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004722 protein serine/threonine phosphatase activity | EXP PMID:19234442 Tyrosine dephosphorylation of H2AX modulates apoptosis and s... | UNDECIDED | Summary: EYA1-associated threonine phosphatase activity is positive, but intrinsic human EYA1 catalysis is unresolved. Reason: The inherited negative excerpts describe the bacterial Eya3 C-terminal fragment tested against pSer139-H2AX in Figure 4F of PMID:19234442; they do not demonstrate inactivity of full-length EYA1. FLAG-EYA1 preparations dephosphorylate pThr58-Myc and endogenous human EYA1 perturbation changes that phosphorylation state (PMID:27795300). Human EYA1 also co-isolates with PP2A-C and pThr activity in PMID:29535359, although the decisive PP2A-dependence experiments use mouse Eya3. Conversely, PMID:33472197 reports multistep-purified full-length Eya1 activity on aPKC-pThr410, a catalytic-mutant comparison and no detectable B55alpha in the active preparation; Figure S6 includes a positive insect-cell lysate control. Its S2/Sf9 and D327A/D328A wording and unspecified construct accession leave exact product attribution unresolved. These competing preparation and catalyst-assignment results warrant uncertainty about intrinsic human EYA1 Ser/Thr catalysis, not an activity-negative conclusion or automatic transfer of the Eya3 mechanism. Supporting Evidence: PMID:19234442 showed minimal activity toward a serine phosphorylated tail peptide PMID:19234442 subsequent data has indicated that, in-vivo, Eya primarily functions as a tyrosine phosphatase |
| GO:0004722 protein serine/threonine phosphatase activity | IEA GO_REF:0000120 | UNDECIDED | Summary: The mapped serine/threonine activity has unresolved catalyst attribution. Reason: UniProt maps EC 3.1.3.16 and Rhea 20629/47004, but the inherited low-pSer H2AX comparison concerns a recombinant Eya3 fragment, not a general negative test of full-length EYA1. PMID:27795300 reports pThr58-Myc dephosphorylation by FLAG-EYA1 affinity preparations and EYA1-dependent cellular effects. PMID:29535359 directly detects PP2A-C associated with human EYA1 preparations; its decisive PP2A mechanism experiments principally concern mouse Eya3 and cannot simply be transferred to EYA1. Conversely, PMID:33472197 reports Eya1-dependent aPKC-pT410 dephosphorylation with no detectable B55alpha in an active insect-cell preparation and positive tissue/Sf9 controls. Exact native-human construct assignment and intrinsic versus associated catalysis remain unresolved across these preparations. Retain uncertainty, not a blanket activity-negative or PP2A-only conclusion. The inherited quotations are preserved with their narrower Eya3 substrate/domain context. Supporting Evidence: PMID:19234442 showed minimal activity toward a serine phosphorylated tail peptide PMID:19234442 subsequent data has indicated that, in-vivo, Eya primarily functions as a tyrosine phosphatase |
| GO:0004725 protein tyrosine phosphatase activity | EXP PMID:19234442 Tyrosine dephosphorylation of H2AX modulates apoptosis and s... | ACCEPT | Summary: EYA1 exhibits protein tyrosine phosphatase activity toward phosphorylated H2AX. Reason: Figure 4B of PMID:19234442 tests affinity-isolated HA-Eya1 from irradiated 293T cells against phosphorylated bovine histones: wild type removes the H2AX phosphotyrosine signal while Eya1 D323A has little effect. Endogenous human EYA1 knockdown also increases H2AX tyrosine phosphorylation. These EYA1-specific results support the general tyrosine-phosphatase activity; the bacterial peptide-specificity experiment is Eya3 and is not reassigned to EYA1. The inherited PMID:16797546 support is retained as prior context, not a newly inspected original in this lane. No equivalence of the three natural human products is established. Supporting Evidence: PMID:19234442 Wild-type Eya effectively removed the phosphotyrosine mark from H2AX, while the phosphatase-inactive mutant Eya proteins (Eya1 D323A or Eya3 D246A) had little or no effect PMID:16797546 BOR-associated mutations lead to a loss of phosphatase activity in Eya1 proteins |
| GO:0004725 protein tyrosine phosphatase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The target inherits a conserved EYA tyrosine-phosphatase activity. Reason: The actual PTHR10190 target leaf PTN002468887 lies below the positive IBD at PTN000022641; its ungapped 592-residue sequence exactly matches displayed human Q99502. No target-path NOT was found. The self Q99502 evidence is legitimate experimental grounding. Independently, PMID:19234442 measures H2AX phosphotyrosine removal by immunopurified Eya1, with catalytic-mutant and human knockdown/mouse-rescue controls; PMID:14628052 assays bacterially expressed mouse Eya1 EYA-domain residues 319β591. These distinct preparations support the conserved activity without equating all natural human products. Supporting Evidence: PMID:14628053 propose a function for it as a non-thiol-based protein tyrosine phosphatase PMID:19234442 Wild-type Eya effectively removed the phosphotyrosine mark from H2AX, while the phosphatase-inactive mutant Eya proteins (Eya1 D323A or Eya3 D246A) had little or no effect |
