Affinage

ETV5

ETS translocation variant 5 · UniProt P41161

Length
510 aa
Mass
57.8 kDa
Annotated
2026-06-09
100 papers in source corpus 41 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ETV5 is a PEA3-subfamily ETS transcription factor that serves as a transcriptional effector positioned downstream of receptor tyrosine kinase/MEK–ERK signaling to control tissue-specific programs of stem-cell maintenance, cell identity, and cancer invasion (PMID:16107850, PMID:28351980, PMID:29321660). Its DNA-binding activity is intrinsically autoinhibited: an α-helix in the C-terminal inhibitory domain packs against the ETS domain to perturb the DNA-recognition helix, while the intrinsically disordered N-terminal inhibitory domain makes transient repressive contacts that are relieved by lysine acetylation, and all PEA3 members crystallize as disulfide-linked dimers whose reduction to monomers raises DNA-binding affinity 40–200-fold, defining a redox-dependent switch (PMID:25866208, PMID:28161714). ETV5 protein levels are tightly set by the ubiquitin–proteasome system: the CRL4COP1 ligase targets ETV5 for degradation, ERK/Ras signaling stabilizes it by inactivating this ligase, and the COP9 signalosome antagonizes CRL4COP1 assembly—a balance disrupted in congenital hyperinsulinism (PMID:28351980, PMID:33911083). Once activated, ETV5 binds ETS consensus elements in target promoters and enhancers to drive defined programs: in Sertoli cells it sustains the spermatogonial stem-cell niche by regulating RET and the chemokine CCL9 and self-renewal factors including Brachyury (PMID:16107850, PMID:19369650, PMID:20799334, PMID:21816850); in the kidney it acts cell-autonomously downstream of GDNF/Ret for ureteric bud branching (PMID:19898483, PMID:20463033); and in alveolar type II cells it maintains epithelial identity as a Ras output (PMID:28351980). In cancer it activates invasion- and angiogenesis-promoting targets including MMP-2, NID1/NUPR1, RET, TWIST1, PIK3CA, the mutant TERT promoter, VEGFA and PD-L1/S100A9 (PMID:17638886, PMID:29321660, PMID:30265861, PMID:31452441, PMID:25924802, PMID:40015948). ETV5 additionally directs Th17 and Th9 differentiation by recruiting histone-modifying enzymes to cytokine loci (PMID:27496971, PMID:24486067), and regulates β-cell insulin exocytosis and hepatic fatty-acid β-oxidation via PPAR response elements (PMID:24190582, PMID:33093014).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2005 High

    Established ETV5 as an in vivo transcriptional controller of a vertebrate stem-cell niche, answering whether this ETS factor has a non-redundant physiological function.

    Evidence Targeted knockout mouse with Sertoli-cell microarray and immunohistochemistry

    PMID:16107850

    Open questions at the time
    • Direct target genes within the niche not yet defined
    • Cell-autonomy in germ vs. Sertoli cells unresolved at this stage
  2. 2006 High

    Showed ETV5 acts combinatorially, cooperating with TTF-1 through its ETS domain to activate surfactant protein C, indicating it works with lineage partners rather than alone.

    Evidence Mammalian two-hybrid, co-IP, EMSA, reporter assays and siRNA in AT2 cells

    PMID:16613858

    Open questions at the time
    • Structural basis of the ETV5–TTF-1 interface not resolved
    • Genome-wide cooperative targets not mapped
  3. 2007 High

    Linked ETV5 to cancer invasion by identifying MMP-2 as a direct transcriptional target driving an invasive phenotype.

    Evidence Overexpression/RNAi, ChIP, zymography and orthotopic model in endometrial cancer

    PMID:17638886

    Open questions at the time
    • Whether MMP-2 alone accounts for invasion not established
    • Upstream signals controlling ETV5 here untested
  4. 2009 High

    Placed ETV5 downstream of GDNF/RET signaling for branching morphogenesis and in spermatogonia, defining a conserved RTK→ETV5 axis with downstream targets.

    Evidence Compound Etv4/Etv5 KO and Etv5 KO mice, transplantation, target-gene identification

    PMID:19369650 PMID:19898483

    Open questions at the time
    • Direct vs. indirect regulation of each target gene not fully separated
    • Redundancy with ETV4 not dissected in all tissues
  5. 2010 High

    Demonstrated ETV5 directly regulates Sertoli-cell chemokine (CCL9) output to attract spermatogonia and acts cell-autonomously downstream of Ret in the kidney.

    Evidence ChIP on Ccl9, chemotaxis/rescue assays, chimeric kidney analysis

    PMID:20463033 PMID:20799334

    Open questions at the time
    • Full chemokine repertoire under ETV5 control incomplete
    • Mechanism of cell rearrangement downstream of ETV5 unknown
  6. 2012 High

    Resolved the upstream cascade for SSC self-renewal, showing FGF2→MAP2K1→ETV5/Bcl6b drives proliferation independently of FGF2 when MAP2K1 is activated.

    Evidence Activated Map2k1 transfection, MEK inhibitor, GS-cell culture, transplantation

    PMID:21816850 PMID:22491947

    Open questions at the time
    • How ERK signaling converts to ETV5 activity (PTM vs. expression) not defined here
  7. 2015 High

    Defined the structural and redox basis of ETV5 DNA-binding autoinhibition, explaining how its activity can be conformationally and oxidatively gated.

    Evidence X-ray crystallography of ETS domain plus redox DNA-binding assays

    PMID:25866208

    Open questions at the time
    • Physiological trigger of disulfide reduction in cells not identified
    • In vivo relevance of dimerization unmeasured
  8. 2017 High

    Extended the autoinhibition model to a disordered N-terminal domain relieved by acetylation, and identified CRL4COP1/DET1 as the ERK-stabilized degradation route controlling ETV5 abundance and AT2 identity.

