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ETV4 (ets variant 4)

Written2010-11Yasuyoshi Miyata
Department of Urology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan

(Note : for Links provided by Atlas : click)


Alias (NCBI)E1A-F
HGNC (Hugo) ETV4
HGNC Alias symbE1A-F
HGNC Alias nameE1A enhancer binding protein
HGNC Previous nameets variant gene 4 (E1A enhancer-binding protein, E1AF)
 ETS variant 4
LocusID (NCBI) 2118
Atlas_Id 133
Location 17q21.31  [Link to chromosome band 17q21]
Location_base_pair Starts at 43527846 and ends at 43545899 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping ETV4.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CANT1 (17q25.3)::ETV4 (17q21.31)DDX5 (17q23.3)::ETV4 (17q21.31)DHX8 (17q21.31)::ETV4 (17q21.31)
ETV4 (17q21.31)::CANT1 (17q25.3)ETV4 (17q21.31)::CCL16 (17q12)ETV4 (17q21.31)::DDX5 (17q23.3)
ETV4 (17q21.31)::EDIL3 (5q14.3)ETV4 (17q21.31)::EWSR1 (22q12.2)ETV4 (17q21.31)::KLK2 (19q13.33)
ETV4 (17q21.31)::TMPRSS2 (21q22.3)EWSR1 (22q12.2)::ETV4 (17q21.31)KLK2 (19q13.33)::ETV4 (17q21.31)
SLC45A3 (1q32.1)::ETV4 (17q21.31)TMPRSS2 (21q22.3)::ETV4 (17q21.31)UBTF (17q21.31)::ETV4 (17q21.31)
XPO7 (8p21.3)::ETV4 (17q21.31)


  GeneLoc map region.
Description 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).


Description ETV4 is a member of ets-oncogene family transcription factors that were cloned by the ability to bind to enhancer motifs of the adenovirus E1A gene (Lavia et al., 2003). It is composed of 555 amino acids, which has a molecular weight ranging 61~70 kDa.
Localisation 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).
Function 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 Breast cancer
Disease 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 Gastric cancer
Disease Correlated with tumor progression via up-regulation of matrilysin in human tissues (Yamamoto et al., 2004).
Entity Lung cancer
Disease 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 Malignant melanoma
Disease 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 Prostate cancer
Disease 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 Colorectal cancer
Disease In early stage of colorectal carcinogenesis, its over-expression plays important roles through MMPs, COX-2, and iNos (Nosho et al., 2005).




