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EPB41L3 (erythrocyte membrane protein band 4.1-like 3)

Identity

Other names4.1B
DAL-1
DAL1
FLJ37633
KIAA0987
HGNC (Hugo) EPB41L3
LocusID (NCBI) 23136
Location 18p11.31
Location_base_pair Starts at 5392380 and ends at 5540555 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Located between ZFP161 (Zinc Finger Protein 161 homolog; 5279018-5286039) and L(3)MBT-Like 4 (5944712-6404910).

DNA/RNA

 
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.

Protein

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 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.

External links

Nomenclature
HGNC (Hugo)EPB41L3   3380
Cards
AtlasEPB41L3ID40458ch18p11
Entrez_Gene (NCBI)EPB41L3  23136  erythrocyte membrane protein band 4.1-like 3
GeneCards (Weizmann)EPB41L3
Ensembl (Hinxton)ENSG00000082397 [Gene_View]  chr18:5392380-5540555 [Contig_View]  EPB41L3 [Vega]
ICGC DataPortalENSG00000082397
cBioPortalEPB41L3
AceView (NCBI)EPB41L3
Genatlas (Paris)EPB41L3
WikiGenes23136
SOURCE (Princeton)NM_001281533 NM_001281534 NM_001281535 NM_012307
Genomic and cartography
GoldenPath (UCSC)EPB41L3  -  18p11.31   chr18:5392380-5540555 -  18p11.32   [Description]    (hg19-Feb_2009)
EnsemblEPB41L3 - 18p11.32 [CytoView]
Mapping of homologs : NCBIEPB41L3 [Mapview]
OMIM605331   
Gene and transcription
Genbank (Entrez)AB023204 AF069072 AF515797 AK094952 AK128531
RefSeq transcript (Entrez)NM_001281533 NM_001281534 NM_001281535 NM_012307
RefSeq genomic (Entrez)AC_000150 NC_000018 NC_018929 NT_010859 NW_001838461 NW_004929409
Consensus coding sequences : CCDS (NCBI)EPB41L3
Cluster EST : UnigeneHs.213394 [ NCBI ]
CGAP (NCI)Hs.213394
Alternative Splicing : Fast-db (Paris)GSHG0014175
Alternative Splicing GalleryENSG00000082397
Gene ExpressionEPB41L3 [ NCBI-GEO ]     EPB41L3 [ SEEK ]   EPB41L3 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9Y2J2 (Uniprot)
NextProtQ9Y2J2  [Medical]
With graphics : InterProQ9Y2J2
Splice isoforms : SwissVarQ9Y2J2 (Swissvar)
Domaine pattern : Prosite (Expaxy)FERM_1 (PS00660)    FERM_2 (PS00661)    FERM_3 (PS50057)   
Domains : Interpro (EBI)Band_4.1_C [organisation]   Band_41_domain [organisation]   Band_41_fam [organisation]   Band_41_protein [organisation]   Ez/rad/moesin_like [organisation]   FERM-adjacent [organisation]   FERM/acyl-CoA-bd_prot_3-hlx [organisation]   FERM_central [organisation]   FERM_CS [organisation]   FERM_domain [organisation]   FERM_N [organisation]   FERM_PH-like_C [organisation]   PH_like_dom [organisation]   SAB_dom [organisation]   Ubiquitin-rel_dom [organisation]  
Related proteins : CluSTrQ9Y2J2
Domain families : Pfam (Sanger)4_1_CTD (PF05902)    FA (PF08736)    FERM_C (PF09380)    FERM_M (PF00373)    FERM_N (PF09379)    SAB (PF04382)   
Domain families : Pfam (NCBI)pfam05902    pfam08736    pfam09380    pfam00373    pfam09379    pfam04382   
Domain families : Smart (EMBL)B41 (SM00295)  
DMDM Disease mutations23136
Blocks (Seattle)Q9Y2J2
PDB (SRS)2HE7    3BIN   
PDB (PDBSum)2HE7    3BIN   