    Evidence Crystallography/NMR/mutagenesis; conditional AT2 KO with injury and Kras models

    PMID:28161714 PMID:28351980

    Open questions at the time
    • Acetyltransferase responsible for NID acetylation unidentified
    • Direct AT2 identity target genes of ETV5 not fully mapped
  9. 2018 High

    Showed ETV5 is a recurrent ERK-stabilized output that drives RET transcription in neuroblastoma and TWIST1 in thyroid cancer, generalizing the RTK/MAPK→ETV5→oncogene logic.

    Evidence ChIP-seq/ChIP-qPCR, reporter assays, RNAi, ALK and MAPK inhibitors

    PMID:29321660 PMID:30265861

    Open questions at the time
    • Relative contribution of stabilization vs. transcriptional induction of ETV5 not quantified
    • Other co-regulated targets at these loci unknown
  10. 2019 High

    Defined signal-dependent genomic relocalization of ETV5 during pluripotency exit and its derepression by loss of the CIC repressor in T cells, showing context determines its enhancer occupancy and output.

    Evidence Triple-KO ESCs with enhancer profiling; CIC conditional KO with Etv5 knockdown

    PMID:28855737 PMID:31031137

    Open questions at the time
    • Determinants of context-specific enhancer selection unresolved
    • How ERK rewires ETV5 binding mechanistically unclear
  11. 2021 High

    Established the COP1/CSN antagonism over CRL4-mediated ETV5 ubiquitylation as a glucose-responsive switch whose disruption causes congenital hyperinsulinism, and showed neddylation inhibition stabilizes ETV5.

    Evidence Csn2 K70E knock-in mice, diet/ob-ob models, CRL4-assembly and ubiquitylation assays, human islets

    PMID:33911083

    Open questions at the time
    • β-cell ETV5 target genes mediating exocytosis not fully defined
    • Generalizability of IP6-CSN mechanism to other tissues untested
  12. 2025 High

    Showed ETV5 transactivates immune-evasion targets PD-L1 and S100A9 in HCC, with S100A9 forming an ERK/NF-κB feed-forward loop, identifying tumor- and myeloid-cell-intrinsic immunosuppressive roles.

    Evidence ChIP-seq, CUT&Tag, RNA-seq, humanized/orthotopic HCC models, myeloid-specific KO

    PMID:40015948

    Open questions at the time
    • Therapeutic targetability of ETV5 in this loop not tested
    • Interplay with the CRL4COP1 degradation axis in tumor immunity unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • How tissue-specific cofactors and signal-driven post-translational modifications jointly direct ETV5 to distinct enhancer sets to produce opposing context-dependent outputs remains unresolved.
  • No unified model linking PTM state to genomic occupancy across tissues
  • Physiological trigger of redox-controlled DNA binding in vivo unknown
  • Cofactor logic distinguishing activator vs. repressor modes incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0003677 DNA binding 4 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-392499 Metabolism of proteins 2
Partners
CICCOP1FOXE1MAST4TTF-1

