Affinage

EYA1

Protein phosphatase EYA1 · UniProt Q99502

Length
592 aa
Mass
64.6 kDa
Annotated
2026-06-09
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EYA1 is a dual-function transcriptional co-activator and protein phosphatase that drives organogenesis of the ear, kidney, thymus, parathyroid, thyroid, pharyngeal arches, and craniofacial structures by acting at the top of a Pax–Eya–Six regulatory hierarchy (PMID:10471511, PMID:12070080). Lacking intrinsic DNA-binding activity, EYA1 is recruited to chromatin and translocated to the nucleus through direct physical interaction with SIX-family homeodomain proteins (SIX1, SIX2); BOR/BO-syndrome mutations in the conserved Eya domain disrupt this EYA1–SIX interaction and cause disease (PMID:11734542, PMID:15141091, PMID:15492887, PMID:25458011). The EYA1–SIX complex activates target genes including Gdnf, Fgf8, Pax3, neurogenic bHLH determinants, and the hair-cell determinant Atoh1, and engages the BRG1/BAF170 SWI/SNF chromatin-remodeling machinery to reprogram cell fate and direct sensory and neuronal development (PMID:10471511, PMID:15496442, PMID:17098221, PMID:21364285, PMID:22513373, PMID:22340499, PMID:34716243); it also represses a distinct gene set through REST-corepressor complexes (Rest, Hdac1, Cdyl, Hltf) (PMID:36130284). Independently of its co-activator role, the conserved C-terminal HAD domain confers both tyrosine and threonine phosphatase activity that dephosphorylates specific substrates: Myc-pT58 to block FBW7-mediated degradation and stabilize Myc, Notch1-ICD-pT2122 to maintain Notch signaling and non-neuronal fate, aPKC-pT410 to control spindle orientation downstream of Shh, and PLK1-pY445 to promote centrosome maturation and mitotic PLK1 activation (PMID:25458011, PMID:27795300, PMID:29140246, PMID:33472197, PMID:38360978); this catalytic activity, distinct from co-activation, drives cyclin D1 induction and proliferation in cancer (PMID:23636126, PMID:25816987). EYA1 protein abundance is itself tightly controlled by APC/C-Cdh1 degradation at mitotic exit, GSK3/Fbw7-mediated ubiquitination (suppressed by Wnt and PI3K/Akt signaling), Akt1 phosphorylation that reduces inhibitory SUMOylation, and OTUB1-mediated deubiquitination (PMID:23263983, PMID:24752894, PMID:24954506, PMID:34773364).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    Established EYA1 as an essential upstream organizer of organ development by showing its loss eliminates ears and kidneys and abolishes downstream Six1 and Gdnf expression, defining the Pax–Eya–Six hierarchy.

    Evidence Targeted Eya1 knockout in mice with in situ marker analysis

    PMID:10471511

    Open questions at the time
    • Did not define the molecular activity (phosphatase vs co-activator) underlying organogenesis
    • Mechanism of how Eya1 controls Six1 expression unresolved
  2. 2002 High

    Extended EYA1's upstream role to pharyngeal organogenesis, showing it is selectively required for Six1 and Gcm2 expression while Hox/Pax genes are preserved, establishing pathway specificity.

    Evidence Eya1 knockout mice with in situ marker analysis across thymus/parathyroid/thyroid primordia

    PMID:12070080

    Open questions at the time
    • Direct transcriptional targets not identified
    • Did not address biochemical mechanism of gene activation
  3. 2004 High

    Defined the physical basis of EYA1 function by showing disease mutations in both EYA1 and SIX1 disrupt the EYA1–SIX1 interaction required to form a transcriptional complex, and that Six-mediated nuclear translocation is essential.

    Evidence Co-IP, yeast two-hybrid, EMSA on patient mutations; immunofluorescence of nuclear translocation

    PMID:15141091 PMID:15226428 PMID:15492887

    Open questions at the time
    • Catalytic contribution of EYA1 not yet separated from co-activation
    • Structural basis of the interaction not resolved
  4. 2006 High

    Mapped EYA1/SIX as upstream regulators of Tbx1, Fgf8, Wnt5b, Pax3 and Pax1 across pharyngeal and myogenic lineages, refining the genetic epistasis and showing context-dependent placement relative to Pax genes.

    Evidence Compound Eya1/Eya2 and Six mutant mice with in situ markers and chromatin-based reporter assays

    PMID:16530750 PMID:16916509 PMID:17098221

    Open questions at the time
    • Whether regulation is direct vs indirect for each target not uniformly shown
    • Phosphatase involvement untested
  5. 2008 Medium

    Showed EYA1 acts in a concentration-dependent manner and partners with Sox2 in sensory progenitors, linking dose to progenitor proliferation versus differentiation.

    Evidence Xenopus gain/loss-of-function, allelic series genetics, Eya1–Sox2 Co-IP and co-localization

    PMID:18571637 PMID:18678597

    Open questions at the time
    • Single-lab Co-IP for Sox2 interaction
    • Mechanism of dose-dependent switching not biochemically defined
  6. 2010 Medium

    Identified Sipl1 and Rbck1 as co-factors that enhance EYA1's co-activator function for Six transcription factors, broadening the EYA1 interactome.

    Evidence Yeast two-hybrid screen, GST pulldown, Co-IP, reporter and zebrafish knockdown

    PMID:20956555

    Open questions at the time
    • Single-lab characterization
    • In vivo mammalian relevance not established
  7. 2012 High

    Connected EYA1/SIX1 to chromatin remodeling and demonstrated cell-fate reprogramming, showing direct interaction with SWI/SNF (BRG1, BAF170) and Sox2 drives ectopic neurogenesis and hair-cell fate via Atoh1/Neurog1/Neurod1.