| GO:0004725 protein tyrosine phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The InterPro and enzyme mappings fit EYA1 tyrosine-phosphatase chemistry. Reason: Current InterPro IPR028472 maps Q99502 residues 45β592 to the EYA family and explicitly carries GO:0004725; the EYA-domain models cover the C-terminal region. The actual UniProt catalytic statement and EC 3.1.3.48 record describe protein-phosphotyrosine hydrolysis. Eya1 H2AX-pTyr dephosphorylation and catalytic-mutant controls in PMID:19234442, together with the purified mouse Eya1-domain assay in PMID:14628052, corroborate this mapping. Direct Rhea endpoint access failed, so its identifiers are traced through the captured UniProt record rather than claimed independently read. Supporting Evidence: PMID:19234442 Wild-type Eya effectively removed the phosphotyrosine mark from H2AX, while the phosphatase-inactive mutant Eya proteins (Eya1 D323A or Eya3 D246A) had little or no effect |
| GO:0005515 protein binding | IPI PMID:15141091 SIX1 mutations cause branchio-oto-renal syndrome by disrupti... | MODIFY | Summary: The reported EYA1βSIX1 interaction is binding to a DNA-binding transcription factor. Reason: PMID:15141091 tests mouse Six1 with Eya1-domain prey in yeast two-hybrid assays and coexpressed Eya1/Six1 in a MEF3 reporter assay; the inspected Methods do not identify the Eya1 insert accession or species. SIX1 is a sequence-specific DNA-binding transcription factor, verified by the paper's MEF3 binding assays and current human Q15475 identity. Independent human EYA1βSIX1 HuRI records support conservation of the pair. GO:0140297 identifies the demonstrated partner class and does not require assuming that every binding event activates transcription. The inherited quotation remains contextual to the tested constructs; the human-cell host alone is not proof of a human EYA1 insert. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:15141091 We demonstrate that all three mutations are crucial for Eya1-Six1 interaction |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: BioPlex 2.0 recovers the human EYA1βSIX1 association, supporting transcription-factor binding. Reason: The actual BioPlex 2.0 network lists Q99502 EYA1 with Q15475 SIX1, and the directed table contains both bait orientations (records 17120β17121). The study uses C-terminal HA-FLAG ORFs and affinity-purification mass spectrometry in HEK293T cells, so this is a cellular association rather than a purified binary assay. SIX1's independently established DNA-binding transcription-factor identity supports GO:0140297. The supporting older excerpts provide functional context; the PMID:19497856 reporter and purified binding experiments use EYA2, whereas its EYA1 experiment is localization. No current natural-product sequence equivalence or transcriptional effect is inferred from the screen. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:15141091 We demonstrate that all three mutations are crucial for Eya1-Six1 interaction PMID:19497856 As a complex, the SIX and EYA proteins are believed to form a bipartite transcription factor where SIX confers DNA binding and EYA confers transactivation activity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: HuRI reports human SIX1 binding to the EYA1 construct labeled Q99502-1. Reason: The original HuRI PSI records pair SIX1 Q15475/ORF 5442 with EYA1 Q99502-1/ORF 56381 in three method records: validated two-hybrid, array and prey-pooling. The proteins are human and the assay host is yeast, with N-terminal GAL4 fusions and partial DNA-sequence identification recorded. Binding to the independently established DNA-binding transcription factor SIX1 supports GO:0140297 without requiring a new coactivator inference from Y2H alone. The study-wide orthogonal validation is not asserted for this exact pair, and the historical construct label is not a verified sequence match to every current EYA1 product. Inherited older excerpts are contextual; the 2009 purified binding/reporter results concern EYA2. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:15141091 We demonstrate that all three mutations are crucial for Eya1-Six1 interaction PMID:19497856 As a complex, the SIX and EYA proteins are believed to form a bipartite transcription factor where SIX confers DNA binding and EYA confers transactivation activity. