Affinage

ETS2

Protein C-ets-2 · UniProt P15036

Length
469 aa
Mass
53.0 kDa
Annotated
2026-06-09
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ETS2 is a sequence-specific transcription factor that converts Ras/MAPK signaling into target-gene programs governing tissue remodeling, angiogenesis, cell survival, and inflammation (PMID:8552081, PMID:9573048). Its central regulatory event is phosphorylation of the conserved Thr-72 residue: ERK1/2 (p42/p44) are the principal ETS2 kinases downstream of growth-factor and CSF-1 signaling (PMID:9710599), and in selected contexts Akt and the p54 JNK isoform also catalyze Thr-72 phosphorylation (PMID:11027273). Phosphorylated Thr-72, together with the Pointed (PNT) domain, recruits the coactivators CBP and p300 to drive transactivation (PMID:15572696), whereas Thr-72-to-Ala knock-in mice lose stromal protease expression, macrophage survival, and inflammatory gene programs in vivo, establishing this residue as the obligate node for ETS2 output (PMID:14612405, PMID:15240733). ETS2 binds Ets-core motifs at numerous promoters to control proteases (MMP-3, MMP-9, MMP-13), survival genes (Bcl-XL), CD13/APN, HO-1, miR-155, and miR-126, and is required for trophoblast stem-cell self-renewal through direct activation of Cdx2 and for embryonic anteroposterior axis patterning in extraembryonic ectoderm (PMID:9573048, PMID:17977525, PMID:16481355, PMID:19411629, PMID:24362029, PMID:14507917, PMID:15590657). ETS1 and ETS2 act redundantly to maintain endothelial survival during angiogenesis (PMID:19411629), and stromal ETS2 in tumor-associated macrophages and fibroblasts promotes angiogenesis, immune-cell recruitment, and metastasis (PMID:20145133, PMID:23977064, PMID:27659014). ETS2 protein levels are limited by CDK10/cyclin M, which phosphorylates ETS2 and targets it for proteasomal degradation (PMID:11313931, PMID:24218572). Context-dependent oncogenic versus tumor-suppressive behavior arises from partner choice: ETS2 cooperates with PU.1, the glucocorticoid receptor, NFAT, MLL, and gain-of-function mutant p53 in activating contexts (PMID:22508727, PMID:23934123, PMID:33821668, PMID:11278399, PMID:11279115), but its N-terminal interaction with the co-repressor ZMYND11 weakens activation relative to ETS1 and lets ETS2 attenuate transcription by competing for shared Ets sites (PMID:28119415). In human macrophages ETS2 is a master driver of the inflammatory state, with a chr21q22 disease-associated haplotype amplifying ETS2 expression (PMID:38839969).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 High

    Established that Ras signaling acts on ETS2 through a single phosphorylation event, defining Thr-72 as the molecular switch for Ras-mediated activation.

    Evidence Reporter assays, site-directed mutagenesis (T72A), and phosphoamino acid analysis of radiolabeled ETS2

    PMID:8552081

    Open questions at the time
    • Did not identify the physiological kinase
    • Did not define how phosphorylation alters transactivation mechanistically
  2. 1998 High

    Identified ERK1/2 as the major physiological ETS2 kinases downstream of CSF-1, connecting receptor signaling to Thr-72 phosphorylation and target-gene induction.

    Evidence Phospho-Thr-72 antibody, MAP kinase immune depletion, MEK inhibitor, in vitro kinase assays with recombinant ETS2 in macrophages and fibroblasts

    PMID:9710599

    Open questions at the time
    • Did not resolve coactivator recruitment
    • Other kinase inputs not excluded
  3. 2000 High

    Showed Thr-72 can be phosphorylated independently of CSF-1/MAPK via Akt and p54 JNK, broadening the signaling inputs converging on ETS2.

    Evidence Akt and JNK immunoprecipitate kinase assays, Co-IP, PI3K inhibitor, in motheaten-viable macrophages

    PMID:11027273

    Open questions at the time
    • Direct kinase identity within the immunoprecipitate not fully purified
    • Relative contribution of Akt vs JNK unresolved
  4. 2001 Medium

    Defined the Pointed domain as a docking site for CDK10, providing the first negative regulator of ETS2 transactivation.

    Evidence Yeast two-hybrid, in vitro binding, reciprocal Co-IP, reporter assays

    PMID:11313931

    Open questions at the time
    • Kinase activity of CDK10 toward ETS2 not yet shown
    • Single lab
  5. 2001 Medium

    Demonstrated combinatorial control of survival genes by showing ETS2 synergizes with PU.1 and with the glucocorticoid receptor to activate distinct promoters.

    Evidence Reporter transactivation, domain mapping, Co-IP/cross-linking, macrophage survival assays

    PMID:11278399 PMID:11279115

    Open questions at the time
    • Endogenous complex stoichiometry not defined
    • Single lab for each interaction
  6. 2003 High

    Proved in vivo that Thr-72 phosphorylation is required for ETS2's stromal and survival functions using a precise knock-in mutant.

    Evidence Ets2 T72A knock-in mice, tumor transplant, macrophage gene expression, motheaten-viable epistasis

    PMID:14612405 PMID:15240733

    Open questions at the time
    • Did not separate which downstream kinase phosphorylates Thr-72 in each tissue
  7. 2003 High

    Placed ETS2 within the apoptotic/tumor-suppressive axis by showing its overexpression triggers p53-dependent apoptosis.

