Affinage

EYA1

Protein phosphatase EYA1 · UniProt Q99502

Length
592 aa
Mass
64.6 kDa
Annotated
2026-04-28
100 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EYA1 is a dual-function protein that serves as both a HAD-domain phosphatase and a transcriptional co-activator, operating within a conserved PAX–EYA–SIX regulatory hierarchy essential for organogenesis of the ear, kidney, thymus, parathyroid, and craniofacial structures (PMID:10471511, PMID:12070080, PMID:21364285). As a co-activator, EYA1 requires physical interaction with SIX-family homeodomain proteins for nuclear translocation and together they recruit SWI/SNF chromatin remodelers (BRG1/BAF170), CBP, and RNA Pol II to activate target genes including Neurog1, NeuroD1, Atoh1, Fgf8, and cyclin D1 (PMID:22513373, PMID:22340499, PMID:23636126). The EYA1 HAD domain possesses both tyrosine and threonine phosphatase activities and directly dephosphorylates aPKC (T410), Notch1 ICD (pT2122), and Myc (pT58), thereby controlling cell division symmetry, Notch signaling stability, and Myc protein turnover (PMID:33472197, PMID:29140246, PMID:27795300). Loss-of-function mutations in EYA1 cause branchio-oto-renal (BOR) syndrome, with disease-associated missense mutations disrupting EYA1–SIX interaction and promoting proteasomal degradation of EYA1 (PMID:9020840, PMID:11734542, PMID:24489909).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Positional cloning of EYA1 established it as the first mammalian member of the eyes absent gene family and identified it as the gene mutated in BOR syndrome, with disease mutations clustering in the conserved C-terminal Eya domain.

    Evidence Positional cloning, mutation screening in BOR families

    PMID:9020840

    Open questions at the time
    • Biochemical function of the Eya domain was unknown
    • No interacting partners identified
    • No animal model to confirm developmental role
  2. 1999 High

    Knockout mice revealed that Eya1 is indispensable for ear and kidney organogenesis and placed it upstream of Six genes in a conserved Pax–Eya–Six regulatory hierarchy, establishing the gene's central role in inductive tissue interactions.

    Evidence Eya1-/- knockout mice with in situ hybridization and genetic epistasis

    PMID:10471511

    Open questions at the time
    • Mechanism of Eya1-dependent Six activation unknown (direct transcription vs. protein stabilization)
    • No biochemical activity assigned to EYA1 protein
  3. 2001 High

    BOR-associated missense mutations in the Eya domain were shown to disrupt EYA1–SIX protein–protein interaction without altering localization, identifying the Eya domain as the critical interaction interface and providing a molecular explanation for disease pathogenesis.

    Evidence Yeast two-hybrid, co-immunoprecipitation, immunofluorescence with disease-associated mutants

    PMID:11734542

    Open questions at the time
    • Whether the interaction is direct or mediated by bridging factors was unresolved
    • Structural basis of the interaction unknown
  4. 2002 High

    The Eya1→Six1 regulatory hierarchy was extended beyond ear and kidney to pharyngeal organ development (thymus, parathyroid, thyroid), establishing EYA1 as a master regulator of multiple organ systems.

    Evidence Eya1-/- knockout mice with in situ hybridization in pharyngeal tissues

    PMID:12070080

    Open questions at the time
    • Direct transcriptional targets in pharyngeal tissues not identified
    • Whether Eya1 has Six-independent roles in these organs was unclear
  5. 2004 High

    Multiple studies converged to demonstrate that EYA1 and SIX1 form a bipartite transcriptional complex: SIX1 is required for EYA1 nuclear translocation, EYA1/SIX1 drive neurogenesis via Neurog2, and they control skeletal muscle fiber-type identity via MEF3 elements, while reciprocal SIX1 mutations in BOR confirmed the obligate partnership.

