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ENAH (enabled homolog (Drosophila))

Identity

Other namesFLJ10773
MENA
NDPP1
HGNC (Hugo) ENAH
LocusID (NCBI) 55740
Location 1q42.12
Location_base_pair Starts at 225674534 and ends at 225840845 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Note ENAH is a member of the Ena / VASP family encoding actin cytoskeleton regulatory proteins controlling cell motility and adhesion.

DNA/RNA

 
  Diagrammatic representation of human ENAH gene trancripts. Exons are enumerated and the relative protein domains are indicated.
Description The human ENAH gene is located on the minus strand of chromosome 1 and is constituted by 15 exons. Other features of the ENAH gene such as promoter or enhancer have not been fully investigated.
Transcription Two alternative splice variants isolated in the human ENAH. The size of the longer variant (hMena+11a or ENAH variant 1) is 1776 nt. The shorter variant (hMena or ENAH variant 2) lacks an internal exon (exon 11a) of 63nt.

Protein

 
  Human ENAH protein, the four conserved domains are indicated with the respective amino acid positions. The 11a peptide is included at position 513 and characterizes the ENAH isoform a (hMena+11a).
Description Mena is a member of Ena/VASP proteins characterized by the presence of specific domains including the NH2-terminal EVH1 domain, which plays a role in intracellular protein localization (Prehoda et al., 1999) and interacts with proteins bearing FPPPP motifs. Among the Ena/VASP proteins only the EVH1 domain of Mena possesses the ability to bind to the LIM3 domain of the oncosuppressor TES (Boeda et al., 2007). The central proline-rich domain mediates the interaction with proteins containing the SH3 and WW domains and with the small actin monomer binding protein profilin (Gertler et al., 1996). The LERER region is constituted by a long repeat of Arg/Leu/Glu amino acids probably acting as a protein protein binding interface, located between the EVH1 and the prol-rich region. Only Mena among the Ena/VASP proteins possesses this domain. The EVH2 COOH-terminal domain, which forms a right handed alpha helical coiled coil structure, is responsible for tetramerization and for the binding to G- and F-actin (Kuhnel et al., 2004); its interaction with the growing ends of the actin filaments is required for targeting the Ena/VASP to lamellipodia and filopodia (Louriero et al., 2002). Human Mena (hMena or ENAH isoform b) is a 570 amino acid protein. The longer hMena+11a isoform (ENAH isoform a) presents an additional internal peptide of 21aa located in the EVH2 domain of the protein. This isoform undergoes phosphorylation upon treatment of breast cancer cell lines with EGF and NRG1 (Di Modugno et al., 2007).
Mena is alternately spliced to give rise to multiple isoforms, an additional reported isoform is the neuronal specific Mena-140 found in mouse and humans (Gertler et al., 1996; Urbanelli et al., 2006).
Expression In normal tissues, hMena expression was confined to isolated epithelia (i.e.pancreas). Mammary epithelium was negative and hMena was overexpressed in about 75% of breast primary tumors tested, with a variable staining intensity.
Localisation Predominantly in cytoplasm and in some tumor cells with a reinforced juxtamembrane staining.
Function Mena controls cell shape and movement (Bear et al., 2002; Vasioukhin et al., 2000; Krause et al., 2003) by protecting actin filaments from capping proteins at their barbed ends (Barzik et al., 2005). It controls actin organization on cadherin adhesion contact (Scott et al., 2006).
Homology The sequence of hMena (ENAH isoform b) displays 87% identity with the murine protein but is longer with the majority of the additional aminoacids located in the Arg/Leu/Glu rich region (LERER). The human hMena sequence conserved the two serine phosphorylation sites of murine Mena, whereas the tyrosine residue, site of phosphorylation in mouse Mena (Tani et al., 2003), is substituted by a glutamine residue in the human sequence.

