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EML4 (echinoderm microtubule associated protein like 4)

Written2009-07Sven Perner, Theresia Wilbertz, Ann-Cathrin Stiedl, Mark A Rubin
Institute of Pathology, Comprehensive Cancer Center, University Hospitals of Tubingen, Tubingen, Germany (SP, TW, ACS); Department of Pathology, Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA (MAR)

(Note : for Links provided by Atlas : click)


Alias (NCBI)C2orf2
HGNC (Hugo) EML4
HGNC Alias symbROPP120
HGNC Previous nameC2orf2
HGNC Previous nameechinoderm microtubule associated protein like 4
LocusID (NCBI) 27436
Atlas_Id 44353
Location 2p21  [Link to chromosome band 2p21]
Location_base_pair Starts at 42169353 and ends at 42332548 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping EML4.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)
ALK (2p23.2)::EML4 (2p21)DCUN1D4 (4q12)::EML4 (2p21)EHBP1 (2p15)::EML4 (2p21)
EML4 (2p21)::ALK (2p23.2)EML4 (2p21)::CASK (Xp11.4)EML4 (2p21)::COX7A2L (2p21)
EML4 (2p21)::EML4 (2p21)EML4 (2p21)::MRPL35 (2p11.2)EML4 (2p21)::NTRK3 (15q25.3)
EML4 (2p21)::PLPP7 (9q34.13)THADA (2p21)::EML4 (2p21)ZNF587 (19q13.43)::EML4 (2p21)
Note Gene type: protein coding; Member of the EMAP-family.


  2p with location of EML4 and ALK relative to each other.
Description 23 exons; DNA-length: 163,173 kb.
Transcription Two transcript variants.


Note Strongly expressed during mitosis.
2 isoforms:
- Isoform a (= variant 1): longer transcript,
- Isoform b (= variant 2): shorter transcript, lacks an alternate in-frame exon.
Description Weight: 120 kDa.
At least 2 Domains: HELP motif, WD40 repeat.
Exon 2 encodes for coiled-coil domain.
Expression Ubiquitous.
Localisation Intracellular.
Function Microtubule binding.
Necessary for correct microtubule formation (stabilizes microtubules).
May modify the assembly dynamics of microtubules, such that microtubules are slightly longer, but more dynamic.
Homology Mouse, rat.

Implicated in

Entity Non-small cell lung carcinoma (NSCLC)
Note Mouse models suggest that EML4-ALK fusion might play an essential role in NSCLC carcinogenesis.
EML4-ALK-fusion-transcript is detectable in a low amount (frequency between 2,7% and 6,7%) of NSCLC-samples and NSCLC-cell-lines. So far, the fusion-protein could only be detected by mass-spectrometry. Immunohistochemical detection of the Alk-protein in fusion-transcript-positive primary NSCLC-samples is contentious.
Alk-inhibitors impede proliferation in EML4-ALK-fusion positive lung cancer cell-lines. In experiments with transgenic mice, treatment with ALK-inhibitors resulted in reduced tumor mass.
The role of EML4-ALK-fusion as a specific biomarker for NSCLC remains controversial.
Disease NSCLC, frequency between 2,7% and 6,7%.
Prognosis Controversially discussed. Limited informative because of low numbers studied so far.
Cytogenetics EML4-ALK-Fusion. , other fusion-mechanisms suggested.
Hybrid/Mutated Gene EML4-ALK.
Fusion of EML4-ALK. a) wild type EML4 and ALK. b) fused EML4-ALK.
Abnormal Protein EML4-ALK = tyrosine-kinase, which is constitutively dimerized and thus activated.
For known fusion partners of ALK, see ALK. For example, TPM3, TFG, MYH9, NPM, ATIC, MSN, ALO17 are ALK partners in anaplasic large cell lymphoma, CLTC in diffuse large cell lymphoma, and TPM4 in inflammatory myofibroblastic tumors.


  EML4-ALK fusion isoforms (numbers = exon number).
Note Known variants:
Variant 1: exon 1-13 (EML4) + exon 20-29 (ALK)
Variant 2: exon 1-20 (EML4) + exon 20-29 (ALK)
Variant 3a: exon 1-6a (EML4) + exon 20-29 (ALK)
Variant 3b: exon 1-6b (EML4) + exon 20-29 (ALK)
Variant 4a : exon 15 (EML4) + exon 20-29 (ALK)
Variant 4b : exon 14 (EML4) + linker of 11bp + exon 20-29 (ALK)
Variant 5a : exon 2 (EML4) + exon 20-29 (ALK)
Variant 5b : exon 2 (EML4) + intron 19 (ALK) + exon 20-29 (ALK)