    Evidence SIX1 BOR mutation analysis, Eya1-/- and Six1-/- knockouts, yeast two-hybrid, immunofluorescence, muscle overexpression

    PMID:15141091 PMID:15226428 PMID:15492887 PMID:15496442

    Open questions at the time
    • Whether EYA1 contributes enzymatic activity to the complex or only structural co-activation was unknown
    • No chromatin-level mechanism for target gene activation
  6. 2006 High

    Compound Eya1/Eya2 knockout phenocopied the Six1/Six4 double knockout in hypaxial myogenesis, providing genetic proof that Eya proteins are the essential co-factors for Six-dependent transcription during somite development.

    Evidence Compound Eya1-/-;Eya2-/- and Six1-/-;Six4-/- knockouts with in vivo transcription reporters

    PMID:17098221

    Open questions at the time
    • Biochemical mechanism by which Eya potentiates Six transcriptional activity remained undefined
  7. 2008 High

    EYA1 was found to physically interact with SOX2 and co-localize in sensory progenitors of the inner ear, revealing a Sox2–Eya1 partnership that expanded the known co-activator network beyond SIX proteins.

    Evidence Co-immunoprecipitation, immunofluorescence, Eya1 allelic series in inner ear

    PMID:18678597

    Open questions at the time
    • Functional significance of Sox2–Eya1 interaction for target gene activation not yet tested with enhancer mutagenesis
  8. 2011 High

    Two studies established that Eya1 controls morphogenesis through distinct mechanisms at different tissue sites: it regulates cell polarity and asymmetric division via aPKC/Numb/Notch in lung epithelium, and the Six1/Eya1 complex directly activates Fgf8 in a Tbx1-dependent pathway controlling cardiovascular and craniofacial development.

    Evidence Eya1-/- knockout with Notch genetic rescue in lung; compound Six1/Eya1 knockouts with ChIP for Fgf8 and genetic interaction with Tbx1

    PMID:21364285 PMID:21385765

    Open questions at the time
    • Direct phosphatase substrate in aPKC/Numb pathway not biochemically identified at this point
    • Whether Eya1 phosphatase activity is required for Fgf8 regulation untested
  9. 2012 High

    The chromatin-remodeling mechanism of EYA1/SIX1 was defined: they recruit the SWI/SNF complex (BRG1/BAF170) to activate Neurog1 and NeuroD1 transcription, and cooperate with SOX2 to activate Atoh1 via direct binding to conserved enhancer elements, while EYA1 protein levels are themselves regulated by APC/C-Cdh1-mediated proteasomal degradation during the cell cycle.

    Evidence Co-immunoprecipitation of SWI/SNF subunits, BRG1 ATPase-dead rescue, cochlear explant overexpression with enhancer mutagenesis, cell-cycle synchronization with Cdh1 gain/loss-of-function

    PMID:22340499 PMID:22513373 PMID:23263983

    Open questions at the time
    • Whether SWI/SNF recruitment is direct or bridged by additional factors unclear
    • Functional consequence of cell-cycle-dependent EYA1 oscillation for developmental decisions not tested
  10. 2013 High

    A 2.0 Å crystal structure of SIX1 bound to EYA2 revealed the atomic interface and showed that a single-helix contact is essential for EYA interaction, EMT, and metastasis, rationalizing BOR mutations; concurrently, EYA1 phosphatase activity was shown to be required for cyclin D1 transcription via recruitment of CBP and RNA Pol II to the AP-1 promoter site.

    Evidence X-ray crystallography of SIX1–EYA2, mutagenesis, mouse metastasis model; phosphatase-dead mutant rescue with ChIP at cyclin D1 promoter

    PMID:23435380 PMID:23636126

    Open questions at the time
    • Structure solved with EYA2, not EYA1; whether interface is identical for EYA1 assumed but not demonstrated crystallographically
    • How phosphatase activity mechanistically links to CBP recruitment unresolved
  11. 2014 High

    Multiple studies defined EYA1 regulation and substrate specificity: its threonine phosphatase activity dephosphorylates Myc pT58 to stabilize Myc and maintain nephron progenitor self-renewal; Six proteins protect EYA1 from proteasomal degradation (BOR mutations disrupt this); and PI3K/Akt phosphorylation of EYA1 reduces its inhibitory SUMOylation to enhance transcriptional activity.