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 ETV5 (ERM) is expressed exclusively in Sertoli cells in the testis and is required for spermatogonial stem cell (SSC) self-renewal; targeted disruption of ETV5 causes progressive germ-cell depletion and Sertoli-cell-only syndrome without blocking spermatogenic differentiation. Microarray analysis of primary Sertoli cells from ETV5-deficient mice showed alterations in secreted factors known to regulate the haematopoietic stem cell niche, identifying ETV5 as a transcriptional controller of the vertebrate stem cell niche. Targeted gene disruption (knockout mouse), microarray analysis of primary Sertoli cells, immunohistochemistry Nature High 16107850
2007 ETV5 mRNA expression in Sertoli cells is upregulated by FGF2 in a time- and dose-dependent manner via both MAPK and PI3K signaling cascades; EGF also stimulates ETV5 mRNA but not GDNF mRNA, indicating distinct upstream regulators for each gene. Treatment of TM4 Sertoli cell line and primary Sertoli cells with FGF2, EGF, TNFα, and pathway inhibitors (PD98059 for MAPK, wortmannin for PI3K); quantitative RT-PCR Experimental cell research Medium 17574550
2007 ETV5 regulates MMP-2 gelatinase activity in endometrial cancer; ETV5 overexpression induces scattering in Hec-1A cells and increased MMP-2 activity. Chromatin immunoprecipitation demonstrated direct ETV5 binding to the MMP-2 promoter, and RNAi knockdown or MMP-2-specific inhibition reversed the invasive phenotype in vitro and in an orthotopic mouse model. Stable overexpression and RNAi knockdown in endometrial cancer cell lines, ChIP, gelatin zymography, orthotopic mouse model Cancer research High 17638886
2008 ETV5 is the fourth ETS family member involved in recurrent gene rearrangements in prostate cancer; TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions drive ETV5 overexpression. In vitro recapitulation of ETV5 overexpression in benign prostatic epithelial RWPE cells induced cell invasion and an invasive transcriptional program. RNA ligase-mediated RACE, quantitative PCR, FISH, stable overexpression in RWPE cells, invasion assays, expression profiling Cancer research High 18172298
2008 ETV5 functions as a transcriptional regulator of cyclooxygenase-2 (PTGS2) in granulosa and cumulus cells; ETV5 increases the transcriptional activity of the 3.2-kb mouse Ptgs2 promoter ~2.5-fold as shown by luciferase reporter assays, and both ETV5 and ETV4 are expressed in granulosa and cumulus cells during folliculogenesis. Luciferase reporter assays with Ptgs2 promoter, RT-PCR expression analysis in mouse ovarian cells The Journal of endocrinology Medium 18492810
2009 Etv4 and Etv5 are positively regulated by Ret receptor tyrosine kinase signaling in ureteric bud tips and are required downstream of GDNF/Ret for kidney branching morphogenesis; double homozygous Etv4/Etv5 knockout mice show complete failure of kidney development. Target genes identified downstream of Etv4/Etv5 include Cxcr4, Myb, Met, and Mmp14. Compound knockout mice (Etv4/Etv5), gene expression analysis, identification of downstream target genes Nature genetics High 19898483
2009 Loss of ETV5 in neonatal mice decreases RET mRNA and protein expression in spermatogonia, reduces spermatogonial proliferation in vivo and in vitro, and transplantation of Etv5-null germ cells failed to establish spermatogenesis, indicating ETV5 is required in both Sertoli and germ cells and acts upstream of RET/GFRA1 signaling. Etv5 knockout mice, immunohistochemistry, quantitative PCR, laser capture microdissection, germ cell transplantation assays Biology of reproduction High 19369650
2010 ETV5 regulates Sertoli cell chemokine expression (including CCL9) to attract stem/progenitor spermatogonia; Etv5-null Sertoli cells show decreased chemotactic activity toward SSCs, and ChIP demonstrates protein-DNA interaction between ETV5 and the Ccl9 promoter, suggesting ETV5 directly regulates Ccl9 transcription. Microarray analysis, chemotaxis assays, ChIP on Ccl9 promoter, recombinant chemokine rescue assays, ETV5 knockout mice Stem cells High 20799334
2010 Etv4 and Etv5 mediate cell-autonomous roles downstream of Ret in cell rearrangements required for ureteric bud formation; Etv4/Etv5 compound mutant cells show limited distribution in the caudal Wolffian duct and ureteric bud, phenocopying Ret-null cells in chimeric kidney analyses. Chimeric kidney analysis, compound mutant mice Development High 20463033
2011 ETV5 mediates GDNF signaling in SSCs by regulating the expression of Bcl6b, Lhx1, Brachyury (T), and Cxcr4. ETV5 binds to the Brachyury promoter region and is associated with active transcription. In vivo transplantation after Brachyury silencing significantly reduced donor-derived spermatogenic colonies, establishing Brachyury as a functional downstream target of ETV5. siRNA knockdown of Etv5, Bcl6b, Pou3f1 in SSC cultures, microarray gene expression profiling, ChIP on Brachyury promoter, in vivo spermatogonial transplantation Biology of reproduction High 21816850
2012 FGF2 mediates SSC self-renewal via MAP2K1 activation leading to upregulation of Etv5 and Bcl6b; GS cells transfected with activated Map2k1 upregulated Etv5 and Bcl6b and proliferated in an FGF2-independent manner, establishing Etv5 downstream of MAP2K1 in the FGF2 signaling pathway. MAP2K1 inhibitor (PD0325091) treatment, transfection of activated Map2k1, GS cell culture, phospho-MAPK1/3 western blots, spermatogonial transplantation Development High 22491947