PDB (IMB)2HE7    3BIN   
PDB (RSDB)2HE7    3BIN   
Human Protein AtlasENSG00000082397 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ9Y2J2
HPRD05622
IPIIPI00032230   IPI00215716   IPI00215717   IPI00643553   IPI01008738   IPI01014554   IPI00922914   IPI00921919   IPI00816190   IPI00643241   
Protein Interaction databases
DIP (DOE-UCLA)Q9Y2J2
IntAct (EBI)Q9Y2J2
FunCoupENSG00000082397
BioGRIDEPB41L3
InParanoidQ9Y2J2
Interologous Interaction database Q9Y2J2
IntegromeDBEPB41L3
STRING (EMBL)EPB41L3
Ontologies - Pathways
Ontology : AmiGOprotein localization to paranode region of axon  actin binding  structural constituent of cytoskeleton  protein binding  cytoplasm  cytoskeleton  plasma membrane  plasma membrane  cell-cell junction  apoptotic process  cytoskeletal anchoring at plasma membrane  biological_process  regulation of cell shape  extrinsic component of membrane  axolemma  cortical cytoskeleton organization  cortical actin cytoskeleton organization  paranodal junction assembly  paranode region of axon  myelin maintenance  juxtaparanode region of axon  neuron projection morphogenesis  protein localization to juxtaparanode region of axon  protein localization to plasma membrane  
Ontology : EGO-EBIprotein localization to paranode region of axon  actin binding  structural constituent of cytoskeleton  protein binding  cytoplasm  cytoskeleton  plasma membrane  plasma membrane  cell-cell junction  apoptotic process  cytoskeletal anchoring at plasma membrane  biological_process  regulation of cell shape  extrinsic component of membrane  axolemma  cortical cytoskeleton organization  cortical actin cytoskeleton organization  paranodal junction assembly  paranode region of axon  myelin maintenance  juxtaparanode region of axon  neuron projection morphogenesis  protein localization to juxtaparanode region of axon  protein localization to plasma membrane  
Pathways : KEGGTight junction   
Protein Interaction DatabaseEPB41L3
Wikipedia pathwaysEPB41L3
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)EPB41L3
snp3D : Map Gene to Disease23136
SNP (GeneSNP Utah)EPB41L3
SNP : HGBaseEPB41L3
Genetic variants : HAPMAPEPB41L3
Exome VariantEPB41L3
1000_GenomesEPB41L3 
ICGC programENSG00000082397 
Somatic Mutations in Cancer : COSMICEPB41L3 
CONAN: Copy Number AnalysisEPB41L3 
Mutations and Diseases : HGMDEPB41L3
Genomic VariantsEPB41L3  EPB41L3 [DGVbeta]
dbVarEPB41L3
ClinVarEPB41L3
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM605331   
MedgenEPB41L3
GENETestsEPB41L3
Disease Genetic AssociationEPB41L3
Huge Navigator EPB41L3 [HugePedia]  EPB41L3 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneEPB41L3
Homology/Alignments : Family Browser (UCSC)EPB41L3
Phylogenetic Trees/Animal Genes : TreeFamEPB41L3
Chemical/Protein Interactions : CTD23136
Chemical/Pharm GKB GenePA27813
Clinical trialEPB41L3
Cancer Resource (Charite)ENSG00000082397
Other databases
Probes
Litterature
PubMed71 Pubmed reference(s) in Entrez
CoreMineEPB41L3
iHOPEPB41L3
OncoSearchEPB41L3

