EPB41L3 (erythrocyte membrane protein band 4.1-like 3)

2008-05-01   Sunny Y Wong 

Howard Hughes Medical Institute, Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA

Identity

HGNC
LOCATION
18p11.31
LOCUSID
ALIAS
4.1B,DAL-1,DAL1
FUSION GENES

DNA/RNA

Atlas Image

Description

The gene consists of 23 exons, with exons 1 and 23 being non-coding. The total gene length is 4,446 bases.

Transcription

The coding sequence (87-3350) generates an approximatively 3.3 kb mRNA transcript.

Proteins

Description

Protein 4.1B is a member of the Protein 4.1 superfamily of proteins, which is characterized by the presence of a conserved N-terminal 4.1/ezrin/radixin/moesin (FERM) domain. The full-length protein consists of the following domains (N- to C-termini): U1-FERM-U2-SABD-U3-CTD ("U" = unique domains, SABD = spectrin/actin binding domain, CTD = C-terminal domain).
This protein consists of 1,088 amino acids and has been detected at sizes between 125-145 kDa by Western blot. A truncated variant of Protein 4.1B (named DAL-1) has also been found to be generated by translational initiation at Met110 and termination at Ser542, relative to full-length 4.1B. DAL-1 lacks the 4.1B N-terminal U1 domain and the entire CTD, and also has internal deletions in portions of the U2 and U3 subdomains. DAL-1 is believed to possess the full tumor suppressive capabilities exhibited by full-length Protein 4.1B.

Expression

Highly expressed in the brain and neurons, as well as in adipose tissue, adrenal gland, testis, placenta and kidney. Moderate expression in lungs and intestines. Lower expression across many other organs.

Localisation

As with other members of the Protein 4.1 superfamily, Protein 4.1B likely functions to link cellular receptors with the cytoskeleton, and thus localizes to the plasma membrane. By immunofluorescence, 4.1B has been reported to display a "honeycomb" pattern, with enrichment at points of cell-cell contact. 4.1B has also been localized to the cytoplasm and, at least in one report, to the nucleus.

Function

The tumor suppressive function of 4.1B has been reported in several studies, both in vitro and in vivo. Overexpression of 4.1B can suppress growth and, in some cases, induce apoptosis in human breast cancer, non-small cell lung cancer and meningioma cells. Although the mechanism by which 4.1B induces apoptosis remains unclear, one report has observed that overexpression of 4.1B increases caspase-8 activity in MCF-7 cells, and that inhibitors of caspase-8 can block 4.1B-mediated apoptosis. Others have reported that overexpression of 4.1B induces Rac1-dependent JNK signaling, which leads to growth suppression of meningioma cells. Truncation studies have also suggested that the U2 region of 4.1B contains the minimal growth suppressive domain when tethered to the membrane by FERM domain-mediated protein-protein interactions. Finally, downregulation of 4.1B by shRNAs has been reported to increase metastatic capability in human prostate cancer cells. However, the growth inhibitory effects of 4.1B are not general and may be cell-type-specific. For instance, overexpression of 4.1B inhibits the growth of some subclones of MCF-7 breast cancer cells, but not others, and 4.1B has been reported not to affect the growth of schwannomas.
4.1B knock-out animals are largely normal and fertile, and do not display any detectable predisposition to spontaneous tumor formation above background levels. However, in the TRAMP tumorigenesis model of prostate cancer, 4.1B null mice have been reported to display increased susceptibility for developing primary tumors and metastases. The only non-tumor phenotype observed in mutant animals is that mammary glands from 4.1B-/- female mice displayed a 60% increase in Ki67-positive epithelial cells during pregnancy, but not during the lactating or involution stages. The precise function of 4.1B remains unclear.

Homology

The FERM domain of Protein 4.1B is 73% homologous with the FERM domain of Protein 4.1R, the founding member of the Protein 4.1 superfamily of proteins. 4.1B is most similar to other members of the Protein 4.1 sub-group (e.g. 4.1R, 4.1G, 4.1N), which is one branch of the Protein 4.1 superfamily.

Mutations

Note

To date, no mutations have been linked to human developmental abnormalities or to cancer. However, the chromosomal region containing 4.1B, 18p11.3, is frequently lost during tumorigenesis for a variety of tumor types (see below).

Implicated in

Entity name
Various cancers
Disease
4.1B was originally identified as a protein whose expression was reduced in human non-small cell lung carcinomas. Subsequent studies have shown that 4.1B levels are downregulated in many different types of tumors. The location of the gene encoding Protein 4.1B, 18p11.3, is a region that has been reported to be lost in 38% of human lung, brain and breast tumors. Others have reported that loss of 18p11.3 is detected in 55% of ductal carcinomas in situ, and in 67% of invasive breast cancers. In addition, 4.1B expression has been reported to be reduced in up to 70% of meningiomas, and is significantly downregulated in several studies of human clinical prostate cancer, particularly in metastatic prostate cancer.

Breakpoints

Note

None.