    Evidence Conditional kidney KO with Co-IP and phosphatase assay; proteasome inhibitor and stability assays with BOR mutants; in vitro kinase and SUMOylation assays with transcription reporters

    PMID:24489909 PMID:24954506 PMID:25458011

    Open questions at the time
    • Whether Akt-dependent de-SUMOylation operates in developmental (non-cancer) contexts untested
    • In vivo validation of PI3K/Akt–EYA1–SUMO axis in organogenesis lacking
  12. 2016 High

    Biochemical dissection of EYA1's HAD domain established it possesses dual tyrosine and threonine phosphatase activities; NMR analysis revealed striking conformational selectivity for Myc pT58 dephosphorylation, and both N- and C-terminal domains contribute to substrate engagement.

    Evidence In vitro phosphatase assays, NMR structural analysis, shRNA depletion with ubiquitination assays

    PMID:27795300

    Open questions at the time
    • Full substrate spectrum of EYA1 phosphatase undefined
    • No high-resolution structure of EYA1 HAD domain with bound substrate
  13. 2017 High

    EYA1 threonine phosphatase was shown to directly dephosphorylate Notch1 ICD at pT2122, stabilizing Notch1 ICD and maintaining Notch signaling in non-neuronal epibranchial placodal cells, providing a mechanistic link between EYA1 phosphatase activity and binary cell fate decisions.

    Evidence Eya1-/- knockout, in vitro phosphatase assay with Notch1 ICD substrate, protein stability and lineage tracing

    PMID:29140246

    Open questions at the time
    • Whether EYA1–Notch axis operates in other Notch-dependent tissues unknown
    • Kinase responsible for Notch1 T2122 phosphorylation not identified
  14. 2021 High

    EYA1 was shown to dephosphorylate aPKC at T410 in its activation loop, directly inactivating the kinase and thereby promoting symmetric cell divisions downstream of Shh signaling in cerebellar granule cell precursors, completing the biochemical identification of the aPKC substrate first implicated in 2011.

    Evidence In vitro phosphatase assay with aPKC substrate, Shh pathway gain/loss-of-function, spindle orientation imaging

    PMID:33472197

    Open questions at the time
    • Whether EYA1 dephosphorylates aPKC in lung epithelium (as hypothesized in 2011) not directly tested
    • Whether other cell polarity substrates exist beyond aPKC unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full substrate repertoire of EYA1's dual phosphatase activity, whether its phosphatase and co-activator functions are always coupled or independently deployed in different contexts, and the structural basis for EYA1's own HAD domain with substrate bound.
  • No high-resolution structure of EYA1 HAD domain (structures available are for SIX1–EYA2)
  • Complete phosphatase substrate catalog undefined
  • Relative in vivo contributions of phosphatase vs. co-activator functions untested in most organ systems

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0140110 transcription regulator activity 6
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 8 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 1 R-HSA-4839726 Chromatin organization 1
Partners
AKT1BAF170BRG1CDH1SIX1SIX2SOX2
Complex memberships
EYA1–SIX1 transcriptional complexEYA1–SIX1–SWI/SNF (BRG1/BAF170)

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 EYA1 encodes a human homologue of the Drosophila eyes absent gene and defines a novel gene family sharing a highly conserved 271-amino acid C-terminal region (eyaHR/Eya domain); mutations cluster within this domain in BOR syndrome patients. Positional cloning, sequence analysis, mutation screening Nature genetics High 9020840
1999 Eya1 homozygous knockout mice lack ears and kidneys due to defective inductive tissue interactions and apoptotic regression of organ primordia; Six (but not Pax) expression is Eya1-dependent in ear and kidney, placing Eya1 upstream of Six in a conserved Pax-Eya-Six regulatory hierarchy; Gdnf expression in metanephric mesenchyme requires Eya1, positioning Eya1 upstream of Gdnf in the kidney developmental cascade. Gene knockout (Eya1-/- mice), in situ hybridization, genetic epistasis Nature genetics High 10471511
2001 BOR-associated missense point mutations in the Eya domain do not alter EYA1 protein subcellular localization but disrupt protein-protein interactions (with Six proteins) in both yeast two-hybrid and mammalian cell assays, identifying the Eya domain as the protein-protein interaction interface. Yeast two-hybrid, co-immunoprecipitation in mammalian cells, immunofluorescence localization Human molecular genetics High 11734542
2002 Eya1 is required for the morphogenesis of thymus, parathyroid, and thyroid; Six1 expression in pharyngeal arch mesenchyme, pouch endoderm, and surface ectoderm is Eya1-dependent, extending the Eya1→Six1 regulatory hierarchy to pharyngeal organogenesis. Eya1-/- mouse knockout, in situ hybridization, marker gene expression analysis Development (Cambridge, England) High 12070080
2004 SIX1 mutations causing BOR/BO syndrome disrupt EYA1-SIX1 protein-protein interaction and SIX1-DNA binding, demonstrating that EYA1 and SIX1 function together as a bipartite transcription complex requiring direct interaction for organogenesis. Mutation identification by sequencing, protein-protein interaction assays, protein-DNA interaction assays Proceedings of the National Academy of Sciences of the United States of America High 15141091
2004 Eya1 and Six1 are required for cranial sensory neurogenesis; in the epibranchial placodes, epibranchial progenitor cells fail to express Neurog2 and downstream bHLH and Phox2 genes in Eya1 mutants, placing Eya1 upstream of Neurog2 and neuronal differentiation genes in a conserved Eya-Six regulatory hierarchy. Eya1-/- and Six1-/- mouse knockouts, in situ hybridization, marker gene expression analysis Development (Cambridge, England) High 15496442
2004 Six1 and Eya1 proteins accumulate preferentially in nuclei of fast-twitch muscles; forced coexpression of Six1 and Eya1 in slow-twitch soleus muscle drives fiber-type transition to fast-twitch glycolytic phenotype, identifying Six1/Eya1 as a transcriptional complex controlling skeletal muscle fiber-type identity via MEF3 DNA binding elements. Immunofluorescence localization, in vivo forced expression in adult muscle, fiber-type marker analysis Molecular and cellular biology High 15226428
2004 Eya1HR (Eya domain) interacts with Six1 in yeast two-hybrid assays; Six1 co-expression causes nuclear translocation of cytoplasmic Eya1HR/Eya4HR, demonstrating that Six proteins are required for nuclear localization of Eya proteins. Yeast two-hybrid, immunofluorescence co-localization Journal of the Association for Research in Otolaryngology : JARO Medium 15492887
2006 Eya1 and Eya2 act genetically upstream of Pax3 in the formation of ventrolateral dermomyotome hypaxial lips; Six proteins recruit Eya proteins to drive transcription via MEF3 DNA sites during embryogenesis in the somites; double Eya1/Eya2 knockout recapitulates the Six1/Six4 double knockout muscle phenotype, indicating Eya-Six biochemical cooperation is essential for hypaxial myogenesis. Compound mouse knockouts (Eya1-/-;Eya2-/-, Six1-/-;Six4-/-), genetic epistasis, in vivo transcription reporter assays Developmental biology High 17098221