    Evidence ETS2 transgenic mice crossed to p53-/-, thymic apoptosis assays

    PMID:12554679

    Open questions at the time
    • Mechanism by which ETS2 elevates p53 not fully resolved
  8. 2004 High

    Resolved the mechanistic basis of Thr-72 phosphorylation by showing it drives preferential recruitment of CBP/p300 coactivators, requiring both the phosphosite and the PNT domain.

    Evidence Affinity chromatography of nuclear extracts, purified-protein binding, in vivo Co-IP, reporter assays

    PMID:15572696

    Open questions at the time
    • Structural basis of phospho-dependent coactivator binding not solved
  9. 2008 Medium

    Mapped direct ETS2 target promoters across diverse genes, defining its Ets-core DNA-binding repertoire (CD13/APN, HO-1, MMP-3, p53, junB, cdc2, beta-APP).

    Evidence EMSA, promoter mutagenesis, reporter assays, dominant-negative and siRNA across multiple studies

    PMID:12890557 PMID:14507917 PMID:15590657 PMID:7867724 PMID:8463255 PMID:8649821 PMID:8943340

    Open questions at the time
    • Several targets validated in single labs
    • In vivo occupancy not confirmed for all
  10. 2009 High

    Established essential developmental and vascular roles, including redundancy with ETS1 in endothelial survival and direct activation of self-renewal/angiogenic targets.

    Evidence Endothelial- and trophoblast-specific conditional knockouts, ChIP, gene expression profiling, apoptosis assays

    PMID:16481355 PMID:17977525 PMID:19411629 PMID:9573048

    Open questions at the time
    • Degree of ETS1/ETS2 functional overlap across tissues not fully mapped
  11. 2013 High

    Defined the CDK10/cyclin M kinase complex as the degradation-promoting regulator that sets ETS2 protein levels and dampens MAPK output.

    Evidence In vitro kinase assays, cyclin M silencing, proteasome inhibition, STAR syndrome patient cells

    PMID:24218572

    Open questions at the time
    • E3 ligase recognizing phosphorylated ETS2 not identified
  12. 2013 High

    Revealed stromal and tumor-cell-context functions, including MLL-dependent H3K4me3 deposition at MMP promoters and dual oncogenic vs tumor-suppressive roles via MET.

    Evidence Co-IP, ChIP with histone-mark readout, conditional fibroblast KO, siRNA epistasis in lung and hepatocellular cancer models

    PMID:20145133 PMID:22508727 PMID:23659968 PMID:23934123 PMID:23977064

    Open questions at the time
    • Contextual determinants of oncogenic vs suppressive output not unified
    • MET-suppression mechanism characterized in single lab
  13. 2017 High

    Provided a molecular explanation for ETS2's context-dependent dual function through its N-terminal ZMYND11 co-repressor interaction and competition with ETS1.

    Evidence ETS1/ETS2 ChIP-seq cistrome comparison, Co-IP, N-terminal domain mutants, reporter assays

    PMID:28119415

    Open questions at the time
    • How signaling modulates the ETS2-ZMYND11 balance in vivo not defined
  14. 2021 High

    Connected ERK1/2 and calcineurin signaling in the heart by showing ETS2-NFAT complexes drive hypertrophic gene expression.

    Evidence Cardiomyocyte-specific KO, pressure overload model, ChIP, ETS2-NFAT Co-IP

    PMID:33821668

    Open questions at the time
    • Whether NFAT partnership extends to non-cardiac contexts unknown
  15. 2024 High

    Established ETS2 as a master driver of human inflammatory macrophages and linked its dysregulation to a chr21q22 disease haplotype.

    Evidence Functional genomics in primary human macrophages, ETS2 overexpression, causal regulatory element mapping, drug validation

    PMID:38839969

    Open questions at the time
    • Full set of downstream effector genes in human disease not enumerated
    • Therapeutic targeting validated only in vitro/ex vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single transcription factor integrates competing activating partners (CBP/p300, PU.1, NFAT, MLL, mutant p53) versus repressive interactions (ZMYND11) to produce cell-type-specific oncogenic, tumor-suppressive, developmental, or inflammatory outcomes.
  • No unified structural model of phospho-dependent partner selection
  • E3 ligase for CDK10-primed degradation unidentified
  • Determinants of ETS1 vs ETS2 site choice in shared cistromes unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 5 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2
Partners
CBPCDK10EP300MLLNFATPU.1TP53ZMYND11