Bibliography

Pubmed IDLast YearTitleAuthors
121543702002ERM proteins and merlin: integrators at the cell cortex.Bretscher A et al
121155672002Suppression of growth and increased cellular attachment after expression of DAL-1 in MCF-7 breast cancer cells.Charboneau AL et al
167074552006Protein 4.1B/differentially expressed in adenocarcinoma of the lung-1 functions as a growth suppressor in meningioma cells by activating Rac1-dependent c-Jun-NH(2)-kinase signaling.Gerber MA et al
113007222001The protein 4.1 tumor suppressor, DAL-1, impairs cell motility, but regulates proliferation in a cell-type-specific fashion.Gutmann DH et al
164206932006The tumor suppressor DAL-1/4.1B and protein methylation cooperate in inducing apoptosis in MCF-7 breast cancer cells.Jiang W et al
113059542001Allelic loss on chromosome band 18p11.3 occurs early and reveals heterogeneity in breast cancer progression.Kittiniyom K et al
161578752005An interaction between {alpha}v{beta}8 integrin and Band 4.1B via a highly conserved region of the Band 4.1 C-terminal domain.McCarty JH et al
155173342004Immunolocalization of protein 4.1B/DAL-1 during neoplastic transformation of mouse and human intestinal epithelium.Ohno N et al
150686652004ONCOMINE: a cancer microarray database and integrated data-mining platform.Rhodes DR et al
156880332005Membrane localization of the U2 domain of Protein 4.1B is necessary and sufficient for meningioma growth suppression.Robb VA et al
123569052002Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation.Sun CX et al
145745822003Protein 4.1B in mouse islets of Langerhans and beta-cell tumorigenesis.Terada N et al
98921801999A novel member of the NF2/ERM/4.1 superfamily with growth suppressing properties in lung cancer.Tran YK et al
176409042007Protein 4.1B suppresses prostate cancer progression and metastasis.Wong SY et al
162606182005Loss of the putative tumor suppressor band 4.1B/Dal1 gene is dispensable for normal development and does not predispose to cancer.Yi C et al

Other Information

Locus ID:

NCBI: 23136
MIM: 605331
HGNC: 3380
Ensembl: ENSG00000082397

Variants:

dbSNP: 23136
ClinVar: 23136
TCGA: ENSG00000082397
COSMIC: EPB41L3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000082397ENST00000341928Q9Y2J2
ENSG00000082397ENST00000342933A0A0A0MRA8
ENSG00000082397ENST00000400111A0A0A0MSA4
ENSG00000082397ENST00000540638Q9Y2J2
ENSG00000082397ENST00000544123Q9Y2J2
ENSG00000082397ENST00000545076A8K968
ENSG00000082397ENST00000578503J3QS55
ENSG00000082397ENST00000578524A0A0J9YY18
ENSG00000082397ENST00000579271A0A0J9YWS4
ENSG00000082397ENST00000579951J3QS83
ENSG00000082397ENST00000580179J3QRQ6
ENSG00000082397ENST00000580308J3QR33
ENSG00000082397ENST00000580316A0A0J9YW26
ENSG00000082397ENST00000580647A0A0J9YWN0
ENSG00000082397ENST00000580866A0A0U1RR92
ENSG00000082397ENST00000580989J3QKK4
ENSG00000082397ENST00000581292A0A0J9YW31
ENSG00000082397ENST00000581387A0A0J9YWE1
ENSG00000082397ENST00000581833J3KRD1
ENSG00000082397ENST00000582592J3QLU5
ENSG00000082397ENST00000582703J3KS70
ENSG00000082397ENST00000584015J3QR33
ENSG00000082397ENST00000584651J3QS55
ENSG00000082397ENST00000584670J3KT37
ENSG00000082397ENST00000585142J3QKY2
ENSG00000082397ENST00000637651A0A1B0GTF8

Expression (GTEx)

0
10
20
30
40
50
60
70
80

Pathways

PathwaySourceExternal ID
Neuronal SystemREACTOMER-HSA-112316
Protein-protein interactions at synapsesREACTOMER-HSA-6794362
Interactions of neurexins and neuroligins at synapsesREACTOMER-HSA-6794361

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
216283942011miRNA-223 promotes gastric cancer invasion and metastasis by targeting tumor suppressor EPB41L3.149
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
191655272009Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.56
122349732002Direct association of TSLC1 and DAL-1, two distinct tumor suppressor proteins in lung cancer.52
217966282012A four-gene methylation marker panel as triage test in high-risk human papillomavirus positive patients.42
258812952015MicroRNA-223 delivered by platelet-derived microvesicles promotes lung cancer cell invasion via targeting tumor suppressor EPB41L3.41
153340602004DAL-1/4.1B tumor suppressor interacts with protein arginine N-methyltransferase 3 (PRMT3) and inhibits its ability to methylate substrates in vitro and in vivo.31
172600992007Downregulation of TSLC1 and DAL-1 expression occurs frequently in breast cancer.31
176409042007Protein 4.1B suppresses prostate cancer progression and metastasis.26
161525852006Promoter hypermethylation of the potential tumor suppressor DAL-1/4.1B gene in renal clear cell carcinoma.23

Citation

Sunny Y Wong

EPB41L3 (erythrocyte membrane protein band 4.1-like 3)

Atlas Genet Cytogenet Oncol Haematol. 2008-05-01

Online version: http://atlasgeneticsoncology.org/gene/40458/epb41l3