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: BioPlex 3.0 recovers human EYA1βSIX1 association in its HEK293T network. Reason: The actual HEK293T network contains Q99502βQ15475 and both directed bait orientations (42548β42549). C-terminal FLAG-HA affinity purification and mass spectrometry establish association in cellular assemblies, not purified binary binding or transcriptional activation by that preparation. SIX1's independently established DNA-binding transcription-factor identity supports GO:0140297. No EYA1 record was located in the inspected HCT116 files; this is a dataset observation, not evidence of biological absence. The construct label and shared-peptide identification do not resolve all three natural products. The inherited 2009 general bipartite-factor excerpt is contextual rather than an EYA1-specific reporter result. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:15141091 We demonstrate that all three mutations are crucial for Eya1-Six1 interaction PMID:19497856 As a complex, the SIX and EYA proteins are believed to form a bipartite transcription factor where SIX confers DNA binding and EYA confers transactivation activity. |
| GO:0005634 nucleus | EXP PMID:12500905 Six and Eya expression during human somitogenesis and MyoD g... | ACCEPT | Summary: Nuclear EYA1 is independently established, while the precise 2003 somitogenesis assay remains uninspected. Reason: The verified PMID:12500905 abstract reports predominantly cytoplasmic Eya1/Eya2 in human embryonic myogenin-positive cells; its full Methods and Results could not be recovered. This does not refute the curator's nuclear assertion. Independent original evidence shows HA-Eya1 at nuclear gamma-H2AX foci after irradiation (PMID:19234442) and SIX1-dependent EYA1 nuclear fractionation in MCF7 cells (PMID:19497856). Retain the clearly supported gene-level nuclear location while distinguishing those experiments from verification of the inaccessible original assay. The inherited 1999 translocation support concerns mouse Eya1/Six constructs in COS7 cells. Supporting Evidence: PMID:12500905 Eya1 and Eya2 proteins, potential Six cofactors, were also detected in myogenin positive cells, but their accumulation was delayed and was mainly cytoplasmic. PMID:10490620 Coexpression of Six2, Six4, or Six5 induced nuclear translocation of Eya1, Eya2, and Eya3, which were otherwise distributed in the cytoplasm. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear localization is supported by target ancestry and independent experiments. Reason: Human Q99502 descends from the positive nucleus IBD at PTN000022641, with exact displayed-sequence MSA placement and no target-path loss assertion. PMID:19234442 reports tagged Eya1 at nuclear damage foci in 293T cells. PMID:10490620 separately measures SIX-dependent nuclear redistribution of mouse Eya1 in COS7 cells; that is not a native-human product assay. Current human HPA images also support nuclear localization. The broad nuclear assertion remains valid alongside the more specific nucleoplasm contexts. Supporting Evidence: PMID:10490620 Coexpression of Six2, Six4, or Six5 induced nuclear translocation of Eya1, Eya2, and Eya3, which were otherwise distributed in the cytoplasm. PMID:19234442 immunostaining of transfected HA-tagged Eya1 or Eya3 protein in 293T embryonic kidney cells revealed a clear co-localization of Eya with Ξ³H2AX foci after treatment with IR |
| GO:0005634 nucleus | IDA PMID:19234442 Tyrosine dephosphorylation of H2AX modulates apoptosis and s... | ACCEPT | Summary: HA-Eya1 colocalizes with nuclear gamma-H2AX foci after irradiation. Reason: The actual Figure 2D images and caption in PMID:19234442 show tagged Eya1 in 293T cells one hour after 5 Gy irradiation, with gamma-H2AX and nuclear staining. This directly supports the nuclear context. The I-PpoI chromatin-immunoprecipitation experiment elsewhere in the paper is Eya3 and is not used as EYA1-specific evidence. The tag/construct experiment does not establish identical localization of each natural human product. Supporting Evidence: PMID:19234442 immunostaining of transfected HA-tagged Eya1 or Eya3 protein in 293T embryonic kidney cells revealed a clear co-localization of Eya with Ξ³H2AX foci after treatment with IR |
| GO:0005634 nucleus | IDA PMID:19497856 Biochemical and functional characterization of six SIX1 Bran... | ACCEPT | Summary: Full-length FLAG-EYA1 enters the nuclear fraction when coexpressed with SIX1. Reason: PMID:19497856 Figure 5B, its caption and the cell-fractionation Methods distinguish cytoplasmic EYA1 alone from nuclear EYA1 with wild-type SIX1 or the tested mutants other than V17E, with actin/HDAC1 fraction controls. The EYA1 construct is described as full length in pCMVTag2; an accession was not supplied in the inspected Methods. The inherited excerpt states the cytoplasmic comparison, so nuclear support comes from the complete experiment rather than that fragment alone. The paper's EYA2-specific purified binding, stoichiometry and reporter assays are not attributed to EYA1. Supporting Evidence: PMID:19497856 we observed that in the absence of SIX1, EYA1 was localized in the cytoplasm |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt nuclear-location mapping is independently corroborated. Reason: The actual SL-0191 record maps nucleus to GO:0005634, and current Q99502 contains that location statement. Tagged Eya1 damage-foci localization in PMID:19234442, the EYA1 fractionation experiment in PMID:19497856, and human HPA nucleoplasmic staining support nuclear localization. In the latter paper the inspected FLAG-Eya1 construct is not accession-resolved; human host cells alone do not establish which natural EYA1 product was tested. Retain nucleus without claiming exclusively nuclear distribution. Supporting Evidence: PMID:19234442 immunostaining of transfected HA-tagged Eya1 or Eya3 protein in 293T embryonic kidney cells revealed a clear co-localization of Eya with Ξ³H2AX foci after treatment with IR |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Human HPA immunofluorescence supports nucleoplasmic EYA1 signal. Reason: The actual HPA page assigns supported nucleoplasm and nuclear-body localization. HPA028917 images inspected in human Rh30 and U2OS show diffuse/granular nuclear signal with brighter puncta; the selected RPE1 image is weaker. The 146-residue antigen is shared by the three source products, so these images do not resolve their individual distributions. The inherited mouse SIX-dependent localization quotation is corroborating context, not the HPA experiment itself. Supporting Evidence: PMID:10490620 Coexpression of Six2, Six4, or Six5 induced nuclear translocation of Eya1, Eya2, and Eya3, which were otherwise distributed in the cytoplasm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5683964 | ACCEPT | Summary: The actual human Reactome EYA1 participant has its own nucleoplasmic compartment. Reason: R-HSA-5683964 input 5683966 hasMember 5683625, whose reference entity is Q99502, species is human, coordinates are 1β592 and own compartment is GO:0005654. The output candidate route 5683980 to 5683951 likewise identifies phosphorylated EYA1 in nucleoplasm. EYA1 is an ATM substrate in this event; the event does not assign kinase catalysis to EYA1. This modeled localization agrees with independent human imaging and does not establish the location of every shorter product. Supporting Evidence: Reactome:R-HSA-5683964 EYA tyrosine protein phosphatases (EYA1, EYA2 and EYA3) play an important role in repair of DNA double-strand breaks (DSBs) |
| GO:0005737 cytoplasm | EXP PMID:12500905 Six and Eya expression during human somitogenesis and MyoD g... | KEEP AS NON CORE | Summary: Cytoplasmic EYA1 is a supported cellular context. Reason: The verified PMID:12500905 abstract positively reports mainly cytoplasmic Eya1 in human embryonic myogenin-positive cells, although its complete Methods and Results remain unavailable. Independent PMID:19497856 fractionation shows EYA1 in the cytoplasm without coexpressed SIX1. Retain this location as contextual biology; neither source establishes that it is merely an inactive storage pool or that all EYA1 functions occur in the nucleus. Neither assay resolves all three natural products. Supporting Evidence: PMID:12500905 Eya1 and Eya2 proteins, potential Six cofactors, were also detected in myogenin positive cells, but their accumulation was delayed and was mainly cytoplasmic. |
| GO:0005737 cytoplasm | IDA PMID:19497856 Biochemical and functional characterization of six SIX1 Bran... | KEEP AS NON CORE | Summary: EYA1 is cytoplasmic in the tested MCF7 expression condition without SIX1. Reason: The actual PMID:19497856 fractionation experiment and Figure 5B caption support this positive location, with a shift to nuclear EYA1 upon coexpressing compatible SIX1. The result describes a tested condition, not a universally inactive pool or an exclusive compartment. The full-length FLAG-EYA1 construct is not accession-mapped in the inspected Methods, and the EYA2 purified-protein experiments do not resolve EYA1 product behavior. Supporting Evidence: PMID:19497856 we observed that in the absence of SIX1, EYA1 was localized in the cytoplasm |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cytoplasmic EYA1 localization is supported, with context-dependent redistribution. Reason: SL-0086 and the actual UniProt record support cytoplasm. PMID:19497856 Figure 5B includes a full-length FLAG-EYA1 fractionation experiment in MCF7 cells, with redistribution toward nucleus on SIX1 coexpression; its inspected insert is not accession-resolved. PMID:10490620 independently uses mouse Eya1 in COS7 cells. These positive observations justify retaining the cytoplasmic context. They do not establish that the cytoplasmic population is merely an inactive storage pool or that every EYA1 function is nuclear. Supporting Evidence: PMID:10490620 Coexpression of Six2, Six4, or Six5 induced nuclear translocation of Eya1, Eya2, and Eya3, which were otherwise distributed in the cytoplasm. |
