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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)

Identity

Alias_namesC2orf2
Alias_symbol (synonym)ROPP120
ELP120
Other aliasDKFZp686P18118
EMAP-4
EMAPL4
FLJ10942
FLJ32318
HGNC (Hugo) EML4
LocusID (NCBI) 27436
Atlas_Id 44353
Location 2p21  [Link to chromosome band 2p21]
Location_base_pair Starts at 42169338 and ends at 42332548 bp from pter ( according to hg19-Feb_2009)  [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.

DNA/RNA

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

Protein

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

Note
  
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. inv(2)(p21p23), 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.
  

Breakpoints

 
  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)

Bibliography

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
 

Citation

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 ]
On line version : http://AtlasGeneticsOncology.org/Genes/EML4ID44353ch2p21.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 4 ]
  Kidney: ALK-rearranged renal cell carcinoma
Lung: Non-small cell carcinoma with inv(2)(p21p23) EML4/ALK
Lung: Translocations in Adenocarcinoma
Lung: Translocations in Squamous Cell Carcinoma


External links

Nomenclature
HGNC (Hugo)EML4   1316
Cards
AtlasEML4ID44353ch2p21
Entrez_Gene (NCBI)EML4  27436  echinoderm microtubule associated protein like 4
AliasesC2orf2; ELP120; EMAP-4; EMAPL4; 
ROPP120
GeneCards (Weizmann)EML4
Ensembl hg19 (Hinxton)ENSG00000143924 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000143924 [Gene_View]  chr2:42169338-42332548 [Contig_View]  EML4 [Vega]
ICGC DataPortalENSG00000143924
TCGA cBioPortalEML4
AceView (NCBI)EML4
Genatlas (Paris)EML4
WikiGenes27436
SOURCE (Princeton)EML4
Genetics Home Reference (NIH)EML4
Genomic and cartography
GoldenPath hg38 (UCSC)EML4  -     chr2:42169338-42332548 +  2p21   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)EML4  -     2p21   [Description]    (hg19-Feb_2009)
EnsemblEML4 - 2p21 [CytoView hg19]  EML4 - 2p21 [CytoView hg38]
Mapping of homologs : NCBIEML4 [Mapview hg19]  EML4 [Mapview hg38]
OMIM607442   
Gene and transcription
Genbank (Entrez)AF131753 AF177377 AK001804 AK021782 AK056880
RefSeq transcript (Entrez)NM_001145076 NM_019063
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)EML4
Cluster EST : UnigeneHs.713173 [ NCBI ]
CGAP (NCI)Hs.713173
Alternative Splicing GalleryENSG00000143924
Gene ExpressionEML4 [ NCBI-GEO ]   EML4 [ EBI - ARRAY_EXPRESS ]   EML4 [ SEEK ]   EML4 [ MEM ]
Gene Expression Viewer (FireBrowse)EML4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression 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
UniProt/SwissProtQ9HC35   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9HC35  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9HC35
Splice isoforms : SwissVarQ9HC35
PhosPhoSitePlusQ9HC35
Domaine pattern : Prosite (Expaxy)WD_REPEATS_1 (PS00678)    WD_REPEATS_2 (PS50082)    WD_REPEATS_REGION (PS50294)   
Domains : Interpro (EBI)HELP    Quinoprotein_ADH-like_supfam    WD40/YVTN_repeat-like_dom    WD40_repeat    WD40_repeat_CS    WD40_repeat_dom   
Domain families : Pfam (Sanger)HELP (PF03451)    WD40 (PF00400)   
Domain families : Pfam (NCBI)pfam03451    pfam00400   
Domain families : Smart (EMBL)WD40 (SM00320)  
Conserved Domain (NCBI)EML4
DMDM Disease mutations27436
Blocks (Seattle)EML4
PDB (SRS)4CGC   
PDB (PDBSum)4CGC   
PDB (IMB)4CGC   
PDB (RSDB)4CGC   
Structural Biology KnowledgeBase4CGC   
SCOP (Structural Classification of Proteins)4CGC   
CATH (Classification of proteins structures)4CGC   
SuperfamilyQ9HC35