2006 ETV5 (Erm) physically interacts with TTF-1 (thyroid transcription factor 1) and cooperates with it to enhance surfactant protein C (SP-C) transcription; Erm alone has little effect on SP-C promoter activity but significantly enhances TTF-1-mediated transcription. Mapping studies show the Ets domain of Erm and the combined N-terminus/homeodomain of TTF-1 are critical for this interaction. Mammalian two-hybrid assay, co-immunoprecipitation, electrophoretic mobility shift assay (EMSA), co-transfection reporter assays, siRNA knockdown in primary AT2 cells The Journal of biological chemistry High 16613858
2015 Crystal structures of the Etv5 ETS DNA-binding domain revealed an α-helix in the C-terminal inhibitory domain that packs against the ETS domain and perturbs the conformation of the DNA-recognition helix. All three proteins (Etv1, Etv4, Etv5) crystallized as disulfide-linked dimers via a novel interface; reduction to monomers increased DNA-binding affinity 40–200-fold, revealing a redox-dependent regulatory mechanism controlling DNA binding activity. X-ray crystallography (crystal structures alone and in complex with DNA), reduction/oxidation biochemical assays measuring DNA binding affinity The Journal of biological chemistry High 25866208
2017 DNA-binding autoinhibition of ETV5 is mediated by structured and disordered regions: an α-helix in the C-terminal inhibitory domain packs against the ETS domain, while the N-terminal inhibitory domain (NID) is intrinsically disordered but uses transient intramolecular interactions with the DNA-recognition helix to repress DNA binding. Acetylation of selected lysines within the NID activates DNA binding. Crystal structures, NMR spectroscopy, mutagenesis, DNA-binding assays Nucleic acids research High 28161714
2017 ERK activation downstream of Ras stabilizes ETV5 protein through inactivation of the cullin-RING ubiquitin ligase CRL4COP1/DET1 that targets ETV5 for proteasomal degradation in AT2 cells; ETV5 deletion in AT2 cells produced gene and protein signatures characteristic of AT1 cells, and ETV5 deficiency reduced recovery from bleomycin-induced lung injury. Conditional knockout mice (AT2-specific Etv5 deletion), gene/protein expression profiling, bleomycin injury model, Kras-driven tumorigenesis model Proceedings of the National Academy of Sciences of the United States of America High 28351980
2016 ETV5 promotes IL-9 production in Th9 cells by binding the Il9 locus and recruiting histone acetyltransferases at sites distinct from PU.1; ETV5 and PU.1 function in parallel, with combined deficiency producing lower IL-9 than either alone. ChIP, retroviral transduction (overexpression and knockdown), conditional T cell-specific knockout mice, in vivo allergic inflammation model Journal of immunology High 27496971
2014 ETV5 controls TH17 cell differentiation by directly promoting Il17a and Il17f expression; ETV5 is induced downstream of STAT3 and recruits histone-modifying enzymes to the Il17a-Il17f locus, resulting in increased active histone marks and decreased repressive histone marks. ChIP, reporter assays, retroviral transduction, siRNA knockdown, conditional Etv5 knockout in T cells, house dust mite allergic inflammation model The Journal of allergy and clinical immunology High 24486067
2017 ETV5 is derepressed by loss of the transcriptional repressor CIC; CIC-deficient TFH cells show excessive ETV5 expression, and Etv5 knockdown suppresses enhanced TFH cell differentiation in CIC-deficient CD4+ T cells. ETV5 activates Maf as a downstream target in this pathway. T cell-specific conditional CIC knockout mice, siRNA knockdown of Etv5, expression profiling, luciferase reporter assays Nature communications High 28855737
2018 In neuroblastoma, activated ALK signals through an ERK→ETV5→RET oncogenic axis; ALK activation upregulates ETV5 protein through MEK/ERK-dependent stabilization (post-translational), and ETV5 drives RET gene transcription by binding the RET promoter and an upstream enhancer. RNAi-mediated ETV5 inhibition decreases RET expression. ALK inhibitor treatment, RNAi knockdown, luciferase reporter assays for RET transcription, ChIP-seq confirming ETV5 binding on RET promoter and enhancer, western blots for ETV5 protein stabilization Oncogene High 29321660
2018 ETV5 is expressed downstream of the MAPK pathway (activated by BRAF V600E) in papillary thyroid cancer cells and directly upregulates TWIST1 transcription; ChIP-qPCR confirmed ETV5 binding to the TWIST1 promoter and ETV5 is required for PTC cell proliferation. RNAi knockdown, pharmacological MAPK inhibitors, EMT PCR array, ChIP-qPCR, high-throughput proliferation screening Neoplasia High 30265861
2019 ETV5 preferentially binds the mutant -124bp(T) TERT promoter allele and stimulates TERT transcription in thyroid cancer cells; ETV5 functionally cooperates with the transcription factor FOXE1 to further enhance TERTp activity. This ETS factor-specific allele selectivity was confirmed by ChIP and reporter assays. In silico TCGA analysis, immunoprecipitation, ChIP, luciferase reporter assays in thyroid cancer cell lines Thyroid High 31452441