| GO:0006302 double-strand break repair | IMP PMID:19234442 Tyrosine dephosphorylation of H2AX modulates apoptosis and s... | MODIFY | Summary: H2AX tyrosine dephosphorylation positively regulates the response to double-strand breaks. Reason: PMID:19234442 places tagged Eya1 at irradiated nuclear foci and shows EYA1-dependent H2AX tyrosine dephosphorylation after ionizing radiation. The histone-state change supports repair-factor engagement in the double-strand-break response, so GO:2000781 preserves that specificity while identifying EYA1βs regulatory step rather than DNA strand-restoration chemistry. It is a regulatory refinement, not an is_a descendant of GO:0006302. An EYA1-specific completed-break-repair kinetic or ligation assay is not established. Detailed I-PpoI ChIP, S219 mutation, MDC1 knockdown and the plotted rescue concern Eya3; the separately reported murine Eya1 rescue supplement remains uninspected. Proposed replacements: positive regulation of double-strand break repair Supporting Evidence: PMID:19234442 a protein tyrosine phosphatase, EYA, is involved in promoting efficient DNA repair rather than apoptosis in response to genotoxic stress PMID:19234442 Eya siRNA-treated cells showed significantly increasedΞ³H2AX tyrosine phosphorylation levels |
| GO:0006338 chromatin remodeling | IEA GO_REF:0000108 | ACCEPT | Summary: H2AX tyrosine dephosphorylation supports the inherited chromatin-remodeling process. Reason: The current typed ontology path is GO:0140793 is_a GO:0140789 is_a GO:0140993 part_of GO:0006338. This is an activity-to-process connection through part_of, not is_a subsumption of a molecular function by a biological process. The latter includes chromatin reorganization through histone-state changes; it is not restricted to ATP-driven nucleosome sliding. PMID:19234442 demonstrates Eya1-dependent H2AX phosphotyrosine removal, which changes a histone mark that affects repair-factor association. This is a molecular step in chromatin regulation, not merely a downstream phenotype. The detailed repair-factor pull-down and several recruitment experiments concern Eya3 or peptide/nuclear-extract systems, and do not establish an EYA1 ATP-dependent remodeling motor. Supporting Evidence: PMID:19234442 Wild-type Eya effectively removed the phosphotyrosine mark from H2AX, while the phosphatase-inactive mutant Eya proteins (Eya1 D323A or Eya3 D246A) had little or no effect |
| GO:0007605 sensory perception of sound | TAS PMID:9020840 A human homologue of the Drosophila eyes absent gene underli... | UNDECIDED | Summary: The source-specific evidence for participation in sensory perception of sound remains unresolved. Reason: The verified PMID:9020840 abstract identifies human BOR-associated EYA1 and describes murine ear/kidney expression, but the original Methods and Results were not recovered. The inherited PMID:10471511 excerpt concerns ear development, and that complete original also remains unavailable. The accessible sources therefore do not resolve the basis of the curatorβs precise sensory-perception assertion. Retain UNDECIDED pending the operative evidence, without asserting either a developmental-only role or absence of a later auditory function. Supporting Evidence: PMID:9020840 suggests a role in the development of all components of the inner ear, from the emergence of the otic placode PMID:10471511 Inner ear development in Eya1 homozygotes arrests at the otic vesicle stage and all components of the inner ear and specific cranial sensory ganglia fail to form. |
| GO:0009653 anatomical structure morphogenesis | TAS PMID:9020840 A human homologue of the Drosophila eyes absent gene underli... | MODIFY | Summary: Refine broad morphogenesis to the independently supported inner-ear morphogenesis role. Reason: GO:0042472 inner ear morphogenesis is a current is_a descendant of GO:0009653 and is independently accepted for EYA1 from the inspected PTHR10190 tree and GO:0042472 IBD at PTN002565172, ancestral to the exact human Q99502 leaf PTN002468887. GO_REF:0000033 identifies this inference method; the inspected tree, alignment and IBD records supply the target-specific evidence. Mouse Eya1 developmental findings and the conserved Eya1βSix transcriptional mechanism support that specific developmental role. The original PMID:9020840 and PMID:10471511 remain abstract-only here; this refinement uses the independent accepted evidence without claiming their operative experiments were inspected. Replace the broader term with inner ear morphogenesis alone. Metanephros development is a separate accepted developmental context, not an is_a descendant of this term, and is not included in the replacement. Proposed replacements: inner ear morphogenesis Supporting Evidence: PMID:9020840 suggests a role in the development of all components of the inner ear, from the emergence of the otic placode PMID:10471511 In the kidney, Eya1 homozygosity results in an absence of ureteric bud outgrowth and a subsequent failure of metanephric induction. GO_REF:0000033 |