Oncogenic mutations of ALK kinase in neuroblastoma.
Chen Y, Takita J, Choi YL, Kato M, Ohira M, Sanada M, Wang L, Soda M, Kikuchi A, Igarashi T, Nakagawara A, Hayashi Y, Mano H, Ogawa S.
Nature. 2008 Oct 16;455(7215):971-4.
PMID 18923524
Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer.
Choi YL, Takeuchi K, Soda M, Inamura K, Togashi Y, Hatano S, Enomoto M, Hamada T, Haruta H, Watanabe H, Kurashina K, Hatanaka H, Ueno T, Takada S, Yamashita Y, Sugiyama Y, Ishikawa Y, Mano H.
Cancer Res. 2008 Jul 1;68(13):4971-6.
PMID 18593892
Echinoderm microtubule-associated protein like protein 4, a member of the echinoderm microtubule-associated protein family, stabilizes microtubules.
Houtman SH, Rutteman M, De Zeeuw CI, French PJ.
Neuroscience. 2007 Feb 23;144(4):1373-82. Epub 2006 Dec 27.
PMID 17196341
EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers.
Inamura K, Takeuchi K, Togashi Y, Nomura K, Ninomiya H, Okui M, Satoh Y, Okumura S, Nakagawa K, Soda M, Choi YL, Niki T, Mano H, Ishikawa Y.
J Thorac Oncol. 2008 Jan;3(1):13-7.
PMID 18166835
EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.
Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ, Choi HG, Kim J, Chiang D, Thomas R, Lee J, Richards WG, Sugarbaker DJ, Ducko C, Lindeman N, Marcoux JP, Engelman JA, Gray NS, Lee C, Meyerson M, Janne PA.
Clin Cancer Res. 2008 Jul 1;14(13):4275-83.
PMID 18594010
Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer.
Mano H.
Cancer Sci. 2008 Dec;99(12):2349-55. Epub 2008 Nov 20. (REVIEW)
PMID 19032370
EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues.
Martelli MP, Sozzi G, Hernandez L, Pettirossi V, Navarro A, Conte D, Gasparini P, Perrone F, Modena P, Pastorino U, Carbone A, Fabbri A, Sidoni A, Nakamura S, Gambacorta M, Fernandez PL, Ramirez J, Chan JK, Grigioni WF, Campo E, Pileri SA, Falini B.
Am J Pathol. 2009 Feb;174(2):661-70. Epub 2009 Jan 15.
PMID 19147828
EML4-ALK fusion lung cancer: a rare acquired event.
Perner S, Wagner PL, Demichelis F, Mehra R, Lafargue CJ, Moss BJ, Arbogast S, Soltermann A, Weder W, Giordano TJ, Beer DG, Rickman DS, Chinnaiyan AM, Moch H, Rubin MA.
Neoplasia. 2008 Mar;10(3):298-302.
PMID 18320074
Human EML4, a novel member of the EMAP family, is essential for microtubule formation.
Pollmann M, Parwaresch R, Adam-Klages S, Kruse ML, Buck F, Heidebrecht HJ.
Exp Cell Res. 2006 Oct 15;312(17):3241-51. Epub 2006 Jul 8.
PMID 16890222
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H.
Nature. 2007 Aug 2;448(7153):561-6. Epub 2007 Jul 11.
PMID 17625570
A mouse model for EML4-ALK-positive lung cancer.
Soda M, Takada S, Takeuchi K, Choi YL, Enomoto M, Ueno T, Haruta H, Hamada T, Yamashita Y, Ishikawa Y, Sugiyama Y, Mano H.
Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19893-7. Epub 2008 Dec 8.
PMID 19064915
Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts.
Takeuchi K, Choi YL, Soda M, Inamura K, Togashi Y, Hatano S, Enomoto M, Takada S, Yamashita Y, Satoh Y, Okumura S, Nakagawa K, Ishikawa Y, Mano H.
Clin Cancer Res. 2008 Oct 15;14(20):6618-24.
PMID 18927303


This paper should be referenced as such :
Perner, S ; Wilbertz, T ; Stiedl, AC ; Rubin, MA
EML4 (echinoderm microtubule associated protein like 4)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(6):552-554.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  inv(2)(p21p23) EML4::ALK

External links

HGNC (Hugo)EML4   1316
Entrez_Gene (NCBI)EML4    EMAP like 4
AliasesC2orf2; ELP120; EMAP-4; EMAPL4; 
GeneCards (Weizmann)EML4
Ensembl hg19 (Hinxton)ENSG00000143924 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000143924 [Gene_View]  ENSG00000143924 [Sequence]  chr2:42169353-42332548 [Contig_View]  EML4 [Vega]
ICGC DataPortalENSG00000143924
TCGA cBioPortalEML4
AceView (NCBI)EML4
Genatlas (Paris)EML4
SOURCE (Princeton)EML4
Genetics Home Reference (NIH)EML4
Genomic and cartography
GoldenPath hg38 (UCSC)EML4  -     chr2:42169353-42332548 +  2p21   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)EML4  -     2p21   [Description]    (hg19-Feb_2009)
GoldenPathEML4 - 2p21 [CytoView hg19]  EML4 - 2p21 [CytoView hg38]
Genome Data Viewer NCBIEML4 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AF131753 AF177377 AK001804 AK021782 AK056880
RefSeq transcript (Entrez)NM_001145076 NM_019063
Consensus coding sequences : CCDS (NCBI)EML4
Gene ExpressionEML4 [ NCBI-GEO ]   EML4 [ EBI - ARRAY_EXPRESS ]   EML4 [ SEEK ]   EML4 [ MEM ]
Gene Expression Viewer (FireBrowse)EML4 [ Firebrowse - Broad ]
GenevisibleExpression of EML4 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)27436
GTEX Portal (Tissue expression)EML4
Human Protein AtlasENSG00000143924-EML4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)EML4
Human Protein Atlas [tissue]ENSG00000143924-EML4 [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed109 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 21:17:03 CEST 2021

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