Implicated in

Entity Breast Cancer
Disease In human tissues, human ENAH (hMena) protein, not expressed in normal breast, is detectable in a small percentage of low-risk proliferative lesions, with a progressive increase of positivity in benign breast lesions at higher risk of transformation and in in situ and invasive cancers. In the latter, a significant direct correlation was found between hMena, tumor size, proliferation index, and HER-2 overexpression whereas an inverse relationship was evidenced with estrogen receptor (ER) and progesterone receptor (PgR) expression (Di Modugno et al., 2006).
These results suggest that hMena may be a marker of breast cancerogenesis and breast cancer progression.
In cancer cell lines of different histological origin, hMena is overexpressed respect to the normal counterparts (i.e. breast, melanoma, colon, cervical cancer). hMena expression while up-regulated by Neuregulin-1 and EGF, is down-regulated by Herceptin treatment in breast cancer cell lines, thus suggesting that hMena couples tyrosine kinase receptor (TKR) signaling to the actin cytoskeleton.
hMena+11a isoform (ENAH isoform a) is epithelial-specific and is phosphorylated after mitogenic stimuli, such as EGF. This phosphorylation is accompanied by an increased proliferation rate and p42 / 44 MAPK activation in breast cancer cell lines (Di Modugno et al., 2007), thus suggesting a functional role of hMena+11a in breast cancer cell proliferation. In a murine model Mena is overexpressed, among a set of genes coding for the minimum motility machine regulating β-actin polymerization, in a subpopulation of invasive breast tumor cells collected using the in vivo invasion assay in response to EGF (Wang et al., 2004). A role of hMena in the invasive behaviour of human tumor cells has not yet been reported.
  
Entity Pancreatic Cancer
Disease hMena is expressed in primary and metastatic pancreatic cancer. The expression of hMena+11a isoform (ENAH isoform a) characterizes pancreatic cancer cell lines with an epithelial phenotype which express the epithelial marker E-Cadherin and lack the expression of mesenchymal markers as N-Cadherin and Vimentin. These cell lines show a constitutive activated EGFR and are sensitive to the treatment with the EGFR inhibitor Erlotinib. ENAH acts as a mediator of the EGFR signaling pathway and significantly modulates the growth of pancreatic cancer cell lines dependent on EGFR signaling. Thus the expression of hMena/hMena+11a is predictive of in vitro response to EGFR inhibitors (Simo et al., 2008).
  
Entity Tumor Immunity
Disease Human ENAH (hMena) protein is able to induce a cancer-restricted antibody response. Twenty percent of cancer patient sera, showed anti-hMena-specific IgG, while no antibodies were present in healthy donors (Di Modugno et al., 2004).
  