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Ras signaling induces phosphorylation of a conserved threonine residue (Thr-72) in ETS2, and mutation of this residue to alanine abrogates Ras-mediated superactivation of Ets-AP-1 reporter genes, establishing Thr-72 phosphorylation as a necessary molecular component of Ras-mediated ETS2 activation. Transient transfection reporter assays, site-directed mutagenesis, phosphoamino acid analysis of radiolabeled ETS2 Molecular and cellular biology High 8552081
1998 MAP kinases p42 and p44 (ERK1/2) are the major ETS2 kinases downstream of CSF-1/c-fms signaling, phosphorylating ETS2 at Thr-72 in primary macrophages and fibroblasts; persistent ERK activation correlates with activation of the urokinase plasminogen activator (uPA) target gene. Phospho-specific antibody against pThr-72, immune depletion of MAP kinases, MEK inhibitor PD98059, in vitro kinase assays with recombinant ETS2, conditional raf kinase expression Molecular and cellular biology High 9710599
2004 MAPK phosphorylation of ETS2 (and ETS1) at the conserved Thr-72 site results in enhanced transactivation through preferential, direct recruitment of the coactivators CBP and p300; both the phosphoacceptor site and the Pointed (PNT) domain are required for this interaction. Affinity chromatography screen of HeLa nuclear extracts using mock-treated vs ERK2-phosphorylated ETS proteins, binding assays with purified proteins, co-immunoprecipitation in vivo, reporter assays with MEK1 and CBP co-expression Molecular and cellular biology High 15572696
2001 CDK10 interacts with the N-terminus (Pointed domain) of ETS2 and inhibits ETS2 transactivation activity; ETS2 requires an intact Pointed domain to bind CDK10, and CDK10 does not recognize ETS1 in a two-hybrid assay. Yeast two-hybrid assay, in vitro binding, co-immunoprecipitation in mammalian cells, reporter transactivation assays Oncogene Medium 11313931
2013 CDK10 functions as a cyclin-dependent kinase activated by cyclin M (FAM58A product); CDK10/cyclin M phosphorylates ETS2 in vitro and positively controls ETS2 degradation by the proteasome, thereby negatively regulating ETS2 protein levels and downstream MAPK pathway activation. In vitro kinase assay, cyclin M co-expression/silencing, proteasome inhibitor experiments, analysis of STAR syndrome patient cells Proceedings of the National Academy of Sciences of the United States of America High 24218572
1998 Targeted deletion of the ETS2 DNA-binding domain causes defective trophoblast function; ETS2 is required for MMP-9 expression in trophoblasts and mediates FGF-induced MMP-3 and MMP-13 expression in fibroblasts; ectopic ETS2 rescues MMP expression in Ets2-deficient fibroblasts. Gene targeting/knockout mouse, tetraploid aggregation rescue, Northern blot/gene expression, ectopic expression rescue Genes & development High 9573048
2007 Trophoblast stem cell self-renewal requires ETS2; conditional Ets2 inactivation decreases expression of Cdx2 (a direct Ets2 target) and other self-renewal genes while increasing differentiation-associated gene expression. Conditional gene targeting, gene expression analysis, chromatin immunoprecipitation identifying Cdx2 as a direct Ets2 target Developmental biology High 17977525
2006 ETS2 is required in trophoblast for anteroposterior axis patterning of the embryo; Ets2 mutants show reduced extraembryonic ectoderm (EXE) markers, and physical removal of EXE phenocopies Ets2 mutant patterning defects, placing ETS2 downstream of FGF signals in EXE cells that relay patterning signals to the epiblast. Genetic knockout/epistasis, tetraploid aggregation, embryo culture/physical excision of EXE, gene expression analysis Development (Cambridge, England) High 16481355
2009 ETS1 and ETS2 have essential and overlapping functions in endothelial cell survival during embryonic angiogenesis; double mutation of both factors causes embryonic lethality with vascular defects, loss of Mmp9, Bcl-XL, and cIAP2 expression, and increased endothelial apoptosis, with both factors loaded at target promoters. Conditional Cre/loxP knockout (endothelial-specific), chromatin immunoprecipitation, gene expression profiling of isolated embryonic endothelial cells, apoptosis assays in vivo and in vitro Blood High 19411629
2010 ETS2 in tumor-associated macrophages (TAMs) drives a transcriptional program that represses anti-angiogenic gene inhibitors, promotes angiogenesis, and supports breast cancer lung metastasis; conditional Ets2 deletion in TAMs decreases metastasis frequency and tumor angiogenesis. Conditional knockout in macrophages (Cre/loxP), expression profiling, chromatin immunoprecipitation, multiple mouse mammary tumor models Cancer research High 20145133
2012 Mutant p53 (gain-of-function) interacts with ETS2 to regulate gene expression through ETS-binding sites; this complex transactivates TDP2 (a DNA repair enzyme) to promote etoposide resistance in cancer cells. Genome-wide chromatin immunoprecipitation (ChIP), co-immunoprecipitation of mtp53 and ETS2, reporter assays, siRNA knockdown of TDP2 Genes & development High 22508727
2013 ETS2 in tumor fibroblasts promotes angiogenesis in breast cancer; conditional Ets2 deletion in stromal fibroblasts reduces tumor growth and vascularization, and ETS2 in fibroblasts directly promotes blood vessel formation in an in vivo angiogenesis assay independent of tumor cells. Conditional knockout in fibroblasts, gene expression profiling, in vivo angiogenesis assay, multiple PyMT and ErbB2 tumor models PloS one High 23977064
2013 ETS2 suppresses MET proto-oncogene phosphorylation in non-small cell lung cancer cells; ETS2 knockdown activates the HGF/MET pathway and increases cell migration and invasion, while MET knockdown attenuates invasion induced by ETS2 siRNA, placing ETS2 upstream of MET as a tumor suppressor. siRNA knockdown, overexpression, pathway/microarray analysis, MET phosphorylation assays Clinical cancer research Medium 23659968
2024 ETS2 is a central regulator of human inflammatory macrophages; overexpressing ETS2 in resting macrophages reproduces the inflammatory state (including upregulation of TNF and IL-23) linked to chr21q22-associated inflammatory diseases, and ETS2 expression is amplified by a disease-associated intergenic haplotype on chr21q22. Functional genomics in primary human macrophages, ETS2 overexpression, gene expression profiling, identification of causal regulatory element, drug validation in vitro and ex vivo Nature High 38839969