    Evidence Co-IP, gain-of-function in explants and cell lines, BRG1 ATPase-dead mutant, enhancer mutagenesis reporters, conditional KO

    PMID:22340499 PMID:22513373

    Open questions at the time
    • Atoh1-independent pathway components not identified
    • Did not address phosphatase contribution to remodeling
  8. 2013 High

    Separated EYA1's phosphatase function from its co-activator function in cancer, showing phosphatase-dependent recruitment of CBP/Pol II and H3K9ac at the cyclin D1 AP-1 site drives proliferation independently of the SIX1-responsive element.

    Evidence Phosphatase-dead mutant, ChIP, AP-1 site reporter mutagenesis, in vivo tumor growth

    PMID:23636126

    Open questions at the time
    • Phosphatase substrate at the cyclin D1 promoter not identified
    • Generalizability beyond breast cancer untested at this point
  9. 2014 High

    Linked EYA1's threonine phosphatase activity to progenitor self-renewal by showing nuclear Eya1, translocated by Six2, dephosphorylates and stabilizes Myc to maintain nephron progenitors.

    Evidence Conditional KO, cell fate tracing, Eya1–Six2–Myc Co-IP, in vitro threonine phosphatase assay, nuclear fractionation

    PMID:25458011

    Open questions at the time
    • Precise Myc phosphosite not yet defined in this study
    • Coupling between phosphatase and transcriptional roles unresolved
  10. 2014 High

    Defined multiple post-translational controls of EYA1 abundance and activity: GSK3/Fbw7 degradation suppressed by Wnt and PI3K/Akt, and Akt1 phosphorylation that reduces inhibitory SUMOylation to boost transcriptional activity.

    Evidence Ubiquitination assays, GSK3/Fbw7 perturbation, compound mutant mice, Akt1–Eya1 Co-IP, in vitro kinase and SUMO assays, migration rescue

    PMID:24489909 PMID:24752894 PMID:24954506

    Open questions at the time
    • Interplay among the distinct degradation pathways not integrated
    • Stoichiometry of SUMO vs phosphorylation control unquantified
  11. 2015 High

    Placed EYA1 phosphatase activity within Shh signaling, identifying it in an unbiased phosphatome screen as a positive regulator of Gli activators required for hindbrain development and medulloblastoma.

    Evidence shRNA phosphatome screen, Shh reporter assays, conditional cerebellar loss-of-function, tumor growth

    PMID:25816987

    Open questions at the time
    • Direct phosphatase substrate in the Shh pathway not identified in this study
    • Mechanism linking Eya1 to Gli activation unresolved here
  12. 2016 High

    Provided structural and enzymatic definition of EYA1's dual tyrosine/threonine HAD phosphatase activity, demonstrating conformation-specific dephosphorylation of Myc-pT58 that blocks Myc–FBW7 binding and stabilizes Myc.

    Evidence In vitro phosphatase assay, NMR substrate-conformation analysis, Myc–FBW7 Co-IP, ubiquitination assay, shRNA depletion

    PMID:27795300

    Open questions at the time
    • High-resolution co-crystal structure with substrate not obtained
    • Full substrate repertoire not enumerated
  13. 2017 High

    Identified Notch1-ICD-pT2122 as an EYA1 phosphatase substrate, showing dephosphorylation stabilizes Notch1 ICD to specify non-neuronal fate from epibranchial placodes.

    Evidence Eya1 KO, in vitro threonine phosphatase assay on Notch1 ICD, Co-IP, ICD stability assay, genetic rescue

    PMID:29140246

    Open questions at the time
    • How fate choice integrates phosphatase and co-activator activities not resolved
    • Upstream signal controlling this axis not defined
  14. 2021 High

    Expanded the phosphatase substrate set to aPKC-pT410 and PLK1, coupling Shh signaling to spindle orientation/symmetric division (via aPKC inactivation and reduced phospho-Numb) and linking EYA1 to centrosome maturation and mitotic PLK1 activation.

    Evidence In vitro phosphatase assays on aPKC-T410 and PLK1-pY445, Co-IP, molecular dynamics, in vivo genetics, spindle/centrosome imaging, EYA inhibitor

    PMID:33472197 PMID:38360978

    Open questions at the time
    • Whether one EYA1 pool serves both nuclear and mitotic substrates unclear
    • Regulation of substrate selectivity in time and space undefined
  15. 2021 High

    Defined genome-wide chromatin engagement in nephron progenitors, showing reciprocal regulation between Brg1/SWI/SNF and Eya1 (Brg1 occupies an Eya1 enhancer; Eya1/Six2 require Brg1 at Pbx1/Mycn elements) and identifying OTUB1 deubiquitination as a stabilizing input.

    Evidence Tagged knock-in Co-IP, ChIP-seq, conditional Brg1 KO, enhancer reporters; OTUB1–EYA1 MS/Co-IP and ubiquitination assays

    PMID:34716243 PMID:34773364

    Open questions at the time
    • Single-lab OTUB1 interaction validation
    • Direct vs indirect targets among Brg1-dependent sites not fully parsed
  16. 2022 High

    Revealed a repressive arm of EYA1 function, showing it associates with REST-corepressor complexes (Rest, Hdac1, Cdyl, Hltf) at H3K27ac-poor sites whose genes are derepressed upon Eya1 loss, expanding its role beyond activation.