2019 In response to ERK signaling during exit from naive pluripotency, ETV5 switches activity from supporting self-renewal and undergoes genome-wide relocalization linked to commissioning of enhancers activated in formative epiblast. Triple deletion of Etv5, Rbpj, and Tcf3 locks ESCs in self-renewal even under differentiation stimuli. Triple knockout ESC lines, ChIP/enhancer profiling, ERK signaling manipulation, colony morphology and marker analysis Cell stem cell High 31031137
2015 ETV5 directly binds the promoters of Nidogen 1 (NID1) and Nuclear Protein 1 (NUPR1) in endometrial cancer cells as demonstrated by ChIP; inhibition of NID1 and NUPR1 in ETV5-overexpressing cells reduced cell migration and invasion in vitro and reduced tumor growth in an orthotopic endometrial cancer model. ChIP, siRNA knockdown, invasion/migration assays, orthotopic endometrial cancer mouse model Clinical & experimental metastasis High 25924802
2014 ETV5 promotes invasion at the invasive front of endometrial carcinoma through a transcriptional program that includes BDNF as a principal orchestrator of ETV5-mediated EMT; ChIP-on-chip analysis at the invasive front demonstrated ETV5 binding to promoter regions of genes related to migration, adhesion, and invasion. Impairment of BDNF/TrkB/ERK axis reversed the ETV5-promoted invasive phenotype. ChIP-on-chip analysis, endometrial cancer cell line functional assays, BDNF/TrkB/ERK pharmacological inhibition, mouse metastasis model Carcinogenesis High 25233929
2013 ETV5 is required for insulin exocytosis specifically in β-cells; Etv5 knockout mice show impaired glucose-stimulated insulin secretion and reduced insulin exocytosis, while mitochondrial function and Ca2+ channel activity remain intact. Morphometric analysis revealed smaller islets and reduced β-cell size. Etv5 knockout mice, in vivo and in vitro glucose-stimulated insulin secretion, ETV5 knockdown in human β-cells and EndoC-βH1 cells, mitochondrial and Ca2+ channel assays Diabetologia High 24190582
2020 ETV5 regulates hepatic fatty acid β-oxidation through PPAR signaling; ETV5 binds the PPAR response element (PPRE) region of downstream genes and enhances PPAR transactivity. Both viral-mediated and genetic depletion of ETV5 in mice led to increased hepatic lipid accumulation with downregulation of PPAR signaling and fatty acid degradation pathways. Viral-mediated and genetic ETV5 depletion in mice, RNA sequencing, ChIP demonstrating ETV5 binding to PPRE regions, in vitro reporter assays Diabetes High 33093014
2021 COP1 and COP9 signalosome (CSN) antagonistically regulate CRL4-mediated ubiquitylation and proteasomal degradation of ETV5; hyperglycemia reciprocally regulates CRL4-CSN vs. CRL4COP1 assembly to promote ETV5 degradation. Disruption of IP6 binding to CSN2 increases CRL4COP1 assembly and ETV5 ubiquitylation, causing excessive ETV5 degradation and congenital hyperinsulinism. The neddylation inhibitor Pevonedistat stabilizes ETV5. Csn2 knock-in mice (K70E mutation), high-fat diet and ob/ob mouse models, co-immunoprecipitation to measure CRL4 assembly, ubiquitylation assays, human islets and EndoC-βH1 validation Nature communications High 33911083
2022 miR-200c directly targets ETV5 mRNA in human pancreatic islets to reduce insulin secretion; luciferase assay validated ETV5 as a direct target of miR-200c, and western blot confirmed reduced ETV5 protein in EndoC-βH1 cells overexpressing miR-200c. LNA knockdown of miR-200c increased glucose-stimulated insulin secretion in T2D donor islets ~3-fold. TargetScan/Pearson correlation analysis, luciferase 3'UTR reporter assay, western blot, miR-200c overexpression and LNA knockdown, glucose-stimulated insulin secretion assays in human T2D islets Diabetes High 34753799
2019 ETV5 is essential for maintenance of alveolar type II (AT2) cell identity; deletion of Etv5 from AT2 cells produced AT1-cell gene and protein signatures, and ETV5 deficiency markedly reduced recovery from bleomycin-induced lung injury. ETV5 also acts as a critical output of Ras signaling in AT2 cells contributing to lung tumor initiation by KrasG12D. AT2-specific conditional Etv5 knockout, gene/protein expression profiling, bleomycin injury model, KrasG12D-driven tumorigenesis model Proceedings of the National Academy of Sciences of the United States of America High 28351980
2020 ETV5 directly binds the VEGFA promoter to promote VEGFA translation and also upregulates CCL2 by activating STAT3, which then facilitates binding to the CCL2 promoter, thereby driving angiogenesis through two independent pathways in colorectal cancer. ChIP (ETV5 binding to VEGFA and CCL2 promoters via STAT3), in vitro and in vivo angiogenesis assays, gene set enrichment analysis Cell death & disease Medium 33099574
2024 YTHDF2, an m6A reader, recognizes m6A modification in the 5'-UTR of ETV5 mRNA and recruits eIF3b to facilitate ETV5 translation; elevated ETV5 in turn transcriptionally activates PD-L1 and VEGFA expression in hepatocellular carcinoma, promoting immune evasion and angiogenesis. Animal experiments (Ythdf2 KO and overexpression), m6A reading mechanism (YTHDF2 recognition of 5'-UTR m6A on ETV5 mRNA), functional reporter and ChIP assays for PD-L1/VEGFA transcription Advanced science Medium 38247171