2013 ETS2 is required for LPS-induced miR-155 expression in macrophages; ETS2 directly binds to the miR-155 promoter at an Ets-binding site proximal to the transcription start site, and ETS2-deficient mice display decreased LPS-induced miR-155; IL-10 inhibits ETS2 expression to suppress miR-155. Promoter deletion/mutation analysis, chromatin immunoprecipitation, Ets2-deficient mice, overexpression and knockdown The Journal of biological chemistry High 24362029
2013 HGF-MET signaling leads to accumulation of ETS2, which interacts with MLL (mixed lineage leukemia) histone methyltransferase to form a complex on MMP1 and MMP3 promoters; MLL trimethylates H3K4 at these promoters, activating transcription and promoting hepatocellular carcinoma invasion. Co-immunoprecipitation (ETS2-MLL complex), ChIP assays showing MLL-ETS2 occupancy and H3K4me3 at MMP1/MMP3 promoters, Mll-/-, Hgf-/-, Met-/- mouse phenotype comparisons The Journal of clinical investigation High 23934123
2003 ETS2 phosphorylation at Thr-72 (by MAP kinase) is required for stromal support of mammary tumor progression; Ets2A72/A72 knock-in mice (Thr-72 → Ala) have reduced mammary tumor size and decreased MMP-9 and MMP-3 expression in macrophages, indicating that MAP kinase activation of ETS2 acts in the stroma to regulate protease expression. Knock-in mouse (Thr-72→Ala point mutation), tumor transplant, gene expression analysis in isolated macrophages, multiple transgenic tumor models Molecular and cellular biology High 14612405
2004 Ets2 phosphorylation at Thr-72 mediates persistent inflammatory macrophage gene expression (TNF-α, CCL3, MMP-9, integrin αM, Bcl-X) in the motheaten viable model; the Ets2A72 allele reduces inflammation and macrophage survival in vivo, establishing that Thr-72 phosphorylation is required for Ets2's role in macrophage survival and inflammatory gene programs. Genetic combination of Ets2A72 knock-in allele with Hcph(me-v) mutation in mice, gene expression analysis in alveolar macrophages, apoptosis assays, LPS stimulation of bone marrow-derived macrophages Journal of immunology High 15240733
2000 In macrophages from motheaten-viable mice, ETS2 is phosphorylated at Thr-72 in a CSF-1/MAPK-independent manner; Akt immunoprecipitates catalyze Thr-72 phosphorylation of ETS2 in vitro, and the p54 JNK isoform co-immunoprecipitates with Akt and can act as an ETS2 kinase; PI3K inhibition reduces Ets-2 phosphorylation and Bcl-x expression. Phospho-specific Thr-72 antibody, Akt immunoprecipitate kinase assay with recombinant ETS2, co-immunoprecipitation of Akt and JNK, PI3K inhibitor (LY294002) Molecular and cellular biology High 11027273
2002 PTEN overexpression blocks insulin-stimulated ETS2 phosphorylation at Thr-72 by inhibiting ERK/MAP kinase activation (not via PI3K/Akt); this effect is phosphatase activity-dependent and abrogates ETS2-driven uPA Ras-responsive enhancer activity. Overexpression of wild-type and phosphatase-dead PTEN, MEK inhibitor (PD590089), PI3K inhibitor (LY492002), phospho-Thr-72 antibody, reporter assays Human molecular genetics Medium 12095911
2021 ETS2 is phosphorylated and activated by ERK1/2 in cardiomyocytes upon hypertrophic stimulation; ETS2 forms a complex with NFAT to bind promoters of hypertrophic genes (Rcan1.4, miR-223), linking ERK1/2 and calcineurin signaling; cardiomyocyte-specific ETS2 knockout protects mice from pressure overload-induced cardiac hypertrophy. Cardiomyocyte-specific conditional knockout mice, pressure overload model, calcineurin transgenic mouse silencing, ChIP for ETS2 and NFAT at target promoters, Co-IP of ETS2-NFAT complex, primary cardiomyocyte assays Circulation High 33821668
2003 ETS2 overexpression induces apoptosis dependent on the p53 pathway; in ETS2 transgenic mice, increased apoptosis correlates with elevated p53 and downstream p53 pathway factors; crossing with p53-/- mice genetically rescues thymic apoptosis in ETS2 transgenic mice. ETS2 transgenic mice, p53 knockout cross, thymic apoptosis assay, transfection with functional p53 in HeLa cells Human molecular genetics High 12554679
2001 ETS2 and PU.1 synergistically transactivate the bcl-x(L) promoter in macrophages; this synergy requires the transactivation domains of both proteins and is specific to ETS2 and PU.1 (not ETS1); ectopic co-expression of ETS2 and PU.1 increases macrophage survival upon CSF-1 withdrawal. Reporter transactivation assays, domain mapping/mutagenesis, overexpression in primary macrophages, cell survival assays The Journal of biological chemistry Medium 11278399
2001 ETS2 physically interacts with glucocorticoid receptor (GR) and synergistically transactivates the cytochrome P-450c27 promoter; GR binding to an adjacent cryptic GRE enables ETS2 to bind a weak Ets-like site; the GR DNA-binding domain alone (without transactivation domain) suffices for synergy, and the ETS2 transactivation domain is required. Co-immunoprecipitation, chemical cross-linking, transactivation assays with deletion mutants, reporter assays with GR-ETS2 fusion proteins The Journal of biological chemistry Medium 11279115
2017 ETS2 interacts with the co-repressor ZMYND11 (BS69) through its N-terminus, resulting in weaker transcriptional activation compared to ETS1; this interaction allows ETS2 to compete for ETS1 binding sites and attenuate transcription, forming the molecular basis for ETS2's context-dependent tumor suppressive vs. oncogenic function. ETS1/ETS2 cistrome comparison (ChIP-seq), ETS1 deletion experiments, co-immunoprecipitation of ETS2-ZMYND11, reporter assays with N-terminal domain mutants Nucleic acids research High 28119415
2004 ETS2 transactivates the CD13/APN promoter via an Ets-core motif in endothelial cells; a phosphorylation-defective ETS2 T72A mutant fails to transactivate CD13/APN; siRNA knockdown of ETS2 inhibits CD13/APN transcription and prevents endothelial capillary network formation. Reporter assays with Ets-core motif mutations, Ets2 T72A phosphorylation-deficient mutant, siRNA knockdown, endothelial morphogenesis assay The Journal of biological chemistry High 14507917