    Evidence ChIP-seq, RNA-seq, affinity purification-MS, Co-IP validation in nephron progenitors

    PMID:36130284

    Open questions at the time
    • What toggles EYA1 between activator and repressor modes unknown
    • Whether repression requires phosphatase activity untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EYA1 coordinates its distinct activities — co-activation, REST-mediated repression, and substrate-specific phosphatase action across nuclear and mitotic compartments — into a unified developmental and oncogenic program remains unresolved.
  • No integrated model linking phosphatase substrate choice to transcriptional context
  • Spatial/temporal control of activator-vs-repressor switching undefined
  • Full structural basis of substrate selectivity unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0140110 transcription regulator activity 5 GO:0016787 hydrolase activity 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3
Partners
BRG1MYCNOTCH1OTUB1PLK1SIX1SIX2SOX2
Complex memberships
EYA1-SIX transcriptional complexREST corepressor complexSWI/SNF (BRG1/BAF170)

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Eya1 knockout mice lack ears and kidneys due to defective inductive tissue interactions and abnormal apoptosis of organ primordia. In Eya1-/- embryos, Six1 (but not Pax) expression is Eya1-dependent, placing Eya1 upstream of Six1 in a Pax-Eya-Six regulatory hierarchy. Additionally, Gdnf expression is absent in Eya1-/- metanephric mesenchyme, placing Eya1 upstream of Gdnf in kidney development. Targeted gene inactivation in mice (loss-of-function), in situ hybridization for pathway marker expression Nature genetics High 10471511
2001 BOR-associated missense mutations in the conserved Eya domain of EYA1 do not alter protein subcellular localization but disrupt protein-protein interactions (with Six proteins) in both yeast two-hybrid and mammalian co-immunoprecipitation assays, indicating that the Eya domain is required for complex formation. Yeast two-hybrid, co-immunoprecipitation in mammalian cells, immunofluorescence localization Human molecular genetics Medium 11734542
2002 Eya1 is required for initiation of thymus, parathyroid, and thyroid morphogenesis. In Eya1-/- embryos, Six1 expression is markedly reduced in arch mesenchyme, pouch endoderm, and surface ectoderm of the pharyngeal region, confirming Eya1 acts upstream of Six1 in pharyngeal organogenesis. Gcm2 expression in 3rd pouch endoderm is lost in Eya1-/- embryos, while Hox and Pax gene expression is preserved, indicating selective pathway dependence. Targeted gene knockout in mice, in situ hybridization for pathway markers Development (Cambridge, England) High 12070080
2004 SIX1 mutations causing BOR/BO syndrome disrupt EYA1-SIX1 protein-protein interaction, and homeodomain mutations additionally abolish SIX1-DNA binding, demonstrating that EYA1 functions through physical interaction with SIX1 to form a transcriptional complex required for organogenesis. Co-immunoprecipitation, yeast two-hybrid, electrophoretic mobility shift assay (protein-DNA interaction), direct sequencing of patient mutations Proceedings of the National Academy of Sciences of the United States of America High 15141091
2004 Eya1 and Six1 are necessary for normal maintenance of neurogenesis in vestibuloacoustic neurons and epibranchial placode-derived ganglia. In Eya1/Six1 mutants, epibranchial progenitor cells fail to express Neurog2 and other bHLH and Phox2 genes required for neuronal determination, resulting in apoptosis, placing Eya1 upstream of neurogenic determination factors. Genetic loss-of-function (Eya1-/- and Six1-/- mice), in situ hybridization for neurogenic markers Development (Cambridge, England) High 15496442
2004 Six1 and Eya1 proteins expressed together in slow-twitch soleus muscle drive fiber-type transition to fast-twitch glycolytic phenotype. Six1 and Eya1 proteins accumulate preferentially in nuclei of fast-twitch muscles and cooperatively activate MEF3/Six DNA-binding element-dependent transcription of fast-fiber genes. Forced transgenic co-expression in mouse skeletal muscle, reporter assays, immunolocalization, myosin heavy chain isoform analysis Molecular and cellular biology High 15226428
2004 EYA1 Eya domain (EYA1HR) interacts with SIX1 in yeast two-hybrid assays. After co-expression with Six1, EYA1HR is translocated from cytoplasm to nucleus, demonstrating that Six1-mediated nuclear translocation is required for EYA1 transcriptional activity. Yeast two-hybrid, immunofluorescence co-localization, alpha-galactosidase reporter activity Journal of the Association for Research in Otolaryngology : JARO Medium 15492887
2006 Eya1 and Eya2 double knockout results in loss of Pax3 expression in ventrolateral dermomyotomes, preventing hypaxial lip formation and limb muscle progenitor delamination. Six proteins recruit Eya proteins to MEF3 DNA sites to drive transcription in dermomyotomal cells, establishing genetic epistasis: Six and Eya genes act upstream of Pax3 in hypaxial myogenic commitment. Compound Eya1/Eya2 double knockout mice, in situ hybridization, chromatin-based reporter assays, genetic epistasis analysis Developmental biology High 17098221
2006 In pharyngeal pouch development, Eya1 acts upstream of Tbx1, Fgf8, and Wnt5b expression in the pouch endoderm. Pax1 expression in pharyngeal pouches requires both Eya1 and Six1 function, while Eya1 and Six1 expression in the pouches does not require Pax1/Pax9 (i.e., Eya1 is not downstream of Pax1/Pax9 in this context). Genetic loss-of-function (Six1-/-, Six1/Six4 double mutant, Eya1-/- mice), in situ hybridization for pathway markers Developmental biology High 16530750