Expression of the PEA3 group of ETS-related transcription factors in human breast-cancer cells.
Baert JL, Monte D, Musgrove EA, Albagli O, Sutherland RL, de Launoit Y.
Int J Cancer. 1997 Mar 4;70(5):590-7.
PMID 9052761
HER2/Neu and the Ets transcription activator PEA3 are coordinately upregulated in human breast cancer.
Benz CC, O'Hagan RC, Richter B, Scott GK, Chang CH, Xiong X, Chew K, Ljung BM, Edgerton S, Thor A, Hassell JA.
Oncogene. 1997 Sep 25;15(13):1513-25.
PMID 9380403
Expression of PEA3/E1AF/ETV4, an Ets-related transcription factor, in breast tumors: positive links to MMP2, NRG1 and CGB expression.
Bieche I, Tozlu S, Girault I, Onody P, Driouch K, Vidaud M, Lidereau R.
Carcinogenesis. 2004 Mar;25(3):405-11. Epub 2003 Nov 21.
PMID 14633660
E1AF/PEA3 activates the Rho/Rho-associated kinase pathway to increase the malignancy potential of non-small-cell lung cancer cells.
Hakuma N, Kinoshita I, Shimizu Y, Yamazaki K, Yoshida K, Nishimura M, Dosaka-Akita H.
Cancer Res. 2005 Dec 1;65(23):10776-82.
PMID 16322223
Expression 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, Kitamura T, Higashino F, Hida K, Yoshida K, Ohiro Y, Totsuka Y, Kitagawa Y, Shindoh M.
Oncol Rep. 2008 May;19(5):1093-8.
PMID 18425363
Ets-related protein E1A-F can activate three different matrix metalloproteinase gene promoters.
Higashino F, Yoshida K, Noumi T, Seiki M, Fujinaga K.
Oncogene. 1995 Apr 6;10(7):1461-3.
PMID 7731700
Expression of E1AF/PEA3, an Ets-related transcription factor in human non-small-cell lung cancers: its relevance in cell motility and invasion.
Hiroumi H, Dosaka-Akita H, Yoshida K, Shindoh M, Ohbuchi T, Fujinaga K, Nishimura M.
Int J Cancer. 2001 Sep;93(6):786-91.
PMID 11519038
Association of ets-related transcriptional factor E1AF expression with tumour progression and overexpression of MMP-1 and matrilysin in human colorectal cancer.
Horiuchi S, Yamamoto H, Min Y, Adachi Y, Itoh F, Imai K.
J Pathol. 2003 Aug;200(5):568-76.
PMID 12898592
E1AF promotes breast cancer cell cycle progression via upregulation of Cyclin D3 transcription.
Jiang J, Wei Y, Liu D, Zhou J, Shen J, Chen X, Zhang S, Kong X, Gu J.
Biochem Biophys Res Commun. 2007 Jun 22;358(1):53-8. Epub 2007 Apr 18.
PMID 17467662
Function of PEA3 Ets transcription factors in mammary gland development and oncogenesis.
Kurpios NA, Sabolic NA, Shepherd TG, Fidalgo GM, Hassell JA.
J Mammary Gland Biol Neoplasia. 2003 Apr;8(2):177-90. (REVIEW)
PMID 14635793
The role of the ETS gene PEA3 in the development of motor and sensory neurons.
Ladle DR, Frank E.
Physiol Behav. 2002 Dec;77(4-5):571-6.
PMID 12527001
Male sexual dysfunction in mice bearing targeted mutant alleles of the PEA3 ets gene.