2025 ETV5 transactivates PD-L1 and S100A9 expression in HCC cells (confirmed by ChIP-seq, CUT&Tag, and RNA-seq); S100A9 secreted from ETV5-expressing tumor cells recruits PMN-MDSCs via TLR4/RAGE, and S100A9 in the TME reciprocally elevates ETV5 expression via ERK/NF-κB, creating a feed-forward loop. ETV5 in myeloid cells also transcriptionally upregulates PD-L1 to augment immunosuppression. ChIP-seq, CUT&Tag, RNA-seq, humanized mouse models, orthotopic HCC models, DEN/CCl4-induced HCC, flow cytometry, myeloid-specific Etv5 KO Gut High 40015948
1996 The human ERM (ETV5) gene is organized into 14 exons distributed along 65 kb of genomic DNA and is localized to chromosome 3q27-q29. The two main functional domains (acidic domain and ETS DNA-binding domain) are each encoded by three different exons. Genomic cloning, exon mapping, chromosomal localization by fluorescence in situ hybridization Genomics Medium 8661127
2012 ETV5 regulates MMP-2 expression in human chondrosarcoma; ETV5 gene knockdown reduces MMP-2 mRNA, protein production, and enzymatic activity, while ETV5 overexpression upregulates MMP-2. MMP-2 inhibition reduces collagen release from bone chips by 27%, placing MMP-2 downstream of ETV5 in matrix resorption. siRNA knockdown and plasmid overexpression in human chondrosarcoma cells, qRT-PCR, western blot, zymography (MMP-2 activity assay), bone resorption assay with MMP-2 inhibitor Journal of orthopaedic research Medium 22968857
2009 ETV5 overexpression-associated proteomic changes in Hec-1A endometrial cancer cells point to actin regulation and TGFβ and progesterone signaling; ETV5 drives ERM/ETV5-dependent mitochondrial localization of the nuclear dehydrogenase/reductase Hep27, which has a protective role against apoptosis induced by oxidative stress. 2D-DIGE proteomics, pathway analysis, subcellular fractionation/localization of Hep27, functional apoptosis assays under oxidative stress Carcinogenesis Medium 19443906
2015 ETV5 is required for proper ES cell proliferation and induction of differentiation-associated genes; simultaneous deletion of Etv4 and Etv5 in ES cells decreased proliferation (with overexpression of CDK inhibitors p16/p19, p15, p57), altered colony morphology, and blocked ectoderm marker induction (Fgf5, Sox1, Pax3) in embryoid bodies. Artificial re-expression of Etv5 in dKO cells rescued Tcf15 and Gbx2 expression. Etv4/Etv5 double knockout ES cells, microarray expression analysis, re-expression rescue experiments, embryoid body differentiation assay The Journal of biological chemistry Medium 26224636
2019 ETV5 represses NEUROG2 expression in human neural progenitor cells (NPCs) by binding to the NEUROG2 promoter (confirmed by ChIP) through its ETS domain; this repression requires the transcriptional corepressor CoREST. ETV5-mediated NEUROG2 repression blocks glutamatergic neuron formation and promotes GABAergic neuron subtype differentiation. ETV5 overexpression and knockdown in human ES-derived NPCs, ChIP assays on NEUROG2 promoter, reporter assays, CoREST co-expression experiments Stem cell reviews and reports Medium 31273540
2020 MAST4 phosphorylates ETV5 at serine 367 in Sertoli cells; this phosphorylation controls transcription of ETV5 target genes involved in SSC self-renewal. MAST4 knockout mice phenocopy the Etv5-null SSC depletion/SCO phenotype and show decreased expression of spermatogenesis-associated proteins. Mast4 knockout mice, in vitro kinase assay (MAST4 phosphorylation of ERM/ETV5 at S367), RNA-seq, immunohistochemistry Cell death and differentiation Medium 33219327
2013 ETV5 mediates NGF-induced neurite outgrowth in DRG sensory neurons downstream of MEK/ERK signaling; Etv4 and Etv5 mRNAs are induced by NGF (both soma and distal axon application), MEK inhibition blocks their induction, and siRNA knockdown of Etv4/Etv5 inhibits NGF-induced neurite outgrowth while overexpression potentiates neuronal differentiation. Compartmentalized DRG culture with distal axon NGF application, real-time PCR, MEK inhibitor assays, siRNA knockdown, overexpression of Etv4/Etv5 The Journal of neuroscience Medium 24089499
2020 ETV5 links FGFR3 signaling to the Hippo pathway in bladder cancer; FGFR3 mutation induces MAPK/ERK-mediated increase in ETV5 levels, which then increases TAZ (a Hippo co-transcriptional regulator). ETV5 knockdown in FGFR3-mutant bladder cancer cell lines reduces proliferation and anchorage-independent growth. FGFR3 inhibitor treatment, MEK/ERK inhibitor treatment, ETV5 siRNA knockdown, proliferation and anchorage-independent growth assays, TAZ expression analysis Scientific reports Medium 30952872
2021 ETV4 and ETV5 are drivers of synovial sarcoma growth downstream of FGFR signaling (FGFR1/2/3); their knockdown causes striking upregulation of DUX4 and its transcriptional targets (activating zygotic genome/atrophy program). ETV4/ETV5 act primarily through control of the cell cycle. FGFR genetic KO models, FGFR inhibitor BGJ398 treatment, ETV4/ETV5 knockdown in culture and xenograft models, transcriptome analyses, histological analysis The Journal of clinical investigation Medium 33983905
2020 ETV5 directly targets the PIK3CA promoter and drives PIK3CA expression in follicular thyroid cancer cells; ChIP-PCR and luciferase assays confirmed ETV5 binding to the PIK3CA promoter region. ETV5 knockdown reduced cell proliferation, migration, and EMT, and PIK3CA overexpression rescued these effects. ChIP-PCR, luciferase assay, siRNA knockdown, PIK3CA overexpression rescue, cell proliferation and migration assays Life sciences Medium 32325133