2006 Eya1-/- otic epithelium shows reduced cell proliferation from E8.5 and increased apoptosis from E9.0. Genetic evidence shows Pax2 interacts with Eya1 during inner ear morphogenesis—compound Pax2/Eya1 mutants reveal synergistic defects in all sensory areas, indicating functional interaction critical for sensory development. Loss-of-function genetics (Eya1-/-, Pax2-/-, compound mutants), BrdU proliferation assay, TUNEL apoptosis assay, latex paint-filling of inner ear Developmental biology High 16916509
2008 Eya1 and Six1 regulate placodal neurogenesis in Xenopus by expanding SoxB1 gene expression (Sox2, Sox3) at higher doses to maintain progenitor proliferation, and by promoting neuronal differentiation at lower doses, downstream of or parallel to Ngnr1. Loss-of-function (morpholino knockdown) and gain-of-function (mRNA injection) in Xenopus, in situ hybridization for neurogenic markers Developmental biology Medium 18571637
2008 Eya1 co-localizes with Sox2 in sensory progenitors of the inner ear and both proteins physically interact (co-immunoprecipitation). Allelic series experiments show Eya1 acts in a concentration-dependent manner to regulate genes required for sensory development and hair cell differentiation. Allelic series genetics (wild-type, heterozygous, hypomorphic alleles), co-immunoprecipitation of Eya1 and Sox2, immunofluorescence co-localization, hair cell/sensory marker analysis Human molecular genetics Medium 18678597
2010 Sipl1 and Rbck1 are novel Eya1-binding proteins identified by yeast two-hybrid screening and confirmed by GST pulldown and co-immunoprecipitation. Sipl1 and Rbck1 enhance Eya1 function as a co-activator for Six transcription factors. Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, reporter co-activation assay, morpholino knockdown in zebrafish Molecular and cellular biology Medium 20956555
2011 Murine mutation of both Six1 and Eya1 recapitulates del22q11 syndrome features. Fgf8 is a direct downstream effector of the Six1/Eya1 transcriptional complex, as shown by direct regulation assays. Six1/Eya1 genetically interact with Tbx1 (del22q11 gene) and Fgf8, establishing a Tbx1-Six1/Eya1-Fgf8 genetic pathway for cardiovascular and craniofacial morphogenesis. Compound Six1/Eya1 knockout mice, genetic interaction analysis with Tbx1 and Fgf8 compound mutants, direct transcriptional target analysis The Journal of clinical investigation High 21364285
2011 Eya1 regulates cell polarity, mitotic spindle orientation, and Numb asymmetric segregation in distal embryonic lung epithelium, likely through controlling aPKCζ phosphorylation. In Eya1-/- lungs, perpendicular division is not maintained and Numb segregates to both daughter cells, leading to inactivation of Notch signaling. Genetic activation of Notch partially rescues the Eya1-/- lung epithelial phenotype. Eya1-/- mouse knockout, spindle orientation imaging, immunofluorescence localization of polarity proteins, genetic rescue with Notch activation Development (Cambridge, England) High 21385765
2012 EYA1 and SIX1 interact directly with SWI/SNF chromatin-remodeling subunits BRG1 and BAF170 (co-immunoprecipitation) to cooperatively drive neurogenesis. Overexpression of Eya1 and Six1 converts non-neuronal epithelial and 3T3 cells into neurons expressing Neurog1, Neurod1, and mature neuronal markers. BRG1 ATPase activity is required for EYA1/SIX1-induced ectopic neurogenesis and for normal otic neurogenesis. Co-immunoprecipitation, gain-of-function overexpression in otocyst/cochlea/3T3 cells, BRG1 ATPase-dead dominant-negative mutant, in vivo conditional knockout Development (Cambridge, England) High 22513373
2012 Eya1/Six1 coexpression in mouse cochlear explants is sufficient to induce hair cell fate in nonsensory epithelium by activating Atoh1-dependent and Atoh1-independent pathways. Sox2 physically interacts with Eya1/Six1 and cooperates to synergistically activate Atoh1 transcription via direct binding to Sox- and Six-binding sites in Atoh1 enhancers. Cochlear explant overexpression, co-immunoprecipitation of Sox2/Eya1/Six1, reporter assay with Atoh1 enhancer mutations, loss-of-function in Eya1/Six1 mutants Developmental cell High 22340499
2012 Eya1 protein level fluctuates during the cell cycle, peaking during mitosis and dropping at M-to-G1 transition. APC/C-Cdh1 targets EYA1 for ubiquitin-mediated proteasomal degradation during mitotic exit; Cdh1 physically interacts with EYA1, and Cdh1 overexpression reduces EYA1 levels while Cdh1 knockdown stabilizes EYA1. Cell cycle synchronization, co-immunoprecipitation of EYA1-Cdh1, Cdh1 overexpression and siRNA knockdown, ubiquitination assay Molecular and cellular biology High 23263983
2013 EYA1 phosphatase activity is required for breast cancer cell proliferation via cyclin D1 induction. EYA1 is recruited to the cyclin D1 AP-1 promoter site (but not the SIX1-responsive element), and its phosphatase function determines recruitment of CBP, RNA Pol II, and H3K9 acetylation at that site. The EYA1 phosphatase domain (but not transcriptional coactivator function) is required for cyclin D1 induction and proliferation. Phosphatase domain mutant (loss of catalytic activity), ChIP at cyclin D1 promoter, reporter assays with AP-1 site mutation, in vivo tumor growth assay Cancer research High 23636126
2014 Eya1 interacts with Six2 and Myc to control nephron progenitor self-renewal. Six2 mediates nuclear translocation of Eya1; in the nucleus, Eya1 uses its threonine phosphatase activity to dephosphorylate/stabilize Myc in progenitor cells. Conditional Eya1 inactivation leads to loss of Six2 expression and premature epithelialization. Conditional knockout, cell fate tracing (Cre/loxP), co-immunoprecipitation of Eya1-Six2-Myc, in vitro threonine phosphatase assay, nuclear fractionation Developmental cell High 25458011
2014 BOR-associated Eya1 missense mutations S454P, L472R, and L550P lead to enhanced proteasomal degradation of the Eya1 protein. Six proteins protect Eya1 from proteasomal degradation; mutation L550P, which disrupts Six interaction, results in rapid protein degradation. Transfection of mutant constructs in mammalian cells, proteasome inhibitor treatment, co-immunoprecipitation with Six proteins, protein stability assays PloS one Medium 24489909
