ETV4 (ets variant 4)

2010-11-01   Yasuyoshi Miyata 

Department of Urology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan




Atlas Image
GeneLoc map region.


The gene spans approximately 30 kb and contained 14 exons. The largest exon (901 bp) contains the end of the ETS domain, the carboxy-terminal domain and the 3-untranslated region. The remaining exons varied from 48 bp (exon 5) to 266 bp (exon 9).



Nuclear (Monté et al., 1994; Takahashi et al., 2005). Ubiquitinated protein is localized in the dot-like structure in the nuclear (Takahashi et al., 2005).


ETV4 is capable of regulating transcription by binding to the Ets-binding site in the promoter of its target genes. Biologically, it contributes in a number of processes including neuronal pathfinding, mammary gland development, and male sexual function (Laing et al., 2000; Ladle et al., 2002; Kurpios et al., 2003). In various malignancies, its over-expression has been observed and it was also associated with tumor progression and outcome of patients with these malignancies. As mechanism of such function, regulation of hepatocyte growth factor (HGF)-induced cell migration (Hakuma et al., 2005), HER2-mediated malignant potential (Benz et al., 1997), and other ETV4-related factors including cyclooxygenase (COX)-2 and matrix metalloproteinases (MMPs) have been reported (Higashino et al., 1995; Horiuchi et al., 2003; Shindoh et al., 2004). In addition, ETV4 promotes cell cycle progression via upregulation of cyclin D3 transcription in breast cancer cell (MDA231 cell) (Jiang et al., 2007). In contrast, ETV4 function as negative regulator of sonic hedgehog expression (Mao et al., 2009).

Implicated in

Entity name
Breast cancer
Over-expression of ETV4 has been detected in human cancer cell lines (Baert et al., 1997). In animal model and human tissues, its over-expression was also found and it was associated with malignant potential including invasion and metastasis (Trimble et al., 1993; De Launoit et al., 2000; Benz et al., 1997; Bièche et al., 2004). Such ETV4-related functions are controlled via regulation of cyclin D3 transcription (Jiang et al., 2007), HER-2/Neu (Benz et al., 1997), and MMPs (Bièche et al., 2004).
Entity name
Gastric cancer
Correlated with tumor progression via up-regulation of matrilysin in human tissues (Yamamoto et al., 2004).
Entity name
Lung cancer
ETV4 expression was not detected in normal lung tissues. On the other hand, it is expressed in distal lung epithelium during lung development and in human lung cancer cells (Hiroumi et al., 2001; Liu et al., 2003). It was reported to be associated with cell invasion (Hiroumi et al., 2001) and metastasis via regulation of caveolin-1 transcription (Sloan et al., 2009) and Met-related factors (Hakuma et al., 2005).
Entity name
Malignant melanoma
In cell lines, ETV4 plays important roles for malignant behavior including invasion and metastasis thorough up-regulation of MT1-MMP (Hata et al., 2008).
Entity name
Prostate cancer
In human tissues, its expression in cancer cell was significantly higher than that in normal cells and it was also positively associated with pT stage. This finding was influenced with regulation of MMP-7 and MMP-9, but not of MMP-1, MMP-3, and MMP-14 (MT1-MMP) (Maruta et al., 2009).
Entity name
Colorectal cancer
In early stage of colorectal carcinogenesis, its over-expression plays important roles through MMPs, COX-2, and iNos (Nosho et al., 2005).