| GO:0010212 response to ionizing radiation | IDA PMID:19234442 Tyrosine dephosphorylation of H2AX modulates apoptosis and s... | KEEP AS NON CORE | Summary: EYA1 changes its H2AX association and nuclear localization in response to irradiation. Reason: PMID:19234442 reports damage-dependent HA-Eya1/H2AX association and shows colocalization with gamma-H2AX foci after 5 Gy irradiation in 293T cells. These are positive response measurements rather than a mere survival requirement. Retain the radiation-response context alongside the more mechanistic H2AX phosphatase and repair-regulation descriptions; do not transfer the Eya3 S219 mutational mechanism or all natural-product behavior to EYA1. Supporting Evidence: PMID:19234442 We could detect interactions between H2AX and wild-type Eya1 or Eya3 only under DNA damage conditions PMID:19234442 immunostaining of transfected HA-tagged Eya1 or Eya3 protein in 293T embryonic kidney cells revealed a clear co-localization of Eya with Ξ³H2AX foci after treatment with IR |
| GO:0016604 nuclear body | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Supported human HPA nuclear puncta justify retaining the nuclear-body observation. Reason: HPA028917 is assigned supported nuclear-body localization, and the inspected Rh30/U2OS composites show nuclear puncta alongside diffuse signal. The data do not identify a particular body type or establish a specialized EYA1 biochemical function there. The shared antigen does not distinguish the 592-, 559- and 557-residue products. The inherited mouse nuclear-translocation quotation remains contextual rather than direct evidence for a named nuclear body. Supporting Evidence: PMID:10490620 Coexpression of Six2, Six4, or Six5 induced nuclear translocation of Eya1, Eya2, and Eya3, which were otherwise distributed in the cytoplasm. |
| GO:0016925 protein sumoylation | ISS GO_REF:0000024 | REMOVE | Summary: The traced SUMO evidence identifies EYA1 as the modified substrate. Reason: The actual mouse P97767 donor assertion points to IDA PMID:16990542. Its operative main text and supplementary Methods describe Myc-Eya1, HA-SUMO1 and UBC9 in 293T cells, detecting SUMO conjugates on Eya1; the construct numbering follows the cited mouse Eya1 work. PMID:24954506 independently detects SUMO on endogenous human EYA1 and tests mouse Eya1 constructs, with SENP2 and lysine-mutant controls. UBC9 and the conjugation machinery perform SUMO attachment; the inspected evidence does not show EYA1 catalyzing, positioning or otherwise executing that conjugation step. Remove this process attribution while retaining the positive biological fact that EYA1 is SUMO-regulated. This judgment follows actual donor Methods, not an unread title or abstract. Supporting Evidence: PMID:24954506 To confirm that Eya1 is indeed SUMOylated, immunopurified endogenous EYA1 proteins were examined using a SUMO1-specific antibody PMID:24954506 SUMOylation inhibits Eya1 transcription activity |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Conserved differentiation participation is retained as a broad developmental context. Reason: The target descends from the positive cell-differentiation IBD at PTN000022641. The current IBD includes an additional zebrafish descendant not present in the imported WITH list; both version-specific records are preserved. Actual mouse Eya1/SIX reporter and localization experiments in PMID:10490620 support a transcriptional contribution, rather than a substrate-only requirement. The broad developmental process is retained as non-core relative to the specific molecular roles. PMID:10471511 was accessible only as metadata and abstract here; its inherited quotation is not presented as a newly read full developmental experiment. Supporting Evidence: PMID:10471511 Eya1 homozygotes lack ears and kidneys due to defective inductive tissue interactions and apoptotic regression of the organ primordia. |
| GO:0042472 inner ear morphogenesis | IBA GO_REF:0000033 | ACCEPT | Summary: The target inherits a well-supported inner-ear morphogenesis role. Reason: Human EYA1 lies below the positive inner-ear IBD at PTN002565172; the actual family tree and exact displayed-sequence alignment support that placement, without target-path NOT evidence. Mouse P97767 retains experimental donor assertions including PMID:10471511. That paperβs accessible abstract reports otic-vesicle arrest and failure of inner-ear structures; its operative full text was not recovered in this lane. This access limit does not invalidate the independently inspected PAINT ancestral judgment. Retain the developmental role without equating it with direct execution of auditory perception or assigning it separately to each human product. Supporting Evidence: PMID:10471511 Inner ear development in Eya1 homozygotes arrests at the otic vesicle stage and all components of the inner ear and specific cranial sensory ganglia fail to form. |