1993 ETS2 transactivates the human stromelysin (MMP-3) promoter via a proximal PEA-3 site; mutation of the proximal PEA-3 site significantly inhibits the TPA response, and ETS2 fails to transactivate promoters with mutated PEA-3 sites. Promoter deletion and point mutation analysis, co-transfection reporter assays The Journal of biological chemistry Medium 8463255
1996 ETS2 binds to ETS-binding site palindromes in the p53 promoter in gel-shift assays and activates p53 reporter expression 5–10-fold in COS cells; p53 mRNA levels are higher in NIH3T3 cells overexpressing ETS2, suggesting ETS2 is a transcriptional regulator of p53. Gel shift/EMSA assay with palindromic EBS oligonucleotides, CAT reporter co-transfection, Northern blot in ETS2-overexpressing cells Oncogene Medium 8649821
2004 ETS2 directly binds to EBS -93 in the HO-1 promoter (shown by gel shift) and transactivates HO-1 expression in macrophages; mutation of the ETS2 DNA-binding domain prevents HO-1 transactivation; dominant negative ETS2 blunts LPS-induced HO-1 expression. Promoter deletion analysis, gel shift/EMSA, DNA-binding domain mutation, dominant negative ETS2, reporter assays, kinase inhibitors The Journal of biological chemistry Medium 15590657
2010 ETS2 (and ETS1) directly bind to an Ets-binding site ~71–100 bp upstream of the miR-126 transcriptional start site and regulate miR-126 expression; knockdown of endogenous ETS1 and ETS2 decreases miR-126 expression in endothelial cells. Promoter mutation analysis, chromatin immunoprecipitation (ChIP), siRNA knockdown, reporter assays Arteriosclerosis, thrombosis, and vascular biology Medium 20671229
2010 ETS2 activates MKP3/DUSP6 transcription downstream of ERK1/2 activation in MCF-7 breast cancer cells; ETS2-dependent MKP3/DUSP6 induction provides a negative feedback on ERK1/2 activity and shifts the proliferation/growth arrest decision. Reporter assays, knockdown, ETS2 overexpression, ERK1/2 activity measurements, MKP3 induction analysis The Journal of biological chemistry Medium 20554528
2012 ETS2 and MESP1 co-expression converts human dermal fibroblasts into cardiac progenitors (KDR+ cells); ETS2 alone drives cardiac mesoderm commitment in embryonic stem cells, but neither ETS2 nor MESP1 alone generates cardiac progenitors from fibroblasts de novo. Lentivirus-mediated forced expression, embryonic stem cell differentiation assays, Ca2+ transient measurements, sarcomere detection, cardiac transcription factor marker analysis Proceedings of the National Academy of Sciences of the United States of America Medium 22826236
2009 ETS2 overexpression promotes megakaryocyte expansion from wild-type and Gata1-mutant fetal liver progenitors; overexpression of ETS2 facilitates expansion of CD41+ cells from Gata1s knockin progenitors and synergizes with Gata1 mutations to reduce more mature CD42+ fractions. Retroviral overexpression in murine fetal liver progenitors, flow cytometry, serial replating assays, JAK/STAT pathway analysis Blood Medium 19168790
2016 ETS2 in pancreatic stromal fibroblasts directly binds regulatory sequences of chemokine genes (Ccl3, Ccl4, Cxcl4, Cxcl5, Cxcl10) and regulates immune cell recruitment; conditional Ets2 deletion in fibroblasts increases CD8+ T cells and decreases Tregs and myeloid-derived suppressor cells during acinar-to-ductal metaplasia. Conditional Ets2 knockout in fibroblasts, ChIP on chemokine promoters, immune cell flow cytometry in pancreatic ADM model Neoplasia High 27659014
2020 ETS2 directly binds the IL-6 promoter and inhibits IL-6 transcription; ETS2 also suppresses ERK1/2, JNK, p38, and p65 activation downstream of LPS and VSV, functioning as a negative regulator of macrophage inflammatory responses. ChIP assay on IL-6 promoter, ETS2 knockout mice, siRNA knockdown, CLP-induced sepsis model, kinase activation assays (Western blot) Aging Medium 31785145
2003 ETS2 transactivates the beta-APP (amyloid precursor protein) gene via specific ETS-binding sites in the beta-APP promoter and cooperates with AP1; ETS2 transgenic mouse brains and neuronal cultures display elevated beta-APP protein, increased presenilin-1, and increased beta-amyloid production. Reporter assays with EBS mutations, ETS2 transgenic mice, Western blot for APP/presenilin-1/beta-amyloid Biochimica et biophysica acta Medium 12890557
2009 ETS2 and p53 mediate cAMP/PKA-induced MMP-2 expression and trophoblast invasion; antisense inhibition of ETS2 or p53 reduces MMP-2 mRNA, secretion, and invasiveness in forskolin-treated trophoblast cells; ETS2 binds to its consensus site in the MMP-2 promoter in response to forskolin. EMSA binding assay, Northern blot/RT-PCR, antisense transfection, zymography, transwell invasion assay Reproductive biology and endocrinology Medium 19939245
1995 ETS2 transactivates the cdc2 gene promoter via specific ETS-binding sites; cells constitutively expressing ETS2 have increased cdc2 expression, elevated histone H1 kinase activity, and higher cyclin A (but not cyclin B1) levels, and can grow under low serum conditions. Reporter transactivation assays with EBS mutations, constitutive ETS2 expression in BALB/c3T3, kinase assays, Western blot for cyclins Experimental cell research Medium 7867724
1996 Constitutive ETS2 expression in M1D+ myeloblast cells is sufficient to drive macrophage differentiation; ETS2 directly activates junB transcription via Ets-binding sites in the junB promoter, as shown by reporter assays and dominant negative ETS2 inhibition. Stable ETS2 transfection, differentiation marker analysis, transient reporter assays with junB promoter EBS, dominant negative ETS2 Molecular and cellular biology Medium 8943340
2019 EGF activates ETS2 via MEK and PI3K pathways, and phosphorylated ETS2 (Thr-72) suppresses miR-124a promoter activity in pancreatic beta cells; ETS2 binds conserved AGGAANA/TN motifs in three miR-124a promoters; ETS2 knockdown reduces and overexpression promotes insulin biosynthesis. Kinase inhibitors (MEK and PI3K), ETS2 phosphorylation analysis, reporter assays with promoter EBS mutations, ETS2 knockdown/overexpression, insulin secretion/biosynthesis assays International journal of biological sciences Medium 31754329