2008 Eya1 co-localizes with Sox2 in inner ear sensory progenitors, and the two proteins physically interact; Eya1 is initially expressed in all sensory region progenitors and later restricted to differentiating hair cells, indicating a concentration-dependent role in regulating sensory organ patterning and hair cell differentiation. Allelic series (hypomorphic/null), co-immunoprecipitation, immunofluorescence co-localization, marker gene expression Human molecular genetics High 18678597
2010 Sipl1 and Rbck1 are novel Eya1-binding partners identified by GST pulldown and co-immunoprecipitation; these proteins enhance Eya1 co-activator function with Six transcription factors; morpholino knockdown of their zebrafish orthologs produces BOR syndrome-like phenotypes. GST pulldown, co-immunoprecipitation, morpholino knockdown in zebrafish Molecular and cellular biology Medium 20956555
2011 Eya1 regulates cell polarity, mitotic spindle orientation, and asymmetric localization of the cell fate determinant Numb in distal embryonic lung epithelium, probably by controlling aPKCζ phosphorylation; loss of Eya1 leads to symmetric Numb segregation and inactivation of Notch signaling, and genetic activation of Notch partially rescues the Eya1-/- lung phenotype. Eya1-/- mouse knockout, live imaging/immunofluorescence, Notch genetic rescue experiments Development (Cambridge, England) High 21385765
2011 Murine double mutant of Six1 and Eya1 recapitulates del22q11 (DiGeorge) syndrome features; the Six1/Eya1 transcription complex directly regulates Fgf8 as a downstream effector; Six1/Eya1 genetically interacts with Fgf8 and Tbx1, establishing a Tbx1-Six1/Eya1-Fgf8 genetic pathway controlling cardiovascular and craniofacial morphogenesis. Compound mouse knockouts, ChIP/direct target validation, genetic interaction analysis The Journal of clinical investigation High 21364285
2012 EYA1 and SIX1 interact directly with SWI/SNF chromatin-remodeling subunits BRG1 and BAF170; the ATPase activity of BRG1 is required for EYA1/SIX1-induced ectopic neurogenesis and normal otocyst neurogenesis; EYA1/SIX1 drive neurogenesis by recruiting the SWI/SNF complex to mediate Neurog1 and NeuroD1 transcription. Co-immunoprecipitation, gain-of-function overexpression, BRG1 ATPase mutant rescue experiments, in vitro neurogenesis assay Development (Cambridge, England) High 22513373
2012 Eya1/Six1 coexpression in cochlear explants is sufficient to induce hair cell fate in nonsensory epithelium by activating Atoh1-dependent and Atoh1-independent pathways; Sox2 cooperates with Eya1/Six1 to synergistically activate Atoh1 transcription via direct binding to conserved Sox- and Six-binding sites in Atoh1 enhancers; Eya1, Six1, and Sox2 physically interact. Cochlear explant overexpression, reporter assays with enhancer mutagenesis, co-immunoprecipitation Developmental cell High 22340499
2012 EYA1 protein level fluctuates during the cell cycle, peaking in mitosis and dropping at M-to-G1 transition; EYA1 is targeted for ubiquitin-mediated proteasomal degradation by APC/C-Cdh1; Cdh1 physically interacts with EYA1, and Cdh1 overexpression reduces EYA1 levels while Cdh1 knockdown stabilizes EYA1. Co-immunoprecipitation, RNAi knockdown, overexpression, cell cycle synchronization with protein level measurement Molecular and cellular biology High 23263983
2013 Crystal structure of SIX1 bound to EYA2 at 2.0 Å reveals SIX1 uses predominantly a single helix to contact EYA; substitution of a single amino acid in this helix disrupts SIX1-EYA interaction, SIX1-mediated EMT, and metastasis in mouse models; structure rationalizes BOR syndrome missense mutations. X-ray crystallography (2.0 Å), mutagenesis, mouse metastasis model Nature structural & molecular biology High 23435380