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 ERM proteins and merlin: integrators at the cell cortex. Nature reviews. Molecular cell biology 1121 12154370
2010 Organizing the cell cortex: the role of ERM proteins. Nature reviews. Molecular cell biology 858 20308985
1994 Perturbation of cell adhesion and microvilli formation by antisense oligonucleotides to ERM family members. The Journal of cell biology 322 8207064
2000 ERM-Merlin and EBP50 protein families in plasma membrane organization and function. Annual review of cell and developmental biology 319 11031232
1999 ERM proteins in cell adhesion and membrane dynamics. Trends in cell biology 316 10322453
2006 Podoplanin binds ERM proteins to activate RhoA and promote epithelial-mesenchymal transition. Journal of cell science 312 17046996
2000 ERM proteins: from cellular architecture to cell signaling. Biology of the cell 276 11071040
2005 ERM is required for transcriptional control of the spermatogonial stem cell niche. Nature 254 16107850
2008 Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer. Cancer research 211 18172298
2014 ERM proteins in cancer progression. Journal of cell science 195 24421310
2011 Emerging role for ERM proteins in cell adhesion and migration. Cell adhesion & migration 192 21343695
2009 Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nature genetics 179 19898483
2012 FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b through MAP2K1 activation. Development (Cambridge, England) 171 22491947
2009 Merlin and the ERM proteins--regulators of receptor distribution and signaling at the cell cortex. Trends in cell biology 160 19345106
2002 ERM proteins and NF2 tumor suppressor: the Yin and Yang of cortical actin organization and cell growth signaling. Current opinion in cell biology 157 11792551
2004 Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation. The Journal of cell biology 153 15504914
2006 ERM proteins in epithelial cell organization and functions. Biochimica et biophysica acta 135 16904765
2017 Transcription factor Etv5 is essential for the maintenance of alveolar type II cells. Proceedings of the National Academy of Sciences of the United States of America 107 28351980
2014 ERM proteins at a glance. Journal of cell science 102 24951115
2013 Report of ribosomal RNA methylase gene erm(B) in multidrug-resistant Campylobacter coli. The Journal of antimicrobial chemotherapy 96 24335515
2015 A piRNA-like small RNA interacts with and modulates p-ERM proteins in human somatic cells. Nature communications 91 26095918
2019 Complementary Activity of ETV5, RBPJ, and TCF3 Drives Formative Transition from Naive Pluripotency. Cell stem cell 85 31031137
2011 Spermatogonial stem cell self-renewal requires ETV5-mediated downstream activation of Brachyury in mice. Biology of reproduction 83 21816850
2016 A glimpse of the ERM proteins. Journal of biomedical science 82 26983550
2007 Common and distinct factors regulate expression of mRNA for ETV5 and GDNF, Sertoli cell proteins essential for spermatogonial stem cell maintenance. Experimental cell research 77 17574550
2006 Understanding ERM proteins--the awesome power of genetics finally brought to bear. Current opinion in cell biology 72 17175152
2013 The actin-binding ERM protein Moesin binds to and stabilizes microtubules at the cell cortex. The Journal of cell biology 71 23857773
2005 Listeria monocytogenes exploits ERM protein functions to efficiently spread from cell to cell. The EMBO journal 69 15729356
2007 Induction of erm(C) expression by noninducing antibiotics. Antimicrobial agents and chemotherapy 67 18086834
2020 ERM-Dependent Assembly of T Cell Receptor Signaling and Co-stimulatory Molecules on Microvilli prior to Activation. Cell reports 66 32160548
2024 YTHDF2 Is a Therapeutic Target for HCC by Suppressing Immune Evasion and Angiogenesis Through ETV5/PD-L1/VEGFA Axis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 64 38247171
2009 Loss of Etv5 decreases proliferation and RET levels in neonatal mouse testicular germ cells and causes an abnormal first wave of spermatogenesis. Biology of reproduction 64 19369650
2015 ETS-related transcription factors ETV4 and ETV5 are involved in proliferation and induction of differentiation-associated genes in embryonic stem (ES) cells. The Journal of biological chemistry 58 26224636
2020 Dissecting erm(41)-Mediated Macrolide-Inducible Resistance in Mycobacterium abscessus. Antimicrobial agents and chemotherapy 57 31791943
2009 ERM protein moesin is phosphorylated by advanced glycation end products and modulates endothelial permeability. American journal of physiology. Heart and circulatory physiology 57 19395553
2003 Intrinsic macrolide resistance in Mycobacterium smegmatis is conferred by a novel erm gene, erm(38). Antimicrobial agents and chemotherapy 57 14506008
1999 Expression of the Ets transcription factors erm and pea3 in early zebrafish development. Mechanisms of development 57 10534622
2007 Effects of ETV5 (ets variant gene 5) on testis and body growth, time course of spermatogonial stem cell loss, and fertility in mice. Biology of reproduction 56 18032421
2008 erm(B)-carrying elements in tetracycline-resistant pneumococci and correspondence between Tn1545 and Tn6003. Antimicrobial agents and chemotherapy 55 18285489
2020 ETV5 Regulates Hepatic Fatty Acid Metabolism Through PPAR Signaling Pathway. Diabetes 54 33093014
2012 Merlin/ERM proteins establish cortical asymmetry and centrosome position. Genes & development 54 23249734
2007 ERM/ETV5 up-regulation plays a role during myometrial infiltration through matrix metalloproteinase-2 activation in endometrial cancer. Cancer research 54 17638886
2010 Matrix metalloproteinase-2 and matrix metalloproteinase-9 codistribute with transcription factors RUNX1/AML1 and ETV5/ERM at the invasive front of endometrial and ovarian carcinoma. Human pathology 53 20970160
2007 Osmotic cell shrinkage activates ezrin/radixin/moesin (ERM) proteins: activation mechanisms and physiological implications. American journal of physiology. Cell physiology 53 17977945
2020 ERM Proteins at the Crossroad of Leukocyte Polarization, Migration and Intercellular Adhesion. International journal of molecular sciences 51 32098334
2010 The transcription factors Etv4 and Etv5 mediate formation of the ureteric bud tip domain during kidney development. Development (Cambridge, England) 51 20463033
2020 Targeting tumor cell-derived CCL2 as a strategy to overcome Bevacizumab resistance in ETV5+ colorectal cancer. Cell death & disease 50 33099574
2015 Nidogen 1 and Nuclear Protein 1: novel targets of ETV5 transcription factor involved in endometrial cancer invasion. Clinical & experimental metastasis 49 25924802
2013 Pea3 transcription factor family members Etv4 and Etv5 mediate retrograde signaling and axonal growth of DRG sensory neurons in response to NGF. The Journal of neuroscience : the official journal of the Society for Neuroscience 49 24089499
2018 Pea3 Transcription Factors, Etv4 and Etv5, Are Required for Proper Hippocampal Dendrite Development and Plasticity. Cerebral cortex (New York, N.Y. : 1991) 48 27909004
2010 ETV5 regulates sertoli cell chemokines involved in mouse stem/progenitor spermatogonia maintenance. Stem cells (Dayton, Ohio) 48 20799334
2009 Proteomic approach to ETV5 during endometrial carcinoma invasion reveals a link to oxidative stress. Carcinogenesis 48 19443906
