EML4 (echinoderm microtubule associated protein like 4)
2009-07-01 Sven Perner , Theresia Wilbertz , Ann-Cathrin Stiedl , Mark A Rubin AffiliationInstitute 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)
Identity
HGNC
LOCATION
2p21
LOCUSID
ALIAS
C2orf2,ELP120,EMAP-4,EMAPL4,ROPP120
FUSION GENES
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.
Proteins
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.
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.
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.
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 name
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.
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 gene
EML4-ALK.
Fusion of EML4-ALK. a) wild type EML4 and ALK. b) fused EML4-ALK.
Fusion protein
EML4-ALK = tyrosine-kinase, which is constitutively dimerized and thus activated.
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)
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)
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 18923524 | 2008 | Oncogenic mutations of ALK kinase in neuroblastoma. | Chen Y et al |
| 18593892 | 2008 | Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. | Choi YL et al |
| 17196341 | 2007 | Echinoderm microtubule-associated protein like protein 4, a member of the echinoderm microtubule-associated protein family, stabilizes microtubules. | Houtman SH et al |
| 18166835 | 2008 | EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. | Inamura K et al |
| 18594010 | 2008 | EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. | Koivunen JP et al |
| 19032370 | 2008 | Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer. | Mano H et al |
| 19147828 | 2009 | EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. | Martelli MP et al |
| 18320074 | 2008 | EML4-ALK fusion lung cancer: a rare acquired event. | Perner S et al |
| 16890222 | 2006 | Human EML4, a novel member of the EMAP family, is essential for microtubule formation. | Pollmann M et al |
| 17625570 | 2007 | Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. | Soda M et al |
| 19064915 | 2008 | A mouse model for EML4-ALK-positive lung cancer. | Soda M et al |
| 18927303 | 2008 | Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. | Takeuchi K et al |
Other Information
Locus ID:
NCBI: 27436
MIM: 607442
HGNC: 1316
Ensembl: ENSG00000143924
Variants:
dbSNP: 27436
ClinVar: 27436
TCGA: ENSG00000143924
COSMIC: EML4
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000143924 | ENST00000318522 | Q9HC35 |
| ENSG00000143924 | ENST00000401738 | B5MBZ0 |
| ENSG00000143924 | ENST00000402711 | Q9HC35 |
Expression (GTEx)
Pathways
| Pathway | Source | External ID |
|---|---|---|
| Non-small cell lung cancer | KEGG | ko05223 |
| Non-small cell lung cancer | KEGG | hsa05223 |
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA24719 | ALK | Gene | MultilinkAnnotation | associated | 25706305 |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 34783600 | 2022 | The impact of the ALK fusion variant on clinical outcomes in EML4-ALK patients with NSCLC: a systematic review and meta-analysis. | 6 |
| 35074700 | 2022 | Malignant pleural mesothelioma with an EML4-ALK fusion: Expect the unexpected! | 3 |
| 34783600 | 2022 | The impact of the ALK fusion variant on clinical outcomes in EML4-ALK patients with NSCLC: a systematic review and meta-analysis. | 6 |
| 35074700 | 2022 | Malignant pleural mesothelioma with an EML4-ALK fusion: Expect the unexpected! | 3 |
| 32876329 | 2021 | Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma. | 3 |
| 33761896 | 2021 | EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells. | 3 |
| 34378283 | 2021 | An unusual fusion gene EML4-ALK in a patient with congenital mesoblastic nephroma. | 2 |
| 34391065 | 2021 | Identification of a EML4-ALK exon 19 fusion variant in lung adenocarcinoma and alectinib resistance. | 4 |
| 34490727 | 2021 | A novel break site of EML4-ALK report and a rare PRKAR1A-ALK report analyzed by different ALK detection platforms in non-small cell lung cancer patients. | 3 |
| 34661367 | 2021 | Phase-separated foci of EML4-ALK facilitate signalling and depend upon an active kinase conformation. | 23 |
| 32876329 | 2021 | Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma. | 3 |
| 33761896 | 2021 | EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells. | 3 |
| 34378283 | 2021 | An unusual fusion gene EML4-ALK in a patient with congenital mesoblastic nephroma. | 2 |
| 34391065 | 2021 | Identification of a EML4-ALK exon 19 fusion variant in lung adenocarcinoma and alectinib resistance. | 4 |
| 34490727 | 2021 | A novel break site of EML4-ALK report and a rare PRKAR1A-ALK report analyzed by different ALK detection platforms in non-small cell lung cancer patients. | 3 |
Citation
Sven Perner ; Theresia Wilbertz ; Ann-Cathrin Stiedl ; Mark A Rubin
EML4 (echinoderm microtubule associated protein like 4)
Atlas Genet Cytogenet Oncol Haematol. 2009-07-01
Online version: http://atlasgeneticsoncology.org/gene/44353