Atlas Image


Pubmed IDLast YearTitleAuthors
90527611997Expression of the PEA3 group of ETS-related transcription factors in human breast-cancer cells.Baert JL et al
93804031997HER2/Neu and the Ets transcription activator PEA3 are coordinately upregulated in human breast cancer.Benz CC et al
146336602004Expression of PEA3/E1AF/ETV4, an Ets-related transcription factor, in breast tumors: positive links to MMP2, NRG1 and CGB expression.Bièche I et al
163222232005E1AF/PEA3 activates the Rho/Rho-associated kinase pathway to increase the malignancy potential of non-small-cell lung cancer cells.Hakuma N et al
184253632008Expression of E1AF, an ets-oncogene transcription factor, highly correlates with malignant phenotype of malignant melanoma through up-regulation of the membrane-type-1 matrix metalloproteinase gene.Hata H et al
77317001995Ets-related protein E1A-F can activate three different matrix metalloproteinase gene promoters.Higashino F et al
115190382001Expression of E1AF/PEA3, an Ets-related transcription factor in human non-small-cell lung cancers: its relevance in cell motility and invasion.Hiroumi H et al
128985922003Association of ets-related transcriptional factor E1AF expression with tumour progression and overexpression of MMP-1 and matrilysin in human colorectal cancer.Horiuchi S et al
174676622007E1AF promotes breast cancer cell cycle progression via upregulation of Cyclin D3 transcription.Jiang J et al
146357932003Function of PEA3 Ets transcription factors in mammary gland development and oncogenesis.Kurpios NA et al
125270012002The role of the ETS gene PEA3 in the development of motor and sensory neurons.Ladle DR et al
110940842000Male sexual dysfunction in mice bearing targeted mutant alleles of the PEA3 ets gene.Laing MA et al
145282752003Emerging roles of DNA tumor viruses in cell proliferation: new insights into genomic instability.Lavia P et al
129416182003Role for ETS domain transcription factors Pea3/Erm in mouse lung development.Liu Y et al
193862682009Fgf-dependent Etv4/5 activity is required for posterior restriction of Sonic Hedgehog and promoting outgrowth of the vertebrate limb.Mao J et al
198455292009E1AF expression is associated with extra-prostatic growth and matrix metalloproteinase-7 expression in prostate cancer.Maruta S et al
81528001994Molecular cloning and characterization of human ERM, a new member of the Ets family closely related to mouse PEA3 and ER81 transcription factors.Monté D et al
156952372005Association of Ets-related transcriptional factor E1AF expression with overexpression of matrix metalloproteinases, COX-2 and iNOS in the early stage of colorectal carcinogenesis.Nosho K et al
155009432004E1AF, an ets-oncogene family transcription factor.Shindoh M et al
194831892009Increased PEA3/E1AF and decreased Net/Elk-3, both ETS proteins, characterize human NSCLC progression and regulate caveolin-1 transcription in Calu-1 and NCI-H23 NSCLC cell lines.Sloan KA et al
156291522005E1AF degradation by a ubiquitin-proteasome pathway.Takahashi A et al
76923721993PEA3 is overexpressed in mouse metastatic mammary adenocarcinomas.Trimble MS et al
146048922004Expression of ets-related transcriptional factor E1AF is associated with tumor progression and over-expression of matrilysin in human gastric cancer.Yamamoto H et al
109594162000The PEA3 group of ETS-related transcription factors. Role in breast cancer Launoit Y et al

Other Information

Locus ID:

NCBI: 2118
MIM: 600711
HGNC: 3493
Ensembl: ENSG00000175832


dbSNP: 2118
ClinVar: 2118
TCGA: ENSG00000175832


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
Signal TransductionREACTOMER-HSA-162582
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK6/MAPK4 signalingREACTOMER-HSA-5687128

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
165851602006TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer.160
224255842012ETV1, 4 and 5: an oncogenic subfamily of ETS transcription factors.94
186448622008The AIB1 oncogene promotes breast cancer metastasis by activation of PEA3-mediated matrix metalloproteinase 2 (MMP2) and MMP9 expression.88
187941522008A fluorescence in situ hybridization screen for E26 transformation-specific aberrations: identification of DDX5-ETV4 fusion protein in prostate cancer.55
185939492008Steroid receptor coactivator-3/AIB1 promotes cell migration and invasiveness through focal adhesion turnover and matrix metalloproteinase expression.46
210872112011ERK/p90(RSK)/14-3-3 signalling has an impact on expression of PEA3 Ets transcription factors via the transcriptional repressor capicúa.46
278698302017Inactivation of Capicua drives cancer metastasis.37
193073082009Extracellular signal-regulated kinase mitogen-activated protein kinase signaling initiates a dynamic interplay between sumoylation and ubiquitination to regulate the activity of the transcriptional activator PEA3.35
167383192006The LIM domain protein LPP is a coactivator for the ETS domain transcription factor PEA3.31
184511332008Two unique novel prostate-specific and androgen-regulated fusion partners of ETV4 in prostate cancer.31


Yasuyoshi Miyata

ETV4 (ets variant 4)

Atlas Genet Cytogenet Oncol Haematol. 2010-11-01

Online version: