# ERG
**ERG** (ETS transcription factor ERG; Gene ID 2078, HGNC:3446) is a human protein-coding gene that encodes a member of the ETS (E-26 transformation-specific) family of transcription factors, regulators of embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis.[1](https://www.ncbi.nlm.nih.gov/gene/002078) In normal tissue ERG is a central regulator of vascular endothelium and hematopoiesis; in cancer it is best known as the oncogenic partner of recurrent chromosomal fusions, above all the TMPRSS2-ERG fusion of prostate cancer, as well as EWS-ERG in Ewing sarcoma and FUS-ERG in acute myeloid leukemia.[1](https://www.ncbi.nlm.nih.gov/gene/002078)
| Key fact | Detail |
|---|---|
| Gene | ERG, ETS transcription factor ERG; protein coding; chromosome 21q22.2, reverse strand; spans 282 kb with up to 12 potential exons and at least 3 promoters[1](https://www.ncbi.nlm.nih.gov/gene/002078) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5404112/) |
| Protein domains | C-terminal ETS DNA-binding domain recognizing the core motif 5′GGA(A/T)3′; a pointed (PNT) domain involved in protein-protein interaction and dimerization; a C-terminal transcriptional activation domain repressed by an NRT domain[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5404112/) |
| Isoforms | Over 30 transcript variants identified, potentially producing at least 15 polypeptides; the longest encodes 486 amino acids at 54.6 kDa[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5404112/) |
| Normal roles | Endothelial lineage specification, vascular development, angiogenesis, and endothelial homeostasis; regulation of hematopoiesis and megakaryocytic maturation; required for platelet adhesion to the subendothelium[1](https://www.ncbi.nlm.nih.gov/gene/002078) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC6493686/) |
| Cancer fusions | TMPRSS2-ERG and NDRG1-ERG in prostate cancer, EWS-ERG in Ewing sarcoma, FUS-ERG in acute myeloid leukemia[1](https://www.ncbi.nlm.nih.gov/gene/002078) |
| Prostate fusion frequency | ERG was the fusion partner in 58.5% of fusions in the DKFZ_RP prostate cancer cohort, versus 35.7–50% in comparison cohorts[4](https://link.springer.com/article/10.1186/s12885-023-11019-6) |
| Prognostic record | Mixed: a large meta-analysis found no association between ERG overexpression and lethal prostate cancer, while the DKFZ_RP cohort found better 5-year biochemical-recurrence-free survival with the fusion (86.1% vs 64.5%)[5](https://aacrjournals.org/cebp/article-abstract/21/9/1497/69263) • [4](https://link.springer.com/article/10.1186/s12885-023-11019-6) |
## Gene and protein structure
The ERG gene maps to the reverse strand of chromosome 21 at 21q22.2 and spans 282 kb with up to 12 potential exons; it has at least three recognized proximal promoters, and an enhancer 85 kb downstream of the transcription start site is active during normal hematopoiesis and in [T-cell acute lymphoblastic leukemia](https://www.edgepedia.org/t-cell-acute-lymphoblastic-leukemia) cells, where ERG positively regulates its own expression.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5404112/) A study by Zammarchi and colleagues identified over 30 ERG isoform variants, with the potential to produce at least 15 polypeptides; the longest encodes a protein of 486 amino acids with a molecular mass of 54.6 kDa.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5404112/) The isoforms ERG1, ERG2, ERG3 (p55), ERG4 (p49), and ERG5 (p38) encode functional DNA-binding proteins, while ERG7 and ERG8 have open reading frames but lack the C-terminal ETS DNA-binding domain; ERG8 cannot bind DNA, localizes mainly to the cytoplasm, and inhibits the transcriptional activity of other ERG isoforms.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5404112/)
**DNA binding.** The ETS domain, located in the [C-terminus](https://www.edgepedia.org/c-terminus) of the protein, is essential for DNA binding and recognizes a core consensus motif 5′GGA(A/T)3′; flanking bases add specificity, and ChIP-seq studies have characterized extended ERG consensus sequences such as AGGA(A/t)(G/A).[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5404112/) ERG DNA binding is allosterically regulated by autoinhibitory regions adjacent to the ETS domain on both the N- and C-terminal sides.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5404112/) The ~80 amino acid pointed (PNT) domain mediates protein-protein interactions and homo- and hetero-dimerization; deleting it causes a 70% decrease in ERG2 transcriptional activity in a reporter assay.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5404112/)
## Function in the endothelium
ERG is the most highly expressed ETS factor in differentiated quiescent endothelial cells and is essential for endothelial lineage specification, vascular development, and angiogenesis; endothelial-specific deletion of Erg in the mouse causes embryonic lethality due to vascular defects.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5404112/) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC6493686/) In the mature vasculature it maintains endothelial homeostasis by transactivating genes involved in key endothelial functions while repressing pro-inflammatory genes.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5404112/)