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2. Molecular and cellular biology 330 8552081
1998 Defective trophoblast function in mice with a targeted mutation of Ets2. Genes & development 255 9573048
2010 EGFR promotes lung tumorigenesis by activating miR-7 through a Ras/ERK/Myc pathway that targets the Ets2 transcriptional repressor ERF. Cancer research 239 20978205
1990 The product of the c-ets-1 proto-oncogene and the related Ets2 protein act as transcriptional activators of the long terminal repeat of human T cell leukemia virus HTLV-1. The EMBO journal 236 2209540
2007 Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway. Cancer research 232 17332326
1994 Differential expression of ets-1 and ets-2 proto-oncogenes during murine embryogenesis. Oncogene 191 8183549
2012 Mutant p53 cooperates with ETS2 to promote etoposide resistance. Genes & development 173 22508727
2004 Ras/mitogen-activated protein kinase signaling activates Ets-1 and Ets-2 by CBP/p300 recruitment. Molecular and cellular biology 172 15572696
1990 Reciprocal expression of human ETS1 and ETS2 genes during T-cell activation: regulatory role for the protooncogene ETS1. Proceedings of the National Academy of Sciences of the United States of America 166 2187191
1996 Down's syndrome-like skeletal abnormalities in Ets2 transgenic mice. Nature 164 8596630
2012 Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors. Proceedings of the National Academy of Sciences of the United States of America 161 22826236
2009 Ets1 and Ets2 are required for endothelial cell survival during embryonic angiogenesis. Blood 153 19411629
2004 Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: Amplification discloses overexpression of APP, ETS2, and ERG genes. Proceedings of the National Academy of Sciences of the United States of America 145 15007164
2010 Ets-1 and Ets-2 regulate the expression of microRNA-126 in endothelial cells. Arteriosclerosis, thrombosis, and vascular biology 131 20671229
2013 ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non-small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 129 23659968
2024 A disease-associated gene desert directs macrophage inflammation through ETS2. Nature 114 38839969
1993 A polyomavirus enhancer A-binding protein-3 site and Ets-2 protein have a major role in the 12-O-tetradecanoylphorbol-13-acetate response of the human stromelysin gene. The Journal of biological chemistry 111 8463255
2005 Associations and interactions between Ets-1 and Ets-2 and coregulatory proteins, SRC-1, AIB1, and NCoR in breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 105 15788656
2010 An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis. Cancer research 97 20145133
2009 ETS2 and ERG promote megakaryopoiesis and synergize with alterations in GATA-1 to immortalize hematopoietic progenitor cells. Blood 97 19168790
2001 Cdk10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity. Oncogene 93 11313931
2013 The role of Ets2 transcription factor in the induction of microRNA-155 (miR-155) by lipopolysaccharide and its targeting by interleukin-10. The Journal of biological chemistry 91 24362029
1999 Regulation of the human interleukin-5 promoter by Ets transcription factors. Ets1 and Ets2, but not Elf-1, cooperate with GATA3 and HTLV-I Tax1. The Journal of biological chemistry 90 10212281
1998 Persistent activation of mitogen-activated protein kinases p42 and p44 and ets-2 phosphorylation in response to colony-stimulating factor 1/c-fms signaling. Molecular and cellular biology 88 9710599
2011 Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis. Development (Cambridge, England) 85 21989915
2004 Triplex DNA-mediated downregulation of Ets2 expression results in growth inhibition and apoptosis in human prostate cancer cells. Nucleic acids research 81 15314206
2003 ETS2 overexpression in transgenic models and in Down syndrome predisposes to apoptosis via the p53 pathway. Human molecular genetics 80 12554679
2006 Ets2 binding site single nucleotide polymorphism at the hTERT gene promoter--effect on telomerase expression and telomere length maintenance in non-small cell lung cancer. European journal of cancer (Oxford, England : 1990) 79 16737810
1990 Molecular and functional characterization of the promoter of ETS2, the human c-ets-2 gene. Proceedings of the National Academy of Sciences of the United States of America 74 2405393
2021 Cooperative Binding of ETS2 and NFAT Links Erk1/2 and Calcineurin Signaling in the Pathogenesis of Cardiac Hypertrophy. Circulation 70 33821668
2013 CDK10/cyclin M is a protein kinase that controls ETS2 degradation and is deficient in STAR syndrome. Proceedings of the National Academy of Sciences of the United States of America 69 24218572
2006 Ets2 is necessary in trophoblast for normal embryonic anteroposterior axis development. Development (Cambridge, England) 66 16481355
1998 ETS2 function is required to maintain the transformed state of human prostate cancer cells. Oncogene 66 9879994
2007 Ets2 is required for trophoblast stem cell self-renewal. Developmental biology 65 17977525
2002 PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway. Human molecular genetics 63 12095911