2013 EYA1 phosphatase activity is required for breast cancer cell proliferation; EYA1 recruits to the cyclin D1 AP-1 promoter site, and its phosphatase function determines recruitment of CBP, RNA polymerase II, and H3K9 acetylation at that site, driving cyclin D1 transcriptional induction. Phosphatase domain mutant rescue, chromatin immunoprecipitation (ChIP), reporter assay with AP-1 site mutation Cancer research High 23636126
2014 Eya1 interacts with Six2 and Myc in nephron progenitor cells; Six2 mediates nuclear translocation of Eya1; nuclear Eya1 uses its threonine phosphatase activity to dephosphorylate and stabilize Myc, controlling progenitor cell self-renewal; conditional Eya1 inactivation causes loss of Six2 expression and premature epithelialization. Conditional knockout, co-immunoprecipitation, cell fate tracing, phosphatase activity assay Developmental cell High 25458011
2014 BOR-associated Eya1 missense mutations S454P, L472R, and L550P lead to enhanced proteasomal degradation of Eya1 protein; Six proteins protect Eya1 from proteasomal degradation, providing a novel disease mechanism; loss of Six interaction (L550P) is sufficient to cause rapid protein degradation. Proteasome inhibitor assays, co-immunoprecipitation, western blot stability assays PloS one Medium 24489909
2014 PI3K/Akt1 kinase physically interacts with EYA1, phosphorylates a conserved Akt consensus site on EYA1, and this phosphorylation reduces EYA1 SUMOylation; SUMOylation inhibits EYA1 transcription activity; pharmacologic/genetic PI3K/Akt activation reduces EYA1 SUMOylation and enhances its transcriptional activity. Co-immunoprecipitation, in vitro kinase assay, SUMOylation assay, transcription reporter assay, mutant rescue in breast cancer cells Oncogene High 24954506
2015 Eya1 phosphatase activity cooperates with Six1 to promote gene induction in response to Sonic hedgehog (Shh) signaling by regulating Gli transcriptional activators; Eya1 is required for Shh-dependent hindbrain growth and drives medulloblastoma growth. shRNA phosphatome screen, genetic loss-of-function, reporter assay, in vivo mouse brain tumor model Developmental cell High 25816987
2016 EYA1's conserved C-terminal haloacid dehalogenase (HAD) domain has dual phosphatase activities (tyrosine and threonine); EYA1 dephosphorylates phospho-T58 of Myc with striking conformational preference; depletion of EYA1 destabilizes Myc by increasing pT58 and promoting FBW7-mediated ubiquitination; both N- and C-terminal domains of EYA1 interact with substrates to enhance catalytic activity. In vitro phosphatase assay, NMR structural analysis, shRNA depletion, ubiquitination assay, co-immunoprecipitation Molecular and cellular biology High 27795300
2017 Eya1 threonine phosphatase activity dephosphorylates p-threonine-2122 of the Notch1 intracellular domain (Notch1 ICD), increasing Notch1 ICD stability and maintaining Notch signaling activity in non-neuronal epibranchial placodal cells; this Eya1-Notch axis specifies bipotential epibranchial differentiation into neuronal and non-neuronal lineages. Eya1-/- mouse knockout, phosphatase activity assays with Notch1 ICD substrate, protein stability assays, genetic lineage tracing eLife High 29140246
2021 Eya1 phosphatase dephosphorylates a critical threonine (T410) in the activation loop of atypical protein kinase C (aPKC), inactivating aPKC; this reduces phosphorylation of Numb and other spindle orientation regulators, promoting Shh-dependent symmetric cell divisions in cerebellar granule cell precursors (GCPs). In vitro phosphatase assay with aPKC substrate, gain/loss-of-function Shh pathway mutants, spindle orientation imaging, phospho-specific antibodies Developmental neuroscience High 33472197