**Target genes.** ERG drives expression of lineage-specific genes including [CDH5](https://www.edgepedia.org/cdh5) (VE-cadherin), DLL4 (Delta-like protein 4), [CLDN5](https://www.edgepedia.org/cldn5) (claudin-5), and VWF (von Willebrand factor), and controls processes including survival, permeability, and cytoskeletal dynamics.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC6493686/) Knockdown of ERG in endothelial cells markedly increases permeability and reduces CLDN5 expression, showing that ERG controls endothelial permeability through transcriptional regulation of claudin 5.[6](https://www.jbc.org/article/S0021925820611425/pdf) ERG also regulates super-enhancers associated with an endothelial-specific gene expression program, and GWAS data show significant enrichment of risk variants for cardiovascular and other diseases at ERG endothelial enhancers and super-enhancers.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC6493686/)
**Endothelial identity.** A 2025 study describes ERG as a transcriptional safeguard of endothelial identity: ERG loss initiates a progressive but reversible endothelial-to-mesenchymal transition (EndMT) program, with closure of chromatin regions containing ETS motifs and a gain in accessibility of AP1-motif chromatin, and ERG-mediated EndMT programs are prominent in diseases associated with endothelial dysfunction.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC13135260/)
## ERG in prostate cancer: the TMPRSS2-ERG fusion
Identified for the first time in 2005, the TMPRSS2-ERG fusion ranks as one of the most common genomic rearrangements found in any solid tumor and is thought to occur early during the development of prostate cancer.[5](https://aacrjournals.org/cebp/article-abstract/21/9/1497/69263) • [8](https://www.tandfonline.com/doi/full/10.1080/14737159.2026.2669277) The fusion joins the 5′-untranslated region of TMPRSS2 at 21q22, whose expression is driven by androgen-responsive elements, to the coding regions of ERG, linking androgen-driven TMPRSS2 expression to overexpression of the ERG transcription factor in prostate cancer cells.[9](https://www.tandfonline.com/doi/full/10.1080/14737140.2026.2695214) • [10](https://pmc.ncbi.nlm.nih.gov/articles/PMC11988278/) The fusion protein downregulates androgen receptor expression while also binding and inhibiting androgen receptors already present, disrupting cellular differentiation through EZH2-mediated de-differentiation.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC11988278/) Changes in ERG expression also affect the PI3K and Wnt signaling pathways.[11](https://bmccancer.biomedcentral.com/counter/pdf/10.1186/s12885-023-11019-6)
**Prognostic value is unsettled.** Since 2005 the fusion has been studied extensively as a biomarker with mixed results. A cohort study and meta-analysis of 5,074 men after radical prostatectomy found no significant association between the fusion and biochemical recurrence or disease progression, and no association between ERG overexpression and risk of lethal prostate cancer, although fusion-positive tumors were associated with more advanced tumor stage.[5](https://aacrjournals.org/cebp/article-abstract/21/9/1497/69263) • [12](https://www.tandfonline.com/doi/10.4155/fso.15.72) A review of translocation studies notes that early studies tended to interpret TMPRSS2-ERG as a marker of poor prognosis, while later large cohort studies report it as a marker of better prognosis.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC6287620/) In the DKFZ_RP cohort, patients with the fusion had significantly better 5-year biochemical-recurrence-free survival (86.1% with fusion vs 64.5% without, p = 0.00643), whereas a higher total number of fusions per patient (above the median of 6) showed a non-significant worsening of prognosis.[4](https://link.springer.com/article/10.1186/s12885-023-11019-6) The fusion alone has little prognostic impact, but its predictive value improves in combination with other gene-expression panels, and its clinical utility remains in flux.[12](https://www.tandfonline.com/doi/10.4155/fso.15.72) It has also been hypothesized that TMPRSS2/ERG could be a biomarker for [PARP inhibitor](https://www.edgepedia.org/parp-inhibitor) resistance, but present evidence is preliminary and requires further validation.[9](https://www.tandfonline.com/doi/full/10.1080/14737140.2026.2695214)
## ERG fusions in other cancers
ERG gene fusions were initially described in Ewing sarcoma and acute myeloid leukemia before their discovery in prostate cancer.[14](https://pmc.ncbi.nlm.nih.gov/articles/PMC3263025/) In Ewing sarcoma, EWS-ERG fusion was the first cancer alteration of ERG identified, showing that the ERG ETS domain becomes oncogenic through structural fusion.[15](https://affinage.wi.mit.edu/gene/ERG) ERG protein expression identifies ERG-rearranged Ewing sarcoma by immunohistochemistry.[16](https://pubmed.ncbi.nlm.nih.gov/22766791/) In adult acute myeloid leukemia, a retrospective study from 1988 to 2022 found that patients with FUS-ERG fusions had a worse median overall survival of 13 months (95% CI 11.6–14.4) and a worse median disease-free survival of 7.5 months (95% CI 6.5–8.5) than the control group.[17](https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.7042)