2000 ets-2 is a target for an akt (Protein kinase B)/jun N-terminal kinase signaling pathway in macrophages of motheaten-viable mutant mice. Molecular and cellular biology 63 11027273
2014 CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth. Oncogene 61 25241894
1996 ETS1 and ETS2 in p53 regulation: spatial separation of ETS binding sites (EBS) modulate protein: DNA interaction. Oncogene 59 8649821
1997 Ets-1 and Ets-2 proto-oncogenes exhibit differential and restricted expression patterns during Xenopus laevis oogenesis and embryogenesis. The International journal of developmental biology 57 9303349
1990 Rapid and transient expression of Ets2 in mature macrophages following stimulation with cMGF, LPS, and PKC activators. Genes & development 57 2186967
2011 Ets2 determines the inflammatory state of endothelial cells in advanced atherosclerotic lesions. Circulation research 54 21700929
2003 Selective inhibition of transcription of the Ets2 gene in prostate cancer cells by a triplex-forming oligonucleotide. Nucleic acids research 54 12560478
2003 CD13/APN transcription is induced by RAS/MAPK-mediated phosphorylation of Ets-2 in activated endothelial cells. The Journal of biological chemistry 54 14507917
2013 HGF-MET signals via the MLL-ETS2 complex in hepatocellular carcinoma. The Journal of clinical investigation 53 23934123
1998 Activation of the ras-mitogen-activated protein kinase pathway and phosphorylation of ets-2 at position threonine 72 in human ovarian cancer cell lines. Cancer research 53 9605774
2003 Ets2-dependent stromal regulation of mouse mammary tumors. Molecular and cellular biology 52 14612405
2012 Transcriptional regulation of miR-196b by ETS2 in gastric cancer cells. Carcinogenesis 51 22298639
1999 Role of distinct mitogen-activated protein kinase pathways and cooperation between Ets-2, ATF-2, and Jun family members in human urokinase-type plasminogen activator gene induction by interleukin-1 and tetradecanoyl phorbol acetate. Molecular and cellular biology 51 10454570
2004 Role of Ets-2 in the regulation of heme oxygenase-1 by endotoxin. The Journal of biological chemistry 49 15590657
2001 Bcl-XL expression correlates with primary macrophage differentiation, activation of functional competence, and survival and results from synergistic transcriptional activation by Ets2 and PU.1. The Journal of biological chemistry 48 11278399
1999 A single targeted Ets2 allele restricts development of mammary tumors in transgenic mice. Cancer research 48 10485465
1998 Elevated expression of Ets2 or distinct portions of Ets2 can reverse Ras-mediated cellular transformation. The Journal of biological chemistry 48 9668063
1996 Constitutive expression of c-fos and c-jun, overexpression of ets-2, and reduced expression of metastasis suppressor gene nm23-H1 in rheumatoid arthritis. Annals of the rheumatic diseases 48 8660103
2010 Differential up-regulation of MAP kinase phosphatases MKP3/DUSP6 and DUSP5 by Ets2 and c-Jun converge in the control of the growth arrest versus proliferation response of MCF-7 breast cancer cells to phorbol ester. The Journal of biological chemistry 47 20554528
2003 Overexpression of the chromosome 21 transcription factor Ets2 induces neuronal apoptosis. Neurobiology of disease 47 14678752
2004 Activated Ets2 is required for persistent inflammatory responses in the motheaten viable model. Journal of immunology (Baltimore, Md. : 1950) 46 15240733
2018 Aberrant expression of ETS1 and ETS2 proteins in cancer. Cancer reports and reviews 45 29974077
1994 Ets-2 and c-Myb act independently in regulating expression of the hematopoietic stem cell antigen CD34. The Journal of biological chemistry 40 7523384
2007 The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy. Leukemia 38 18094719
2004 Unique and selective effects of five Ets family members, Elf3, Ets1, Ets2, PEA3, and PU.1, on the promoter of the type II transforming growth factor-beta receptor gene. The Journal of biological chemistry 38 14976186
1996 Constitutive c-ets2 expression in M1D+ myeloblast leukemic cells induces their differentiation to macrophages. Molecular and cellular biology 37 8943340
2002 The role of the Ets2 transcription factor in the proliferation, maturation, and survival of mouse thymocytes. Journal of immunology (Baltimore, Md. : 1950) 36 12391198
2001 Physical interaction and functional synergy between glucocorticoid receptor and Ets2 proteins for transcription activation of the rat cytochrome P-450c27 promoter. The Journal of biological chemistry 36 11279115
2019 Ets2 suppresses inflammatory cytokines through MAPK/NF-κB signaling and directly binds to the IL-6 promoter in macrophages. Aging 35 31785145
2020 RNA-binding protein CELF1 enhances cell migration, invasion, and chemoresistance by targeting ETS2 in colorectal cancer. Clinical science (London, England : 1979) 34 32677671
2016 Stromal ETS2 Regulates Chemokine Production and Immune Cell Recruitment during Acinar-to-Ductal Metaplasia. Neoplasia (New York, N.Y.) 34 27659014
2004 Detailed mapping of the ERG-ETS2 interval of human chromosome 21 and comparison with the region of conserved synteny on mouse chromosome 16. Gene 33 14693372