Bibliography

A novel member of the NF2/ERM/4.1 superfamily with growth suppressing properties in lung cancer.
Tran YK., Bogler O, Gorse KM, Wieland I, Green MR, Newsham IF.
Cancer Res. 1999 Jan 1;59(1):35-43.
PMID 9892180
 
Loss of DAL-1, a protein 4.1-related tumor suppressor, is an important early event in the pathogenesis of meningiomas.
Gutmann DH, Donahoe J, Perry A, Lemke N, Gorse K, Kittiniyom K, Rempel SA, Gutierrez JA, Newsham IF.
Hum Mol Genet. 2000 Jun 12;9(10):1495-500.
PMID 10888600
 
The protein 4.1 tumor suppressor, DAL-1, impairs cell motility, but regulates proliferation in a cell-type-specific fashion.
Gutmann DH, Hirbe AC, Huang ZY, Haipek CA.
Neurobiol Dis. 2001 Apr;8(2):266-78.
PMID 11300722
 
Allelic loss on chromosome band 18p11.3 occurs early and reveals heterogeneity in breast cancer progression.
Kittiniyom K, Gorse KM, Dalbegue F, Lichy JH, Taubenberger JK, Newsham IF.
Breast Cancer Res. 2001;3(3):192-8. Epub 2001 Feb 12.
PMID 11305954
 
ERM proteins and merlin: integrators at the cell cortex.
Bretscher A, Edwards K, Fehon RG.
Nat Rev Mol Cell Biol. 2002 Aug;3(8):586-99.
PMID 12154370
 
Suppression of growth and increased cellular attachment after expression of DAL-1 in MCF-7 breast cancer cells.
Charboneau AL, Singh V, Yu T, Newsham IF.
Int J Cancer. 2002 Jul 10;100(2):181-8.
PMID 12115567
 
Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation.
Sun CX, Robb VA, Gutmann DH.
J Cell Sci. 2002 Nov 1;115(Pt 21):3991-4000.
PMID 12356905
 
Protein 4.1B in mouse islets of Langerhans and beta-cell tumorigenesis.
Terada N, Ohno N, Yamakawa H, Baba T, Fujii Y, Christofori G, Ohara O, Ohno S.
Histochem Cell Biol. 2003 Oct;120(4):277-83. Epub 2003 Sep 9.
PMID 14574582
 
Immunolocalization of protein 4.1B/DAL-1 during neoplastic transformation of mouse and human intestinal epithelium.
Ohno N, Terada N, Murata S, Yamakawa H, Newsham IF, Katoh R, Ohara O, Ohno S.
Histochem Cell Biol. 2004 Dec;122(6):579-86. Epub 2004 Oct 29.
PMID 15517334
 
ONCOMINE: a cancer microarray database and integrated data-mining platform.
Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM.
Neoplasia. 2004 Jan-Feb;6(1):1-6.
PMID 15068665
 
An 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, Cook AA, Hynes RO.
Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13479-83. Epub 2005 Sep 12.
PMID 16157875
 
Membrane localization of the U2 domain of protein 4.1B is necessary and sufficient for meningioma growth suppression.
Robb VA, Gerber MA, Hart-Mahon EK, Gutmann DH.
Oncogene. 2005 Mar 10;24(11):1946-57.
PMID 15688033
 
Loss of the putative tumor suppressor Band 4.1B/Dal1 gene is dispensible for normal development and does not predispose to cancer.
Yi C, McCarty JH, Troutman SA, Eckman MS, Bronson RT, Kissil JL.
Mol Cell Biol. 2005 Nov;25(22):10052-9.
PMID 16260618
 
Protein 4.1B/differentially expressed in adenocarcinoma of the lung-1 functions as a growth suppressor in meningioma cells by activating Rac1-dependent c-Jun-NH2-kinase signaling.
Gerber MA, Bahr SM, Gutmann DH.
Cancer Res. 2006 May 15;66(10):5295-303.
PMID 16707455
 
The tumor suppressor DAL-1/4.1B and protein methylation cooperate in inducing apoptosis in MCF-7 breast cancer cells.
Jiang W, Newsham IF.
Mol Cancer. 2006 Jan 18;5:4.
PMID 16420693
 
Protein 4.1B suppresses prostate cancer progression and metastasis.
Wong SY, Haack H, Kissil JL, Barry M, Bronson RT, Shen S, Whittaker CA, Crowley D, Hynes RO.
Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12784-9. Epub 2007 Jul 18.
PMID 17640904
 
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Contributor(s)

Written05-2008Sunny Y Wong
Howard Hughes Medical Institute, Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA

Citation

This paper should be referenced as such :
Wong, SY
EPB41L3 (erythrocyte membrane protein band 4.1-like 3)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(4):265-267.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/EPB41L3ID40458ch18p11.html

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indexed on : Sat Jul 26 14:56:23 CEST 2014

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