**Regulation of the fusion protein.** In ERG-overexpressing prostate cancer cells, dysregulation of the SPOP ubiquitin ligase complex reduces ERG ubiquitination, and stabilized ERG accounts for the enhanced migration and invasion of cells carrying SPOP mutations; the deubiquitinase [USP9X](https://www.edgepedia.org/usp9x), highly expressed in ERG-positive prostate tumors, likewise stabilizes ERG by deubiquitination.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5404112/) ERG is phosphorylated at serine residues S81 and S215 in [VCaP](https://www.edgepedia.org/vcap) prostate cancer cells, and ERK2-dependent phosphorylation at S215 is necessary for overexpressed ERG to drive migration of prostate epithelial cells.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5404112/)
## Diagnostic use and pitfalls
Because ERG is expressed in a subset of prostate carcinomas and Ewing sarcomas due to ERG-involving translocations, ERG immunohistochemistry is of interest in the diagnosis of vascular and other tumors, but it must be used with care: ERG expression in epithelioid sarcoma is not related to ERG-involving translocations, a recognized diagnostic pitfall.[18](https://pmc.ncbi.nlm.nih.gov/articles/PMC3772974/) ERG protein expression assessed by immunohistochemistry in biopsy sets from patients on active surveillance has been evaluated for consistency from diagnostic specimens through rebiopsies to radical prostatectomy specimens, to test the validity of ERG status measured in biopsies.[19](https://pubmed.ncbi.nlm.nih.gov/26060265/)
## References
1. [ERG ETS transcription factor ERG [Homo sapiens (human)], NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/002078)
2. [Shah AV, Birdsey GM, Randi AM (2016). Regulation of endothelial homeostasis, vascular development and angiogenesis by the transcription factor ERG. Vascul Pharmacol.](https://pmc.ncbi.nlm.nih.gov/articles/PMC5404112/)
3. [The Transcription Factor ERG Regulates Super-Enhancers Associated With an Endothelial-Specific Gene Expression Program](https://pmc.ncbi.nlm.nih.gov/articles/PMC6493686/)
4. [Characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer. BMC Cancer (2023)](https://link.springer.com/article/10.1186/s12885-023-11019-6)
5. [The TMPRSS2:ERG Rearrangement, ERG Expression, and Prostate Cancer Outcomes: A Cohort Study and Meta-analysis. Cancer Epidemiol Biomarkers Prev (2012)](https://aacrjournals.org/cebp/article-abstract/21/9/1497/69263)
6. [ETS-related Gene (ERG) Controls Endothelial Cell Permeability via Transcriptional Regulation of the Claudin 5 (CLDN5) Gene. J Biol Chem](https://www.jbc.org/article/S0021925820611425/pdf)
7. [ERG is a regulator of dynamic and reversible endothelial plasticity (2025)](https://pmc.ncbi.nlm.nih.gov/articles/PMC13135260/)
8. [Fusion genes in precision oncology: prostate cancer as a diagnostic case study. Expert Rev Mol Diagn (2026)](https://www.tandfonline.com/doi/full/10.1080/14737159.2026.2669277)
9. [Predictive biomarkers of response in metastatic prostate cancer (2026)](https://www.tandfonline.com/doi/full/10.1080/14737140.2026.2695214)
10. [Clinical characterization and therapeutic targeting of fusion genes in oncology](https://pmc.ncbi.nlm.nih.gov/articles/PMC11988278/)
11. [Characterization and Evaluation of Gene Fusions in Prostate Cancer. BMC Cancer (PDF)](https://bmccancer.biomedcentral.com/counter/pdf/10.1186/s12885-023-11019-6)
12. [Biomarkers for Prostate Cancer: Present Challenges and Future Opportunities (2015)](https://www.tandfonline.com/doi/10.4155/fso.15.72)
13. [Translocations involving ETS family proteins in human cancer](https://pmc.ncbi.nlm.nih.gov/articles/PMC6287620/)
14. [Oncogenic activation of ERG: A predominant mechanism in prostate cancer](https://pmc.ncbi.nlm.nih.gov/articles/PMC3263025/)
15. [ERG, Affinage (Whitehead Institute)](https://affinage.wi.mit.edu/gene/ERG)
16. [Expression of ERG, an Ets family transcription factor, identifies ERG-rearranged Ewing sarcoma. PubMed](https://pubmed.ncbi.nlm.nih.gov/22766791/)
17. [Comparison of characteristics and prognostic impact of FUS-ERG and AML1-MTG16 fusion genes in adult AML patients. J Clin Oncol (2023)](https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.7042)
18. [ERG expression in epithelioid sarcoma – a diagnostic pitfall](https://pmc.ncbi.nlm.nih.gov/articles/PMC3772974/)
19. [ERG protein expression over time: from diagnostic biopsies to radical prostatectomy specimens in clinically localised prostate cancer. PubMed](https://pubmed.ncbi.nlm.nih.gov/26060265/)
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*Topic: Encyclopedia › Life and health › Biological foundations › RNA and gene regulation › Transcription and gene regulation › Transcription factor families and specific factors › GATA and ETS transcription factor families*
*Initially written Sep 17, 2026 · Reviewed: Sep 20, 2026; Sep 30, 2026; Oct 21, 2026 · Edited: Sep 20, 2026; Sep 30, 2026; Oct 11, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license