Laing MA, Coonrod S, Hinton BT, Downie JW, Tozer R, Rudnicki MA, Hassell JA.
Mol Cell Biol. 2000 Dec;20(24):9337-45.
PMID 11094084
Emerging roles of DNA tumor viruses in cell proliferation: new insights into genomic instability.
Lavia P, Mileo AM, Giordano A, Paggi MG.
Oncogene. 2003 Sep 29;22(42):6508-16. (REVIEW)
PMID 14528275
Role for ETS domain transcription factors Pea3/Erm in mouse lung development.
Liu Y, Jiang H, Crawford HC, Hogan BL.
Dev Biol. 2003 Sep 1;261(1):10-24.
PMID 12941618
Fgf-dependent Etv4/5 activity is required for posterior restriction of Sonic Hedgehog and promoting outgrowth of the vertebrate limb.
Mao J, McGlinn E, Huang P, Tabin CJ, McMahon AP.
Dev Cell. 2009 Apr;16(4):600-6.
PMID 19386268
E1AF expression is associated with extra-prostatic growth and matrix metalloproteinase-7 expression in prostate cancer.
Maruta S, Sakai H, Kanda S, Hayashi T, Kanetake H, Miyata Y.
APMIS. 2009 Nov;117(11):791-6.
PMID 19845529
Molecular cloning and characterization of human ERM, a new member of the Ets family closely related to mouse PEA3 and ER81 transcription factors.
Monte D, Baert JL, Defossez PA, de Launoit Y, Stehelin D.
Oncogene. 1994 May;9(5):1397-406.
PMID 8152800
Association 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, Yoshida M, Yamamoto H, Taniguchi H, Adachi Y, Mikami M, Hinoda Y, Imai K.
Carcinogenesis. 2005 May;26(5):892-9. Epub 2005 Feb 3.
PMID 15695237
E1AF, an ets-oncogene family transcription factor.
Shindoh M, Higashino F, Kohgo T.
Cancer Lett. 2004 Dec 8;216(1):1-8. (REVIEW)
PMID 15500943
Increased 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, Marquez HA, Li J, Cao Y, Hinds A, O'Hara CJ, Kathuria S, Ramirez MI, Williams MC, Kathuria H.
Carcinogenesis. 2009 Aug;30(8):1433-42. Epub 2009 May 29.
PMID 19483189
E1AF degradation by a ubiquitin-proteasome pathway.
Takahashi A, Higashino F, Aoyagi M, Yoshida K, Itoh M, Kobayashi M, Totsuka Y, Kohgo T, Shindoh M.
Biochem Biophys Res Commun. 2005 Feb 11;327(2):575-80.
PMID 15629152
PEA3 is overexpressed in mouse metastatic mammary adenocarcinomas.
Trimble MS, Xin JH, Guy CT, Muller WJ, Hassell JA.
Oncogene. 1993 Nov;8(11):3037-42.
PMID 7692372
Expression of ets-related transcriptional factor E1AF is associated with tumor progression and over-expression of matrilysin in human gastric cancer.
Yamamoto H, Horiuchi S, Adachi Y, Taniguchi H, Nosho K, Min Y, Imai K.
Carcinogenesis. 2004 Mar;25(3):325-32. Epub 2003 Nov 6.
PMID 14604892
The PEA3 group of ETS-related transcription factors. Role in breast cancer metastasis.
de Launoit Y, Chotteau-Lelievre A, Beaudoin C, Coutte L, Netzer S, Brenner C, Huvent I, Baert JL.
Adv Exp Med Biol. 2000;480:107-16. (REVIEW)
PMID 10959416


