| 2018 |
The Ser/Thr phosphatase activity of Eya3 is not intrinsic but arises from its direct interaction with the PP2A-B55α holoenzyme. Eya3 alters PP2A regulation of c-Myc by enabling PP2A-B55α to dephosphorylate pT58 on c-Myc, increasing c-Myc stability—in direct contrast to PP2A-B56α-mediated dephosphorylation of pS62 which destabilizes c-Myc. Eya3 and PP2A-B55α promote metastasis in a xenograft model of breast cancer. |
Co-immunoprecipitation, in vitro phosphatase assays, mutagenesis, xenograft model |
Nature communications |
High |
29535359
|
| 2025 |
Cryo-EM and NMR structures of PP2A:B55 with Eya3 reveal that Eya3 binds B55α through an extended peptide in the N-terminal domain. Eya3 and PP2A substrates share a common set of interaction pockets on B55α but with distinct binding mechanisms. The core B55 recruitment motif in Eya3 is conserved across the Eya family. NMR-based dephosphorylation assays demonstrated that B55 recruitment by Eya3 directs selective dephosphorylation of specific phosphosites. |
Cryo-electron microscopy, NMR spectroscopy, NMR-based dephosphorylation assays |
Nature structural & molecular biology |
High |
40247147
|
| 2025 |
Cryo-EM structures of PP2A-B55α bound with Eya3 show that Eya3 binds B55α through an extended peptide in the Eya3 N-terminal domain. A competitive inhibitory peptide (B55i) disrupts the B55α–Eya3 interaction in vitro; when expressed in TNBC cells, B55i increases Myc pT58 and decreases Myc protein levels, confirming functional relevance of the Eya3–PP2A-B55α interaction for Myc stability. |
Cryo-electron microscopy, in vitro binding/inhibition assays, cell-based Myc phosphorylation/protein level assays |
The Journal of biological chemistry |
High |
39975004 40414499
|
| 2018 |
Eya3 utilizes its Thr phosphatase activity (via PP2A-B55α) to dephosphorylate Myc at pT58, producing stabilized Myc, which is required for Eya3-mediated upregulation of PD-L1. Eya3 loss decreases tumor growth in immune-competent mice, increases CD8+ T cell infiltration, and CD8+ T cell depletion reverses the effects of Eya3 knockdown. |
Knockdown experiments, phosphatase assays, CD8+ T cell depletion, in vivo tumor growth assays, rescue experiments (PD-L1 re-expression) |
The Journal of clinical investigation |
High |
29757193
|
| 2025 |
EYA3 up-regulates NF-κB signaling to enhance CCL2 expression, which suppresses cytotoxic NK cell activation and infiltration into the pre-metastatic niche (PMN), thereby promoting TNBC metastasis. Restoration of NF-κB signaling downstream of Eya3 knockdown rescues metastasis without restoring primary tumor growth, isolating EYA3/NF-κB effects to the metastatic site. |
Knockdown experiments, NF-κB pathway rescue, in vitro NK cell activation assays, in vivo PMN analysis |
Science advances |
High |
39211066 40333987
|
| 2018 |
EYA3 tyrosine phosphatase activity promotes the survival of pulmonary arterial smooth muscle cells under DNA-damaging conditions. Transgenic mice with an inactivating mutation in the EYA3 tyrosine phosphatase domain are significantly protected from vascular remodeling. Pharmacological inhibition of EYA3 tyrosine phosphatase substantially reverses vascular remodeling in a rat model of pulmonary hypertension. |
Transgenic mouse with phosphatase-dead EYA3 mutation, pharmacological inhibition, rat disease model |
Nature communications |
High |
31515519
|
| 2018 |
WDR1 is a substrate of EYA3 tyrosine phosphatase but not EYA1. Src kinase phosphorylates tyrosine residues in EYA3, and EYA3 can autodephosphorylate these residues. Src phosphorylation of EYA3 controls its subcellular localization (nuclear and cytoskeletal). EYA3-mediated dephosphorylation of WDR1 induces major changes in cellular actin cytoskeleton organization. |
Phosphotyrosine peptide microarray, in vitro phosphatase assays, subcellular fractionation/localization, actin cytoskeleton imaging |
Scientific reports |
Medium |
29440662
|
| 2019 |
Src kinase phosphorylates EYA3 at 13 tyrosine residues with different phosphorylation and autodephosphorylation kinetics. Residues Y77, Y96, and Y237 are involved in cell proliferation; mutation of these three residues abolishes the pro-proliferative effect of EYA3 overexpression. EYA3 controls its own phosphorylation state through autodephosphorylation. |