2014 Eya1 has an evolutionarily conserved CDC4 phosphodegron (CPD) targeted by GSK3 kinase and Fbw7 ubiquitin ligase for ubiquitination and degradation. PI3K/Akt and canonical Wnt signaling suppress Eya1 ubiquitination by restricting GSK3/Fbw7 activity. Compound Eya1+/-;Wnt9b+/- mutant mice show increased penetrance of renal defects, confirming genetic interaction. Ubiquitination assays, GSK3 pharmacological inhibition, Fbw7 genetic deletion, PI3K/Akt activation, compound mutant mice Molecular and cellular biology High 24752894
2014 Akt1 kinase physically interacts with Eya1 and phosphorylates a conserved Akt consensus site on Eya1. PI3K/Akt signaling enhances Eya1 transcriptional activity by reducing Eya1 SUMOylation; SUMOylation inhibits Eya1 activity; phosphorylation-site mutant Eya1 fails to rescue migration phenotype of EYA1-depleted breast cancer cells. Co-immunoprecipitation of Akt1-Eya1, in vitro Akt phosphorylation assay, SUMO modification assay, rescue experiment with phosphosite mutant, cell migration assay Oncogene High 24954506
2015 Eya1 phosphatase promotes Shh signaling in hindbrain development and medulloblastoma. Eya1 and Six1 together regulate Gli transcriptional activators downstream of Shh. shRNA phosphatome screen identified Eya1 as a positive regulator; the catalytic phosphatase activity of Eya1 is required for Shh pathway gene induction. shRNA screen of phosphatome, Shh pathway reporter assays, Eya1 conditional loss-of-function in cerebellum, medulloblastoma tumor growth assays Developmental cell High 25816987
2016 EYA1's conserved C-terminal HAD domain has dual phosphatase activities (tyrosine and threonine). EYA1 dephosphorylates phospho-T58 of Myc with striking conformational preference demonstrated by NMR and enzymatic assay. EYA1-mediated Myc dephosphorylation at T58 reduces Myc-FBW7 interaction and Myc ubiquitination, stabilizing Myc. Both N- and C-terminal domains of EYA1 interact with substrates to enhance catalytic activity. In vitro phosphatase assay, NMR analysis of substrate conformation specificity, co-immunoprecipitation of Myc-FBW7, ubiquitination assay, shRNA depletion of EYA1 Molecular and cellular biology High 27795300
2017 Eya1 is required for development of epibranchial placodes and proximal pharyngeal arches. Eya1 dephosphorylates phospho-threonine-2122 of Notch1 intracellular domain (Notch1 ICD), increasing Notch1 ICD stability and maintaining Notch signaling in non-neuronal epibranchial placodal cells. This Eya1-Notch regulatory axis specifies the non-neuronal (versus neuronal) cell fate from epibranchial placodes. Eya1-/- mouse knockout, in vitro threonine phosphatase assay on Notch1 ICD substrate, co-immunoprecipitation of Eya1-Notch1, Notch1 ICD stability assay, genetic rescue eLife High 29140246
2021 Eya1 phosphatase inactivates aPKC by dephosphorylating threonine T410 in the aPKC activation loop, downstream of Shh signaling in cerebellar granule cell precursors. This Eya1-dependent aPKC inactivation reduces phosphorylation of Numb, promoting symmetric cell divisions and coupling spindle orientation to cell fate. Loss of Eya1 disrupts this Shh-Eya1-aPKC axis, impairing symmetric division. In vitro phosphatase assay on aPKC T410 substrate, loss-of-function genetics (partial gain/loss Shh pathway mutations), spindle orientation imaging, phospho-Numb immunofluorescence Developmental neuroscience High 33472197
2021 Eya1 and Six2 interact with the Brg1-based SWI/SNF chromatin-remodeling complex during kidney development. Brg1 knockout leads to loss of Eya1 expression; Brg1 occupies a distal enhancer of Eya1 that drives nephron progenitor-specific expression. Brg1 enrichment at Pbx1 and Mycn regulatory elements requires Six2 activity. HA/Flag-tagged Eya1 knock-in mice, co-immunoprecipitation of Eya1-Six2-SWI/SNF, Brg1 conditional knockout, ChIP-seq genome-wide binding analysis, transcriptome profiling, enhancer reporter assays Journal of the American Society of Nephrology : JASN High 34716243
2021 OTUB1 deubiquitinase directly interacts with EYA1 (identified by mass spectrometry and confirmed by co-immunoprecipitation) and deubiquitinates EYA1 to stabilize the protein, thereby promoting papillary thyroid carcinoma cell proliferation. Mass spectrometry interactome, co-immunoprecipitation of OTUB1-EYA1, ubiquitination assay, in vitro and in vivo proliferation assays Journal of cellular and molecular medicine Medium 34773364
2022 Eya1 occupies promoter sequences and physically interacts with REST corepressors (Rest, Hdac1, Cdyl, Hltf), chromatin-remodeling factors, RNA polymerases, and general transcription factors in nephron progenitor cells. REST-binding motifs are enriched at 76% of Eya1-occupied sites lacking H3K27ac, and Eya1 deficiency upregulates genes at these sites, indicating Eya1 exerts transcriptional repression through REST-corepressor complexes in addition to its known activation function. ChIP-seq, RNA-seq, proteomics (affinity purification-MS with HA/Flag-Eya1 knock-in), co-immunoprecipitation validation of Eya1-Rest/Hdac1/Cdyl/Hltf interactions Nucleic acids research High 36130284
2024 EYA1 (and EYA4) directly interact with PLK1 and dephosphorylate pY445 on PLK1 in the G2 phase of the cell cycle. Dephosphorylation of PLK1-pY445 is required for centrosome maturation, PLK1 localization to centrosomes, and polo-box domain (PBD)-dependent PLK1 activation complex interactions. Depletion of EYA1 or chemical inhibition of EYA phosphatase activity reduces PLK1 activation, causing mitotic defects and cell death. Co-immunoprecipitation of EYA1-PLK1, in vitro tyrosine phosphatase assay on PLK1 pY445, molecular dynamics simulations, EYA1/EYA4 depletion, centrosome imaging, chemical EYA inhibitor treatment Nature communications High 38360978