Human Protein Atlas [tissue]ENSG00000143924-EML4 [tissue]
Peptide AtlasQ9HC35
HPRD06310
IPIIPI00001466   IPI01018328   IPI00063047   IPI00854834   IPI00893067   
Protein Interaction databases
DIP (DOE-UCLA)Q9HC35
IntAct (EBI)Q9HC35
FunCoupENSG00000143924
BioGRIDEML4
STRING (EMBL)EML4
ZODIACEML4
Ontologies - Pathways
QuickGOQ9HC35
Ontology : AmiGOmitotic cell cycle  molecular_function  cytoplasm  microtubule  microtubule-based process  microtubule binding  microtubule cytoskeleton  membrane  
Ontology : EGO-EBImitotic cell cycle  molecular_function  cytoplasm  microtubule  microtubule-based process  microtubule binding  microtubule cytoskeleton  membrane  
Pathways : KEGGNon-small cell lung cancer   
NDEx NetworkEML4
Atlas of Cancer Signalling NetworkEML4
Wikipedia pathwaysEML4
Orthology - Evolution
OrthoDB27436
GeneTree (enSembl)ENSG00000143924
Phylogenetic Trees/Animal Genes : TreeFamEML4
HOVERGENQ9HC35
HOGENOMQ9HC35
Homologs : HomoloGeneEML4
Homology/Alignments : Family Browser (UCSC)EML4
Gene fusions - Rearrangements
Fusion : MitelmanEML4/ALK [2p21/2p23.2]  
Fusion : MitelmanEML4/CASK [2p21/Xp11.4]  [t(X;2)(p11;p21)]  
Fusion : COSMICEML4 [2p21]  -  ALK [2p23.2]  [fusion_1062]  [fusion_1063]  [fusion_1064]  [fusion_1065]  [fusion_1127]  [fusion_1128]  [fusion_1296]  
[fusion_1297]  [fusion_1368]  [fusion_1376]  [fusion_1539]  [fusion_1540]  [fusion_1541]  [fusion_1542]  [fusion_1543]  [fusion_1544]  [fusion_1545]  
[fusion_408]  [fusion_409]  [fusion_410]  [fusion_411]  [fusion_413]  [fusion_414]  [fusion_462]  [fusion_463]  [fusion_464]  [fusion_465]  
[fusion_473]  [fusion_474]  [fusion_475]  [fusion_476]  [fusion_477]  [fusion_478]  [fusion_479]  [fusion_480]  [fusion_487]  [fusion_488]  
[fusion_489]  [fusion_490]  [fusion_491]  [fusion_493]  [fusion_730]  [fusion_731]  [fusion_732]  [fusion_733]  [fusion_734]  
Fusion: TCGAEML4 2p21 ALK 2p23.2 LUAD THCA
Fusion: TCGAEML4 2p21 CASK Xp11.4 GBM
Fusion: TCGAEML4 2p21 COX7A2L 2p21 BRCA
Fusion: TCGATHADA 2p21 EML4 2p21 LUSC
Fusion : TICdbEML4 [2p21]  -  ALK [2p23.2]
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerEML4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)EML4
dbVarEML4
ClinVarEML4
1000_GenomesEML4 
Exome Variant ServerEML4
ExAC (Exome Aggregation Consortium)ENSG00000143924
GNOMAD BrowserENSG00000143924
Genetic variants : HAPMAP27436
Genomic Variants (DGV)EML4 [DGVbeta]
DECIPHEREML4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisEML4 
Mutations
ICGC Data PortalEML4 
TCGA Data PortalEML4 
Broad Tumor PortalEML4
OASIS PortalEML4 [ Somatic mutations - Copy number]
Cancer Gene: CensusEML4 
Somatic Mutations in Cancer : COSMICEML4  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDEML4
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch EML4
DgiDB (Drug Gene Interaction Database)EML4
DoCM (Curated mutations)EML4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)EML4 (select a term)
intoGenEML4
NCG5 (London)EML4
Cancer3DEML4(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM607442   
Orphanet22213   
MedgenEML4
Genetic Testing Registry EML4
NextProtQ9HC35 [Medical]
TSGene27436
GENETestsEML4
Target ValidationEML4
Huge Navigator EML4 [HugePedia]
snp3D : Map Gene to Disease27436
BioCentury BCIQEML4
ClinGenEML4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD27436
Chemical/Pharm GKB GenePA27769
Clinical trialEML4
Miscellaneous
canSAR (ICR)EML4 (select the gene name)
Probes
Litterature
PubMed76 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineEML4
EVEXEML4
GoPubMedEML4
iHOPEML4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Oct 12 16:21:15 CEST 2017

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