| GO:0045739 positive regulation of DNA repair | IBA GO_REF:0000033 | ACCEPT | Summary: Conserved H2AX phosphotyrosine regulation supports positive DNA repair. Reason: The positive PTN000022641 IBD places human EYA1 within the inherited DNA-repair regulatory clade; its own experimental evidence is a valid source. PMID:19234442 directly connects Eya1 phosphotyrosine removal to H2AX state, with human EYA1 depletion and mouse wild-type versus catalytic-mutant rescue. This molecular histone-state contribution supports repair regulation. The pY-dependent repair-factor association assays and several localization/recruitment experiments have distinct Eya3 or peptide/extract scopes; no claim is made that every repair outcome was isolated to each natural human EYA1 product. Supporting Evidence: PMID:19234442 a protein tyrosine phosphatase, EYA, is involved in promoting efficient DNA repair rather than apoptosis in response to genotoxic stress PMID:19234442 Eya siRNA-treated cells showed significantly increasedΞ³H2AX tyrosine phosphorylation levels |
| GO:0045739 positive regulation of DNA repair | IMP PMID:19234442 Tyrosine dephosphorylation of H2AX modulates apoptosis and s... | ACCEPT | Summary: EYA1-dependent H2AX tyrosine dephosphorylation supports a repair-permissive damage response. Reason: The EYA1-specific affinity-isolate assay, endogenous human knockdown and damage-site localization in PMID:19234442 support a regulatory H2AX step favoring repair-factor engagement over apoptotic signaling. They substantiate positive regulation of DNA repair without establishing that EYA1 directly ligates or resynthesizes broken DNA. The detailed I-PpoI/MDC1 experiments and plotted murine rescue are Eya3-specific; Eya1 rescue is reported in the main text for a supplement not inspected here. The inherited broad EYA statements are retained within this explicitly bounded interpretation, not as proof of an EYA1-specific completed-repair assay. Supporting Evidence: PMID:19234442 a protein tyrosine phosphatase, EYA, is involved in promoting efficient DNA repair rather than apoptosis in response to genotoxic stress PMID:19234442 Eya siRNA-treated cells showed significantly increasedΞ³H2AX tyrosine phosphorylation levels |
| GO:0140793 histone H2AXY142 phosphatase activity | IDA PMID:19234442 Tyrosine dephosphorylation of H2AX modulates apoptosis and s... | ACCEPT | Summary: EYA1 dephosphorylates H2AX tyrosine 142 in biochemical and cellular experiments. Reason: PMID:19234442 Figure 4B compares wild-type affinity-isolated HA-Eya1 with D323A on H2AX, and Figure 4C shows increased H2AX tyrosine phosphorylation after endogenous human EYA1 knockdown. The paper identifies Tyr142 through H2AX residue substitutions; the separately purified phosphopeptide assay is Eya3. Together these support the substrate-specific EYA1 activity without attributing Eya3-only assays or identical function to all three natural products. PMID:19351884 independently tests recombinant human EYA2/EYA3 domains and EYA3 depletion, leaving EYA1 untested rather than reporting an EYA1 negative. It is family-mechanism context and does not replace the EYA1-specific experiments in PMID:19234442. Supporting Evidence: PMID:19234442 Wild-type Eya effectively removed the phosphotyrosine mark from H2AX, while the phosphatase-inactive mutant Eya proteins (Eya1 D323A or Eya3 D246A) had little or no effect PMID:19234442 Eya siRNA-treated cells showed significantly increasedΞ³H2AX tyrosine phosphorylation levels |
| GO:0003713 transcription coactivator activity | IDA PMID:10490620 Cooperation of six and eya in activation of their target gen... | NEW | Summary: The inherited coactivator assertion is retained as a conserved EYA1 function with explicit construct boundaries. Reason: This is a reassessment of an already present NEW row, not a newly added assertion or a new gap claim. PMID:10490620 directly tests mouse Eya1 cDNA from embryonic material with mouse Six proteins in COS7 cells: Eya1 enhances the myogenin/Six-element reporter with site-mutant controls. PMID:15141091 adds Eya1/Six1 reporter cooperation, although the Eya1 insert accession/species is unstated there; independent human EYA1βSIX1 interaction records corroborate the conserved partnership. These are positive coactivation experiments, not inference from binding or necessity alone. The inherited PMID:19497856 excerpt is general context, with its purified/reporter assays using EYA2; the detailed coactivator-recruitment experiments in PMID:14628042 use Eya3, and its antibody recognizes Eya1/3. The retained SUMO excerpt concerns modulation of activity, not an additional coactivator demonstration. No human reporter experiment or universal natural-product equivalence is manufactured. The first inherited excerpt describes nuclear