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nature genetics 534 10471511
2004 SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proceedings of the National Academy of Sciences of the United States of America 306 15141091
2012 Eya1-Six1 interaction is sufficient to induce hair cell fate in the cochlea by activating Atoh1 expression in cooperation with Sox2. Developmental cell 197 22340499
2002 Eya1 is required for the morphogenesis of mammalian thymus, parathyroid and thyroid. Development (Cambridge, England) 197 12070080
2004 Eya1 and Six1 are essential for early steps of sensory neurogenesis in mammalian cranial placodes. Development (Cambridge, England) 195 15496442
1997 Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1. Human molecular genetics 178 9361030
2004 Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences. Human mutation 165 15146463
2004 Six1 and Eya1 expression can reprogram adult muscle from the slow-twitch phenotype into the fast-twitch phenotype. Molecular and cellular biology 162 15226428
1999 The zebrafish eya1 gene and its expression pattern during embryogenesis. Development genes and evolution 149 10370123
2000 Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies. Human molecular genetics 124 10655545
1997 BOR and BO syndromes are allelic defects of EYA1. European journal of human genetics : EJHG 124 9359046
2006 Eya1 and Eya2 proteins are required for hypaxial somitic myogenesis in the mouse embryo. Developmental biology 123 17098221
2011 A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis. The Journal of clinical investigation 113 21364285
2012 EYA1 and SIX1 drive the neuronal developmental program in cooperation with the SWI/SNF chromatin-remodeling complex and SOX2 in the mammalian inner ear. Development (Cambridge, England) 110 22513373
2005 The zebrafish dog-eared mutation disrupts eya1, a gene required for cell survival and differentiation in the inner ear and lateral line. Developmental biology 105 15572137
2014 Eya1 interacts with Six2 and Myc to regulate expansion of the nephron progenitor pool during nephrogenesis. Developmental cell 99 25458011
2006 Patterning of the third pharyngeal pouch into thymus/parathyroid by Six and Eya1. Developmental biology 94 16530750
2008 Eya1 and Six1 promote neurogenesis in the cranial placodes in a SoxB1-dependent fashion. Developmental biology 89 18571637
2008 Eya1 gene dosage critically affects the development of sensory epithelia in the mammalian inner ear. Human molecular genetics 86 18678597
2001 Molecular effects of Eya1 domain mutations causing organ defects in BOR syndrome. Human molecular genetics 86 11734542
1998 Eya1 expression in the developing ear and kidney: towards the understanding of the pathogenesis of Branchio-Oto-Renal (BOR) syndrome. Developmental dynamics : an official publication of the American Association of Anatomists 82 9853969
2013 EYA1 phosphatase function is essential to drive breast cancer cell proliferation through cyclin D1. Cancer research 80 23636126
2011 Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations. Human mutation 80 21280147
2008 Branchio-oto-renal syndrome (BOR): novel mutations in the EYA1 gene, and a review of the mutational genetics of BOR. Human mutation 79 18220287
2006 Eya1 regulates the growth of otic epithelium and interacts with Pax2 during the development of all sensory areas in the inner ear. Developmental biology 77 16916509
2001 Xenopus Eya1 demarcates all neurogenic placodes as well as migrating hypaxial muscle precursors. Mechanisms of development 67 11335132
1999 Inner ear and kidney anomalies caused by IAP insertion in an intron of the Eya1 gene in a mouse model of BOR syndrome. Human molecular genetics 67 10072433
1998 Identification of three novel mutations in human EYA1 protein associated with branchio-oto-renal syndrome. Human mutation 65 9603436
2007 Branchio-oto-renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses. European journal of human genetics : EJHG 60 17637804
2006 Eya1 is required for lineage-specific differentiation, but not for cell survival in the zebrafish adenohypophysis. Developmental biology 55 16458879
2005 Pax6-dependence of Six3, Eya1 and Dach1 expression during lens and nasal placode induction. Gene expression patterns : GEP 51 16024294
2001 Oto-facio-cervical (OFC) syndrome is a contiguous gene deletion syndrome involving EYA1: molecular analysis confirms allelism with BOR syndrome and further narrows the Duane syndrome critical region to 1 cM. Human genetics 51 11409867
2004 A comparative study of Eya1 and Eya4 protein function and its implication in branchio-oto-renal syndrome and DFNA10. Journal of the Association for Research in Otolaryngology : JARO 46 15492887
2011 Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic lung epithelium. Development (Cambridge, England) 45 21385765