Native and bottom-up mass spectrometry, site-directed mutagenesis, cell cycle analysis in HEK293T cells |
International journal of molecular sciences |
Medium |
31847183
|
| 2012 |
EYA3 is regulated by the EWS/FLI1 fusion protein via repression of miR-708, which targets the EYA3 3'-UTR, rather than through direct promoter binding. EYA3 knockdown in Ewing sarcoma cells sensitizes them to DNA-damaging chemotherapeutics and impairs DNA damage repair, implicating EYA3 as a mediator of chemoresistance. |
miRNA luciferase reporter assay, EYA3 knockdown, DNA damage/repair assays, chemotherapy sensitivity assays |
Molecular cancer research : MCR |
Medium |
22723308
|
| 2021 |
EYA3 tyrosine phosphatase activity regulates VEGFA levels in Ewing sarcoma tumors and promotes DNA damage repair and cell survival. Pharmacological inhibition of EYA3 tyrosine phosphatase (benzarone) inhibits tumor growth and angiogenesis. Elevated EYA3 substrate H2AX-pY142 upon EYA3 loss confirms H2AX-pY142 as an EYA3 substrate in vivo. |
Genetic knockdown and pharmacological inhibition, xenograft tumor model, patient-derived xenograft, H2AX-pY142 substrate measurement |
Molecular cancer therapeutics |
Medium |
33649104
|
| 2010 |
Eya3 and its partner Six1 synergistically activate TSHβ expression in the pars tuberalis upon long-day photoperiod stimulation, and this activation is further enhanced by Tef and Hlf. Eya3 expression is acutely induced by late-night light stimulation and precedes TSHβ induction, placing Eya3 upstream of TSHβ in the photoperiodic pathway. |
Genome-wide expression analysis, transcriptional reporter assays, acute light stimulation experiments in CBA/N mice |
Current biology : CB |
Medium |
20434341 21129973
|
| 2008 |
Ski directly interacts with Six1 and Eya3 via the Dachshund homology domain of Ski to form a complex that binds the MEF3 site on the Myog regulatory region and activates myogenin (Myog) transcription during muscle terminal differentiation. This interaction is required for Ski-mediated promotion of myoblast differentiation. |
Chromatin immunoprecipitation (ChIP), transcriptional reporter assays, retroviral overexpression/knockdown, co-immunoprecipitation |
The Journal of biological chemistry |
Medium |
19008232
|
| 2022 |
Hypoxia-induced EYA3 couples with SIX5 and the histone acetyltransferase p300 to form a complex that transactivates EGFR, VEGFD, and multiple MMPs (MMP3, MMP7, MMP8, MMP21, MMP26) by binding their promoters in colorectal cancer. Disruption of the EYA3-SIX5-p300 complex decreases expression of these targets and inhibits CRC cell growth. |
Co-immunoprecipitation, mass spectrometry, chromatin immunoprecipitation (ChIP), tumor xenograft model, benzarone inhibitor treatment |
Annals of translational medicine |
Medium |
35957720
|
| 2023 |
RBFOX2 regulates alternative splicing of EYA3 exon 7, generating tissue-specific isoforms. Different EYA3 isoforms differentially partner with either SIX4 or ZBTB1 transcription factors to dictate gene expression during myogenesis. EYA3 expression is required for myoblast proliferation and differentiation. |
Mass spectrometry-based proteomics, genome-wide transcriptomics, knockdown experiments, alternative splicing analysis |
iScience |
Medium |
38026174
|
| 2021 |
A missense variant in EYA3 (p.Asn358Ser) increases the half-life of the mutated protein without affecting its ability to dephosphorylate H2AFX following DNA damage repair pathway induction. Knockdown of eya3 in zebrafish embryos produces craniofacial abnormalities consistent with oculo-auriculo-vertebral spectrum. |
Cellular protein stability assay, H2AFX dephosphorylation assay, zebrafish knockdown morphant analysis, exome sequencing |
Human genetics |
Medium |
33475861
|
| 2024 |
EYA3 promotes gastric cancer cell proliferation by activating the mTORC1 signaling pathway and inhibiting autophagy. EYA3 silencing reduces cell proliferation in vitro and slows tumor growth in vivo in a xenograft model. |
Gene silencing, gene set enrichment analysis, in vitro proliferation assays, xenograft tumor model |
Scientific reports |
Low |
39550476
|