translocation and is retained only as localization context; coactivator support comes from the actual mouse Eya1/Six reporter experiments in PMID:10490620 and PMID:15141091, not from that excerpt alone. Supporting Evidence: PMID:10490620 Coexpression of Six2, Six4, or Six5 induced nuclear translocation of Eya1, Eya2, and Eya3, which were otherwise distributed in the cytoplasm. PMID:19497856 As a complex, the SIX and EYA proteins are believed to form a bipartite transcription factor where SIX confers DNA binding and EYA confers transactivation activity. PMID:14628042 The phosphatase function of Eya switches the function of Six1-Dach from repression to activation, causing transcriptional activation through recruitment of co-activators. PMID:24954506 SUMOylation inhibits Eya1 transcription activity |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:10490620 Cooperation of six and eya in activation of their target gen... | NEW | Summary: The inherited positive Pol II transcription assertion is retained with conserved Eya1 reporter evidence. Reason: The already present assertion is supported by the measured enhancement of a myogenin promoter/Six-element reporter by mouse Eya1 with Six partners in PMID:10490620, including promoter-site controls, together with the conserved human EYA1βSIX1 association. Eya1 supplies coactivation in that experiment rather than merely being required for an outcome. The human gene-level interpretation is conserved regulatory participation; it is not a claim that the mouse construct is one of the three current human products. The inherited general bipartite-factor quotation from PMID:19497856 remains context only: that paper's reporter experiment uses EYA2. No new annotation row is added. Supporting Evidence: PMID:10490620 A clear synergistic activation of these promoters was observed in certain combinations of Six and Eya. PMID:19497856 As a complex, the SIX and EYA proteins are believed to form a bipartite transcription factor where SIX confers DNA binding and EYA confers transactivation activity. |
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Download this section (compressed HTML)Q: Do the three natural human EYA1 products provide intrinsic phosphothreonine catalysis, under which substrate and cellular conditions, and when does activity instead depend on associated PP2A or another phosphatase?
Q: Which SIX-responsive endogenous genes require EYA1 tyrosine-phosphatase catalysis rather than its coactivator interaction, and do the 592-, 559- and 557-residue human products differ in these contributions?
Q: How much of the H2AX Tyr142-dependent repair response is executed specifically by EYA1, and how does its cooperation with EYA3 vary between cell types and DNA-damage conditions?
Experiment: Compare sequence-verified full-length human EYA1 products purified by orthogonal methods, with proteomic measurement of copurifying phosphatases, against H2AX-pTyr142, Myc-pThr58 and aPKC-pThr410 substrates. Use matched catalytic-site controls mapped to each actual sequence, PP2A depletion and add-back, and inhibitor controls whose selectivity is independently measured. Quantify phosphate release and substrate-site loss to distinguish EYA1 catalysis from activity carried by an associated enzyme.
Hypothesis: Phosphothreonine dephosphorylation associated with EYA1 may be intrinsic or mediated by an associated enzyme, with their relative contributions depending on the substrate and protein preparation.
Type: Biochemical reconstitution and catalyst attribution
Experiment: In human renal or otic progenitor models, replace endogenous EYA1 with each sequence-verified natural product at matched abundance. Compare wild type, catalytic-site mutants and SIX-binding separation-of-function mutants after verifying folding and localization. Measure SIX/EYA1 occupancy, nascent transcription and phosphotyrosine changes at selected endogenous targets to distinguish catalytic and noncatalytic contributions.
Hypothesis: EYA1 coactivator interactions and tyrosine-phosphatase chemistry have separable, target-dependent effects on developmental transcription.
Type: Product-resolved rescue and transcriptional analysis
Experiment: Independently deplete EYA1 and EYA3, singly and together, in matched human cell models and rescue with sequence-verified wild-type or catalytic-site variants. Following a defined DNA-damage pulse, quantify H2AX-pTyr142 and pSer139, recruitment of repair factors, completed-break-repair kinetics and apoptosis. Use the paired chemical and repair endpoints to separate histone-state regulation from any claimed execution of strand repair.
Hypothesis: EYA1-dependent H2AX tyrosine dephosphorylation contributes to repair regulation, while the degree of dependence on EYA3 varies with cellular context.
Type: Factor-specific damage-response kinetics and rescue
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