2016 MicroRNA-101 inhibits cell proliferation and induces apoptosis by targeting EYA1 in breast cancer. International journal of molecular medicine 42 27082308
2016 Dissecting the pre-placodal transcriptome to reveal presumptive direct targets of Six1 and Eya1 in cranial placodes. eLife 42 27576864
2010 Sipl1 and Rbck1 are novel Eya1-binding proteins with a role in craniofacial development. Molecular and cellular biology 39 20956555
2002 Genomic rearrangements of EYA1 account for a large fraction of families with BOR syndrome. European journal of human genetics : EJHG 39 12404110
2015 The Eya1 phosphatase promotes Shh signaling during hindbrain development and oncogenesis. Developmental cell 38 25816987
2013 Mutational analysis of EYA1, SIX1 and SIX5 genes and strategies for management of hearing loss in patients with BOR/BO syndrome. PloS one 36 23840632
2010 Canonical Wnt signaling modulates Tbx1, Eya1, and Six1 expression, restricting neurogenesis in the otic vesicle. Developmental dynamics : an official publication of the American Association of Anatomists 36 20503367
2010 HERV-mediated genomic rearrangement of EYA1 in an individual with branchio-oto-renal syndrome. American journal of medical genetics. Part A 35 20979191
2019 SIX1 Activates STAT3 Signaling to Promote the Proliferation of Thyroid Carcinoma via EYA1. Frontiers in oncology 34 31921695
2011 Six1 and Eya1 are critical regulators of peri-cloacal mesenchymal progenitors during genitourinary tract development. Developmental biology 34 21968101
2017 An Eya1-Notch axis specifies bipotential epibranchial differentiation in mammalian craniofacial morphogenesis. eLife 32 29140246
2016 EYA1's Conformation Specificity in Dephosphorylating Phosphothreonine in Myc and Its Activity on Myc Stabilization in Breast Cancer. Molecular and cellular biology 32 27795300
2005 Eya1 acts upstream of Tbx1, Neurogenin 1, NeuroD and the neurotrophins BDNF and NT-3 during inner ear development. Mechanisms of development 31 15817220
2013 Branchio-Oto-Renal Syndrome (BOR) associated with focal glomerulosclerosis in a patient with a novel EYA1 splice site mutation. BMC nephrology 30 23506628
2010 EYA1 mutations associated with the branchio-oto-renal syndrome result in defective otic development in Xenopus laevis. Biology of the cell 30 19951260
2012 Mutation screening of the EYA1, SIX1, and SIX5 genes in an East Asian cohort with branchio-oto-renal syndrome. The Laryngoscope 28 22447252
2012 EYA1-SIX1 complex in neurosensory cell fate induction in the mammalian inner ear. Hearing research 28 23104013
2010 Branchio-oto-renal syndrome caused by partial EYA1 deletion due to LINE-1 insertion. Pediatric nephrology (Berlin, Germany) 27 20130917
2010 Eyes absent 1 (Eya1) is a critical coordinator of epithelial, mesenchymal and vascular morphogenesis in the mammalian lung. Developmental biology 27 21129374
2008 Differential expression of Eya1 and Eya2 during chick early embryonic development. Gene expression patterns : GEP 27 18316249
2006 Point mutation of an EYA1-gene splice site in a patient with oto-facio-cervical syndrome. Annals of human genetics 26 16441263
2020 BCOR Binding to MLL-AF9 Is Essential for Leukemia via Altered EYA1, SIX, and MYC Activity. Blood cancer discovery 25 32954361
2000 Exclusion of the branchio-oto-renal syndrome locus (EYA1) from patients with branchio-oculo-facial syndrome. American journal of medical genetics 25 10767004
2019 Direct reprogramming to human nephron progenitor-like cells using inducible piggyBac transposon expression of SNAI2-EYA1-SIX1. Kidney international 24 30827514
2018 A novel mutation in EYA1 in a Chinese family with Branchio-oto-renal syndrome. BMC medical genetics 24 30086703
2014 The PI3K/Akt signal hyperactivates Eya1 via the SUMOylation pathway. Oncogene 24 24954506
2008 Multiple evolutionarily conserved enhancers control expression of Eya1. Developmental dynamics : an official publication of the American Association of Anatomists 24 18816442
2006 EYA1 and SIX1 gene mutations in Japanese patients with branchio-oto-renal (BOR) syndrome and related conditions. Pediatric nephrology (Berlin, Germany) 24 16491411
2001 A family affected by branchio-oto syndrome with EYA1 mutations. Auris, nasus, larynx 24 11683347
1999 EYA1 nonsense mutation in a Japanese branchio-oto-renal syndrome family. Journal of human genetics 24 10429368
2013 Abrogation of Eya1/Six1 disrupts the saccular phase of lung morphogenesis and causes remodeling. Developmental biology 22 23895934
2007 Phenotypic consequences in a Japanese family having branchio-oto-renal syndrome with a novel frameshift mutation in the gene EYA1. Acta oto-laryngologica 22 17364338
2005 The C. elegans eyes absent ortholog EYA-1 is required for tissue differentiation and plays partially redundant roles with PAX-6. Developmental biology 21 16154558
2019 EYA1 promotes cell migration and tumor metastasis in hepatocellular carcinoma. American journal of translational research 20 31105839