2004 Nuclear ERM (ezrin, radixin, moesin) proteins: regulation by cell density and nuclear import. Experimental cell research 46 15149851
2011 ETV5 transcription factor is overexpressed in ovarian cancer and regulates cell adhesion in ovarian cancer cells. International journal of cancer 45 21520040
2007 ETV5 is required for continuous spermatogenesis in adult mice and may mediate blood testes barrier function and testicular immune privilege. Annals of the New York Academy of Sciences 45 17911411
2016 The ETS Family Transcription Factors Etv5 and PU.1 Function in Parallel To Promote Th9 Cell Development. Journal of immunology (Baltimore, Md. : 1950) 44 27496971
2004 Macrolide resistance based on the Erm-mediated rRNA methylation. Current drug targets. Infectious disorders 44 15379730
2018 Activated ALK signals through the ERK-ETV5-RET pathway to drive neuroblastoma oncogenesis. Oncogene 40 29321660
2015 Structures of the Ets Protein DNA-binding Domains of Transcription Factors Etv1, Etv4, Etv5, and Fev: DETERMINANTS OF DNA BINDING AND REDOX REGULATION BY DISULFIDE BOND FORMATION. The Journal of biological chemistry 40 25866208
2013 Re-defining ERM function in lymphocyte activation and migration. Immunological reviews 38 24117813
2014 The transcription factor Etv5 controls TH17 cell development and allergic airway inflammation. The Journal of allergy and clinical immunology 37 24486067
2017 Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5. Nature communications 36 28855737
2019 ETS Factor ETV5 Activates the Mutant Telomerase Reverse Transcriptase Promoter in Thyroid Cancer. Thyroid : official journal of the American Thyroid Association 34 31452441
2005 Protein kinase C regulates the phosphorylation and oligomerization of ERM binding phosphoprotein 50. Experimental cell research 34 15878350
2022 Human Islet MicroRNA-200c Is Elevated in Type 2 Diabetes and Targets the Transcription Factor ETV5 to Reduce Insulin Secretion. Diabetes 33 34753799
2018 The Transcription Factor ETV5 Mediates BRAFV600E-Induced Proliferation and TWIST1 Expression in Papillary Thyroid Cancer Cells. Neoplasia (New York, N.Y.) 32 30265861
2005 Up-regulation of ERM/ETV5 correlates with the degree of myometrial infiltration in endometrioid endometrial carcinoma. The Journal of pathology 32 16175655
2020 Physiological Roles of ERM Proteins and Transcriptional Regulators in Supporting Membrane Expression of Efflux Transporters as Factors of Drug Resistance in Cancer. Cancers 31 33198344
2017 Structured and disordered regions cooperatively mediate DNA-binding autoinhibition of ETS factors ETV1, ETV4 and ETV5. Nucleic acids research 31 28161714
2016 The utility of ETV1, ETV4 and ETV5 RNA in-situ hybridization in the diagnosis of CIC-DUX sarcomas. Histopathology 31 27790742
2010 Glucose-induced ERM protein activation and translocation regulates insulin secretion. American journal of physiology. Endocrinology and metabolism 31 20739507
2008 Etv5, an ETS transcription factor, is expressed in granulosa and cumulus cells and serves as a transcriptional regulator of the cyclooxygenase-2. The Journal of endocrinology 31 18492810
2021 Lymphocyte egress signal sphingosine-1-phosphate promotes ERM-guided, bleb-based migration. The Journal of cell biology 30 33764397
2021 ETV4 and ETV5 drive synovial sarcoma through cell cycle and DUX4 embryonic pathway control. The Journal of clinical investigation 30 33983905
2013 The role of the transcription factor ETV5 in insulin exocytosis. Diabetologia 30 24190582
2008 Semaphorin 3A inhibits ERM protein phosphorylation in growth cone filopodia through inactivation of PI3K. Developmental neurobiology 30 18327764
2021 IP6-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion. Nature communications 28 33911083
2019 ETV5 is Essential for Neuronal Differentiation of Human Neural Progenitor Cells by Repressing NEUROG2 Expression. Stem cell reviews and reports 27 31273540
2014 ETV5 transcription program links BDNF and promotion of EMT at invasive front of endometrial carcinomas. Carcinogenesis 27 25233929
2025 E-twenty-six-specific sequence variant 5 (ETV5) facilitates hepatocellular carcinoma progression and metastasis through enhancing polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC)-mediated immunosuppression. Gut 26 40015948
2022 CD44/ERM/F-actin complex mediates targeted nuclear degranulation and excessive neutrophil extracellular trap formation during sepsis. Journal of cellular and molecular medicine 25 35146909
2015 MT1-MMP recognition by ERM proteins and its implication in CD44 shedding. Genes to cells : devoted to molecular & cellular mechanisms 25 26289026
2014 ICAM-2 regulates vascular permeability and N-cadherin localization through ezrin-radixin-moesin (ERM) proteins and Rac-1 signalling. Cell communication and signaling : CCS 25 24593809
2004 Crk associates with ERM proteins and promotes cell motility toward hyaluronic acid. The Journal of biological chemistry 25 15326184
1996 Genomic organization of the human ERM (ETV5) gene, a PEA3 group member of ETS transcription factors. Genomics 25 8661127
2017 The ERM protein Moesin is essential for neuronal morphogenesis and long-term memory in Drosophila. Molecular brain 24 28851405
2017 The ERM Protein Moesin Regulates CD8+ Regulatory T Cell Homeostasis and Self-Tolerance. Journal of immunology (Baltimore, Md. : 1950) 24 28978692
2016 The Drosophila ETV5 Homologue Ets96B: Molecular Link between Obesity and Bipolar Disorder. PLoS genetics 24 27280443
2006 Erm/thyroid transcription factor 1 interactions modulate surfactant protein C transcription. The Journal of biological chemistry 24 16613858
2019 ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer. Scientific reports 23 30952872
2012 Genetic variants in the ETV5 gene in fertile and infertile men with nonobstructive azoospermia associated with Sertoli cell-only syndrome. Fertility and sterility 23 22771031
2011 CD43 interaction with ezrin-radixin-moesin (ERM) proteins regulates T-cell trafficking and CD43 phosphorylation. Molecular biology of the cell 23 21289089
2018 ICAM3 mediates tumor metastasis via a LFA-1-ICAM3-ERM dependent manner. Biochimica et biophysica acta. Molecular basis of disease 22 29729315
2014 Erm(X)-mediated resistance to macrolides, lincosamides and streptogramins in Actinobaculum schaalii. The Journal of antimicrobial chemotherapy 22 24710027
2020 ETV5 overexpression contributes to tumor growth and progression of thyroid cancer through PIK3CA. Life sciences 20 32325133
2015 Anchoring of protein kinase A by ERM (ezrin-radixin-moesin) proteins is required for proper netrin signaling through DCC (deleted in colorectal cancer). The Journal of biological chemistry 20 25575591
2020 Mast4 knockout shows the regulation of spermatogonial stem cell self-renewal via the FGF2/ERM pathway. Cell death and differentiation 19 33219327
2015 Macrolide resistance gene erm(TR) and erm(TR)-carrying genetic elements in Streptococcus agalactiae: characterization of ICESagTR7, a new composite element containing IMESp2907. The Journal of antimicrobial chemotherapy 19 26679245
2011 MIG-15 and ERM-1 promote growth cone directional migration in parallel to UNC-116 and WVE-1. Development (Cambridge, England) 19 21937599
2012 ETV5 as a regulator of matrix metalloproteinase 2 in human chondrosarcoma. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 18 22968857

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