EML4 (echinoderm microtubule associated protein like 4)

2009-07-01 Sven Perner , Theresia Wilbertz , Ann-Cathrin Stiedl , Mark A Rubin Affiliation

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)

Identity

HGNC

EML4

LOCATION

2p21

LOCUSID

27436

ALIAS

C2orf2,ELP120,EMAP-4,EMAPL4,ROPP120

FUSION GENES

Show Gene Fusions

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.

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 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.

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.

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

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)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Non-small cell lung cancer	KEGG	ko05223
Non-small cell lung cancer	KEGG	hsa05223

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PK	PD	PMIDs
PA24719	ALK	Gene	MultilinkAnnotation	associated			25706305

References

Pubmed ID	Year	Title	Citations
19667264	2009	Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.	550
18594010	2008	EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.	293
18927303	2008	Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts.	158
18166835	2008	EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers.	145
18593892	2008	Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer.	143
26019170	2015	Induction of PD-L1 Expression by the EML4-ALK Oncoprotein and Downstream Signaling Pathways in Non-Small Cell Lung Cancer.	132
20624322	2010	Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression.	123
20624322	2010	Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression.	123
20183914	2010	Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene.	109
19737969	2009	Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers.	106

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/eml4-(echinoderm-microtubule-associated-protein-like-4)