2020 Exosomal miR-663b targets Ets2-repressor factor to promote proliferation and the epithelial-mesenchymal transition of bladder cancer cells. Cell biology international 32 31872468
2009 Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 32 19407855
1995 ets-2 regulates cdc2 kinase activity in mammalian cells: coordinated expression of cdc2 and cyclin A. Experimental cell research 31 7867724
2003 The chromosome 21 transcription factor ETS2 transactivates the beta-APP promoter: implications for Down syndrome. Biochimica et biophysica acta 30 12890557
2015 VEGFA Expression Is Inhibited by Arsenic Trioxide in HUVECs through the Upregulation of Ets-2 and miRNA-126. PloS one 29 26274316
2013 Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer. PloS one 29 23977064
2013 Transcription factor Ets1, but not the closely related factor Ets2, inhibits antibody-secreting cell differentiation. Molecular and cellular biology 28 24277931
2011 Ets2 regulates colonic stem cells and sensitivity to tumorigenesis. Stem cells (Dayton, Ohio) 28 21425406
2006 The transcriptional ETS2 repressor factor associates with active and inactive Erks through distinct FXF motifs. The Journal of biological chemistry 28 16799155
2020 ΔNp73/ETS2 complex drives glioblastoma pathogenesis- targeting downstream mediators by rebastinib prolongs survival in preclinical models of glioblastoma. Neuro-oncology 27 31763674
2019 MicroRNA-146b Overexpression Promotes Human Bladder Cancer Invasion via Enhancing ETS2-Mediated mmp2 mRNA Transcription. Molecular therapy. Nucleic acids 27 31071529
2019 Kcnq1ot1/miR-381-3p/ETS2 Axis Regulates Inflammation in Mouse Models of Acute Respiratory Distress Syndrome. Molecular therapy. Nucleic acids 27 31841990
2016 ETS2 and Twist1 promote invasiveness of Helicobacter pylori-infected gastric cancer cells by inducing Siah2. The Biochemical journal 26 27048589
2009 Ets2 transcription factor, telomerase activity and breast cancer. Clinical and experimental pharmacology & physiology 26 19566835
1997 Altered expression of Erg and Ets-2 transcription factors is associated with genetic changes at 21q22.2-22.3 in immortal and cervical carcinoma cell lines. Oncogene 26 9174050
1991 Positive and negative factors regulate the transcription of the ETS2 gene via an oncogene-responsive-like unit within the ETS2 promoter region. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 26 1888697
2017 Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2. Nucleic acids research 25 28119415
2005 Ets2 transcription factor in normal and neoplastic human breast tissue. European journal of cancer (Oxford, England : 1990) 25 16380248
2016 Mutant p53 and ETS2, a Tale of Reciprocity. Frontiers in oncology 24 26925389
2009 Complex contributions of Ets2 to craniofacial and thymus phenotypes of trisomic "Down syndrome" mice. American journal of medical genetics. Part A 24 19764029
2009 Ets-2 and p53 mediate cAMP-induced MMP-2 expression, activity and trophoblast invasion. Reproductive biology and endocrinology : RB&E 23 19939245
2007 Ets-2 repressor factor silences extrasynaptic utrophin by N-box mediated repression in skeletal muscle. Molecular biology of the cell 23 17507653
1998 Selective inhibition of prolactin gene transcription by the ETS-2 repressor factor. The Journal of biological chemistry 23 9822660
1992 Influence of nucleotides flanking the ggaa core sequence on ets1 and ets2 DNA-binding activity and the mechanism of ets1 autoregulation. International journal of oncology 23 21584592
2023 ETS2 promotes cardiomyocyte apoptosis and autophagy in heart failure by regulating lncRNA TUG1/miR-129-5p/ATG7 axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 37171262
2010 New insights for Ets2 function in trophoblast using lentivirus-mediated gene knockdown in trophoblast stem cells. Placenta 22 20569982
2023 A distal super-enhancer activates oncogenic ETS2 via recruiting MECOM in inflammatory bowel disease and colorectal cancer. Cell death & disease 21 36609474
2016 The C-ETS2-TFEB Axis Promotes Neuron Survival under Oxidative Stress by Regulating Lysosome Activity. Oxidative medicine and cellular longevity 21 27195074
2014 MicroRNA 17-92 cluster mediates ETS1 and ETS2-dependent RAS-oncogenic transformation. PloS one 21 24968297
2014 Elf5 and Ets2 maintain the mouse extraembryonic ectoderm in a dosage dependent synergistic manner. Developmental biology 21 25446535
2001 Beta-amyloid precursor protein, ETS-2 and collagen alpha 1 (VI) chain precursor, encoded on chromosome 21, are not overexpressed in fetal Down syndrome: further evidence against gene dosage effect. Journal of neural transmission. Supplementum 21 11771756
2019 EGF suppresses the expression of miR-124a in pancreatic β cell lines via ETS2 activation through the MEK and PI3K signaling pathways. International journal of biological sciences 20 31754329
2013 Hepatitis B virus core protein enhances human telomerase reverse transcriptase expression and hepatocellular carcinoma cell proliferation in a c-Ets2-dependent manner. The international journal of biochemistry & cell biology 20 23542016

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