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
1997 A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family. Nature genetics 513 9020840
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 305 15141091
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
2012 Eya1-Six1 interaction is sufficient to induce hair cell fate in the cochlea by activating Atoh1 expression in cooperation with Sox2. Developmental cell 193 22340499
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 164 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 148 10370123
1978 Genetic aspects of the BOR syndrome--branchial fistulas, ear pits, hearing loss, and renal anomalies. American journal of medical genetics 139 263442
1987 Complete amino acid sequences of variable regions of two human IgM rheumatoid factors, BOR and KAS of the Wa idiotypic family, reveal restricted use of heavy and light chain variable and joining region gene segments. The Journal of experimental medicine 133 2439644
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 122 17098221
2011 A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis. The Journal of clinical investigation 112 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) 109 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 97 25458011
2013 Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome. Nature structural & molecular biology 96 23435380
1994 A proposed new contiguous gene syndrome on 8q consists of Branchio-Oto-Renal (BOR) syndrome, Duane syndrome, a dominant form of hydrocephalus and trapeze aplasia; implications for the mapping of the BOR gene. Human molecular genetics 96 7849713
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 88 18571637
2004 Diversity and abundance of Bacteria and Archaea in the Bor Khlueng Hot Spring in Thailand. Journal of basic microbiology 88 15558824
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
1995 bor gene of phage lambda, involved in serum resistance, encodes a widely conserved outer membrane lipoprotein. Journal of bacteriology 84 7868598
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 78 21280147
2008 Branchio-oto-renal syndrome (BOR): novel mutations in the EYA1 gene, and a review of the mutational genetics of BOR. Human mutation 78 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
2008 SIX1 mutation screening in 247 branchio-oto-renal syndrome families: a recurrent missense mutation associated with BOR. Human mutation 71 18330911
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 59 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 Dissecting the pre-placodal transcriptome to reveal presumptive direct targets of Six1 and Eya1 in cranial placodes. eLife 42 27576864
2016 MicroRNA-101 inhibits cell proliferation and induces apoptosis by targeting EYA1 in breast cancer. International journal of molecular medicine 41 27082308
1998 Autosomal-dominant branchio-otic (BO) syndrome is not allelic to the branchio-oto-renal (BOR) gene at 8q13. American journal of medical genetics 41 9556298
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
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
2013 Mutational analysis of EYA1, SIX1 and SIX5 genes and strategies for management of hearing loss in patients with BOR/BO syndrome. PloS one 34 23840632
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
1998 Description of a large kindred with autosomal dominant inheritance of branchial arch anomalies, hearing loss, and ear pits, and exclusion of the branchio-oto-renal (BOR) syndrome gene locus (chromosome 8q13.3). American journal of medical genetics 31 9788564
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
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
2012 EYA1-SIX1 complex in neurosensory cell fate induction in the mammalian inner ear. Hearing research 26 23104013
2006 Point mutation of an EYA1-gene splice site in a patient with oto-facio-cervical syndrome. Annals of human genetics 26 16441263
2000 Exclusion of the branchio-oto-renal syndrome locus (EYA1) from patients with branchio-oculo-facial syndrome. American journal of medical genetics 25 10767004
2020 BCOR Binding to MLL-AF9 Is Essential for Leukemia via Altered EYA1, SIX, and MYC Activity. Blood cancer discovery 24 32954361
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
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
2006 EYA1 and SIX1 gene mutations in Japanese patients with branchio-oto-renal (BOR) syndrome and related conditions. Pediatric nephrology (Berlin, Germany) 23 16491411
1999 New' manifestations of BOR syndrome. Clinical genetics 23 10636449
2013 Abrogation of Eya1/Six1 disrupts the saccular phase of lung morphogenesis and causes remodeling. Developmental biology 22 23895934
2007 Detection of Iss and Bor on the surface of Escherichia coli. Journal of applied microbiology 22 17309614
2007 Phenotypic consequences in a Japanese family having branchio-oto-renal syndrome with a novel frameshift mutation in the gene EYA1. Acta oto-laryngologica 21 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
1996 Detection of a megabase deletion in a patient with branchio-oto-renal syndrome (BOR) and tricho-rhino-phalangeal syndrome (TRPS): implications for mapping and cloning the BOR gene. Genomics 21 8824802
2019 EYA1 promotes cell migration and tumor metastasis in hepatocellular carcinoma. American journal of translational research 20 31105839
2018 Molecular characterization of the genome-wide BOR transporter gene family and genetic analysis of BnaC04.BOR1;1c in Brassica napus. BMC plant biology 20 30217178
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
2005 Chromosome-borne class A BOR-1 beta-Lactamase of Bordetella bronchiseptica and Bordetella parapertussis. Antimicrobial agents and chemotherapy 20 15917575
2004 EYA1 mutation in a newborn female presenting with cardiofacial syndrome. Pediatric cardiology 20 15493068
2016 Biochemical parameters of Spodoptera frugiperda (J. E. Smith) treated with citronella oil (Cymbopogon winterianus Jowitt ex Bor) and its influence on reproduction. Acta histochemica 19 27012436
2006 Characterization of a novel cyclomaltodextrinase expressed from environmental DNA isolated from Bor Khleung hot spring in Thailand. FEMS microbiology letters 19 16790023
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
2018 EYA1 promotes tumor angiogenesis by activating the PI3K pathway in colorectal cancer. Experimental cell research 15 29496520
1994 Localization of branchio-oto-renal (BOR) syndrome to a 3 Mb region of chromosome 8q. American journal of medical genetics 15 8092198
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
2022 Molecular Characterization, Evolutionary Analysis, and Expression Profiling of BOR Genes in Important Cereals. Plants (Basel, Switzerland) 13 35406892