2009 A recurrent EYA1 mutation causing alternative RNA splicing in branchio-oto-renal syndrome: implications for molecular diagnostics and disease mechanism. American journal of medical genetics. Part A 20 19206155
2004 EYA1 mutation in a newborn female presenting with cardiofacial syndrome. Pediatric cardiology 20 15493068
2001 Genetic features of hearing loss associated with ear anomalies: PDS and EYA1 mutation analysis. Journal of human genetics 19 11558900
2017 Six1 and Eya1 both promote and arrest neuronal differentiation by activating multiple Notch pathway genes. Developmental biology 18 28947179
2014 BOR-syndrome-associated Eya1 mutations lead to enhanced proteasomal degradation of Eya1 protein. PloS one 18 24489909
2007 Stickler and branchio-oto-renal syndromes in a patient with mutations in EYA1 and COL2A1 genes. Clinical genetics 18 18177466
2017 Novel EYA1 variants causing Branchio-oto-renal syndrome. International journal of pediatric otorhinolaryngology 17 28583505
2012 The phosphatase-transcription activator EYA1 is targeted by anaphase-promoting complex/Cdh1 for degradation at M-to-G1 transition. Molecular and cellular biology 17 23263983
2005 Identification of a novel mutation in the EYA1 gene in a Korean family with branchio-oto-renal (BOR) syndrome. International journal of pediatric otorhinolaryngology 17 16005355
2003 Mutation of the EYA1 gene in patients with branchio-oto syndrome. Acta oto-laryngologica 16 12701758
2021 Chromatin Remodelers Interact with Eya1 and Six2 to Target Enhancers to Control Nephron Progenitor Cell Maintenance. Journal of the American Society of Nephrology : JASN 15 34716243
2018 EYA1 promotes tumor angiogenesis by activating the PI3K pathway in colorectal cancer. Experimental cell research 15 29496520
2021 The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors. Developmental neuroscience 14 33472197
2014 EYA1-related disorders: two clinical cases and a literature review. International journal of pediatric otorhinolaryngology 14 24803398
2018 A de novo and novel mutation in the EYA1 gene in a Chinese child with branchio-oto-renal syndrome. Intractable & rare diseases research 13 29552445
2009 A novel splice site mutation in the EYA1 gene in a Korean family with branchio-oto (BO) syndrome. Acta oto-laryngologica 13 18763178
2006 Novel EYA1 mutation in a Korean branchio-oto-renal syndrome family. International journal of pediatric otorhinolaryngology 13 17049623
2001 Branchio-oto-renal syndrome: identification of a novel mutation in the EYA1 gene. Pediatric nephrology (Berlin, Germany) 13 11465802
2022 The transcriptional coactivator Eya1 exerts transcriptional repressive activity by interacting with REST corepressors and REST-binding sequences to maintain nephron progenitor identity. Nucleic acids research 12 36130284
2021 The deubiquitinase OTUB1 fosters papillary thyroid carcinoma growth through EYA1 stabilization. Journal of cellular and molecular medicine 12 34773364
2019 EYA1 mutations leads to Branchio-Oto syndrome in two Chinese Han deaf families. International journal of pediatric otorhinolaryngology 12 31102969
2012 Eya1 protein phosphatase regulates tight junction formation in lung distal epithelium. Journal of cell science 12 22685326
2021 Phage display targeting identifies EYA1 as a regulator of glioblastoma stem cell maintenance and proliferation. Stem cells (Dayton, Ohio) 11 33594762
2020 Expression of Eya1 in mouse taste buds. Cell and tissue research 11 33242174
2014 EYA1 expression in gastric carcinoma and its association with clinicopathological characteristics: a pilot study. Medical oncology (Northwood, London, England) 11 24729159
2014 The canonical wnt signal restricts the glycogen synthase kinase 3/fbw7-dependent ubiquitination and degradation of eya1 phosphatase. Molecular and cellular biology 11 24752894
2024 The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation. Nature communications 10 38360978
2006 A novel nonsense mutation in the EYA1 gene associated with branchio-oto-renal/branchiootic syndrome in an Afrikaner kindred. Clinical genetics 10 16813606
2020 Targeted next-generation sequencing identifies a novel frameshift EYA1 variant causing branchio-otic syndrome in a Chinese family. International journal of pediatric otorhinolaryngology 9 32717629
2018 The first case of NSHL by direct impression on EYA1 gene and identification of one novel mutation in MYO7A in the Iranian families. Iranian journal of basic medical sciences 9 29511501
2017 Eyes absent gene (EYA1) is a pathogenic driver and a therapeutic target for melanoma. Oncotarget 9 29285235
2023 A Novel EYA1 Mutation Causing Alternative RNA Splicing in a Chinese Family With Branchio-Oto Syndrome: Implications for Molecular Diagnosis and Clinical Application. Clinical and experimental otorhinolaryngology 8 37817567

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