This paper should be referenced as such :
Miyata, Y
ETV4 (ets variant 4)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(7):554-556.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 3 ]
  t(16;21)(p11;q22) FUS::ERG
t(17;17)(q21;q21) DHX08::ETV4
DHX8::ETV4 (17q21)

External links


HGNC (Hugo)ETV4   3493
Entrez_Gene (NCBI)ETV4    ETS variant transcription factor 4
AliasesE1A-F; E1AF; PEA3; PEAS3
GeneCards (Weizmann)ETV4
Ensembl hg19 (Hinxton)ENSG00000175832 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000175832 [Gene_View]  ENSG00000175832 [Sequence]  chr17:43527846-43545899 [Contig_View]  ETV4 [Vega]
ICGC DataPortalENSG00000175832
TCGA cBioPortalETV4
AceView (NCBI)ETV4
Genatlas (Paris)ETV4
SOURCE (Princeton)ETV4
Genetics Home Reference (NIH)ETV4
Genomic and cartography
GoldenPath hg38 (UCSC)ETV4  -     chr17:43527846-43545899 -  17q21.31   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ETV4  -     17q21.31   [Description]    (hg19-Feb_2009)
GoldenPathETV4 - 17q21.31 [CytoView hg19]  ETV4 - 17q21.31 [CytoView hg38]
Genome Data Viewer NCBIETV4 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AK290429 AK298872 AK299019 AK312934 AK315961
RefSeq transcript (Entrez)NM_001079675 NM_001261437 NM_001261438 NM_001261439 NM_001369366 NM_001369367 NM_001369368 NM_001986
Consensus coding sequences : CCDS (NCBI)ETV4
Gene ExpressionETV4 [ NCBI-GEO ]   ETV4 [ EBI - ARRAY_EXPRESS ]   ETV4 [ SEEK ]   ETV4 [ MEM ]
Gene Expression Viewer (FireBrowse)ETV4 [ Firebrowse - Broad ]
GenevisibleExpression of ETV4 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2118
GTEX Portal (Tissue expression)ETV4
Human Protein AtlasENSG00000175832-ETV4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP43268   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP43268  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP43268
Domaine pattern : Prosite (Expaxy)ETS_DOMAIN_1 (PS00345)    ETS_DOMAIN_2 (PS00346)    ETS_DOMAIN_3 (PS50061)   
Domains : Interpro (EBI)Ets_dom    ETS_PEA3_N    WH-like_DNA-bd_sf    WH_DNA-bd_sf   
Domain families : Pfam (Sanger)Ets (PF00178)    ETS_PEA3_N (PF04621)   
Domain families : Pfam (NCBI)pfam00178    pfam04621   
Domain families : Smart (EMBL)ETS (SM00413)  
Conserved Domain (NCBI)ETV4
PDB (RSDB)4CO8    4UUV    5ILU   
PDB Europe4CO8    4UUV    5ILU   
PDB (PDBSum)4CO8    4UUV    5ILU   
PDB (IMB)4CO8    4UUV    5ILU   
Structural Biology KnowledgeBase4CO8    4UUV    5ILU   
SCOP (Structural Classification of Proteins)4CO8    4UUV    5ILU   
CATH (Classification of proteins structures)4CO8    4UUV    5ILU   
AlphaFold pdb e-kbP43268   
Human Protein Atlas [tissue]ENSG00000175832-ETV4 [tissue]
Protein Interaction databases
IntAct (EBI)P43268
Ontologies - Pathways
Ontology : AmiGOchromatin  RNA polymerase II cis-regulatory region sequence-specific DNA binding  DNA-binding transcription factor activity, RNA polymerase II-specific  DNA-binding transcription factor activity, RNA polymerase II-specific  DNA-binding transcription activator activity, RNA polymerase II-specific  protein binding  nucleus  nucleoplasm  chromosome  nucleolus  regulation of transcription by RNA polymerase II  cell differentiation  positive regulation of keratinocyte differentiation  positive regulation of transcription by RNA polymerase II  sequence-specific double-stranded DNA binding  
Ontology : EGO-EBIchromatin  RNA polymerase II cis-regulatory region sequence-specific DNA binding  DNA-binding transcription factor activity, RNA polymerase II-specific  DNA-binding transcription factor activity, RNA polymerase II-specific  DNA-binding transcription activator activity, RNA polymerase II-specific  protein binding  nucleus  nucleoplasm  chromosome  nucleolus  regulation of transcription by RNA polymerase II  cell differentiation  positive regulation of keratinocyte differentiation  positive regulation of transcription by RNA polymerase II  sequence-specific double-stranded DNA binding  
Pathways : KEGGTranscriptional misregulation in cancer   
REACTOMEP43268 [protein]
REACTOME PathwaysR-HSA-5687128 [pathway]   
NDEx NetworkETV4
Atlas of Cancer Signalling NetworkETV4
Wikipedia pathwaysETV4
Orthology - Evolution
GeneTree (enSembl)ENSG00000175832
Phylogenetic Trees/Animal Genes : TreeFamETV4
Homologs : HomoloGeneETV4
Homology/Alignments : Family Browser (UCSC)ETV4
Gene fusions - Rearrangements
Fusion : Mitelman-::17q21.31 [ETV4/t(17;17)(p13;q21)]  
Fusion : MitelmanCANT1::ETV4 [17q25.3/17q21.31]  
Fusion : MitelmanDDX5::ETV4 [17q23.3/17q21.31]  
Fusion : MitelmanDHX8::ETV4 [17q21.31/17q21.31]  
Fusion : MitelmanETV4::CCL16 [17q21.31/17q12]  
Fusion : MitelmanEWSR1::ETV4 [22q12.2/17q21.31]  
Fusion : COSMICTMPRSS2 [21q22.3]  -  ETV4 [17q21.31]  [fusion_212]  [fusion_214]  [fusion_44]  
Fusion : QuiverETV4
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerETV4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ETV4
Exome Variant ServerETV4
GNOMAD BrowserENSG00000175832
Varsome BrowserETV4
ACMGETV4 variants
Genomic Variants (DGV)ETV4 [DGVbeta]
DECIPHERETV4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisETV4 
ICGC Data PortalETV4 
TCGA Data PortalETV4 
Broad Tumor PortalETV4
OASIS PortalETV4 [ Somatic mutations - Copy number]
Cancer Gene: CensusETV4 
Somatic Mutations in Cancer : COSMICETV4  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DETV4
Mutations and Diseases : HGMDETV4
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)ETV4
DoCM (Curated mutations)ETV4
CIViC (Clinical Interpretations of Variants in Cancer)ETV4
NCG (London)ETV4
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry ETV4
NextProtP43268 [Medical]
Target ValidationETV4
Huge Navigator ETV4 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDETV4
Pharm GKB GenePA27907
Clinical trialETV4
DataMed IndexETV4
PubMed117 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:17:30 CEST 2021

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