External links

Nomenclature
HGNC (Hugo)ENAH   18271
Cards
AtlasENAHID44148ch1q42
Entrez_Gene (NCBI)ENAH  55740  enabled homolog (Drosophila)
GeneCards (Weizmann)ENAH
Ensembl (Hinxton)ENSG00000154380 [Gene_View]  chr1:225674534-225840845 [Contig_View]  ENAH [Vega]
ICGC DataPortalENSG00000154380
cBioPortalENAH
AceView (NCBI)ENAH
Genatlas (Paris)ENAH
WikiGenes55740
SOURCE (Princeton)NM_001008493 NM_018212
Genomic and cartography
GoldenPath (UCSC)ENAH  -  1q42.12   chr1:225674534-225840845 -  1q32.2   [Description]    (hg19-Feb_2009)
EnsemblENAH - 1q32.2 [CytoView]
Mapping of homologs : NCBIENAH [Mapview]
OMIM609061   
Gene and transcription
Genbank (Entrez)AF519769 AK001635 AK025108 AK096246 AK126894
RefSeq transcript (Entrez)NM_001008493 NM_018212
RefSeq genomic (Entrez)AC_000133 NC_000001 NC_018912 NT_167186 NW_001838543 NW_004929294
Consensus coding sequences : CCDS (NCBI)ENAH
Cluster EST : UnigeneHs.497893 [ NCBI ]
CGAP (NCI)Hs.497893
Alternative Splicing : Fast-db (Paris)GSHG0002989
Alternative Splicing GalleryENSG00000154380
Gene ExpressionENAH [ NCBI-GEO ]     ENAH [ SEEK ]   ENAH [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8N8S7 (Uniprot)
NextProtQ8N8S7  [Medical]
With graphics : InterProQ8N8S7
Splice isoforms : SwissVarQ8N8S7 (Swissvar)
Domaine pattern : Prosite (Expaxy)WH1 (PS50229)   
Domains : Interpro (EBI)PH_like_dom [organisation]   Ran_bind_dom [organisation]   VASP_tetra [organisation]   WH1/EVH1 [organisation]  
Related proteins : CluSTrQ8N8S7
Domain families : Pfam (Sanger)VASP_tetra (PF08776)    WH1 (PF00568)   
Domain families : Pfam (NCBI)pfam08776    pfam00568   
Domain families : Smart (EMBL)RanBD (SM00160)  WH1 (SM00461)  
DMDM Disease mutations55740
Blocks (Seattle)Q8N8S7
PDB (SRS)2HO2    2IYB    2XQN   
PDB (PDBSum)2HO2    2IYB    2XQN   
PDB (IMB)2HO2    2IYB    2XQN   
PDB (RSDB)2HO2    2IYB    2XQN   
Human Protein AtlasENSG00000154380 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ8N8S7
HPRD12360
IPIIPI00411623   IPI00374054   IPI00976226   IPI00749432   IPI00646954   
Protein Interaction databases
DIP (DOE-UCLA)Q8N8S7
IntAct (EBI)Q8N8S7
FunCoupENSG00000154380
BioGRIDENAH
InParanoidQ8N8S7
Interologous Interaction database Q8N8S7
IntegromeDBENAH
STRING (EMBL)ENAH
Ontologies - Pathways
Ontology : AmiGOstress fiber  neural tube closure  actin binding  protein binding  cytoplasm  cytosol  plasma membrane  focal adhesion  axon guidance  actin polymerization or depolymerization  SH3 domain binding  lamellipodium  cell junction  filopodium  synapse  intracellular transport  WW domain binding  T cell receptor signaling pathway  
Ontology : EGO-EBIstress fiber  neural tube closure  actin binding  protein binding  cytoplasm  cytosol  plasma membrane  focal adhesion  axon guidance  actin polymerization or depolymerization  SH3 domain binding  lamellipodium  cell junction  filopodium  synapse  intracellular transport  WW domain binding  T cell receptor signaling pathway  
Pathways : KEGGRegulation of actin cytoskeleton   
Protein Interaction DatabaseENAH
Wikipedia pathwaysENAH
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)ENAH
snp3D : Map Gene to Disease55740
SNP (GeneSNP Utah)ENAH
SNP : HGBaseENAH
Genetic variants : HAPMAPENAH
Exome VariantENAH
1000_GenomesENAH 
ICGC programENSG00000154380 
Somatic Mutations in Cancer : COSMICENAH 
CONAN: Copy Number AnalysisENAH 
Mutations and Diseases : HGMDENAH
Genomic VariantsENAH  ENAH [DGVbeta]
dbVarENAH
ClinVarENAH
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM609061   
MedgenENAH
GENETestsENAH
Disease Genetic AssociationENAH
Huge Navigator ENAH [HugePedia]  ENAH [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneENAH
Homology/Alignments : Family Browser (UCSC)ENAH
Phylogenetic Trees/Animal Genes : TreeFamENAH
Chemical/Protein Interactions : CTD55740
Chemical/Pharm GKB GenePA38517
Clinical trialENAH
Cancer Resource (Charite)ENSG00000154380
Other databases
Probes
Litterature
PubMed69 Pubmed reference(s) in Entrez
CoreMineENAH
iHOPENAH
OncoSearchENAH

Bibliography

Mena, a relative of VASP and Drosophila Enabled, is implicated in the control of microfilament dynamics.
Gertler FB, Niebuhr K, Reinhard M, Wehland J, Soriano P.
Cell. 1996 Oct 18;87(2):227-39.
PMID 8861907
 
Structure of the enabled/VASP homology 1 domain-peptide complex: a key component in the spatial control of actin assembly.
Prehoda KE, Lee DJ, Lim WA.
Cell. 1999 May 14;97(4):471-80.
PMID 10338211
 
Directed actin polymerization is the driving force for epithelial cell-cell adhesion.
Vasioukhin V, Bauer C, Yin M, Fuchs E.
Cell. 2000 Jan 21;100(2):209-19.
PMID 10660044
 
Antagonism between Ena/VASP proteins and actin filament capping regulates fibroblast motility.
Bear JE, Svitkina TM, Krause M, Schafer DA, Loureiro JJ, Strasser GA, Maly IV, Chaga OY, Cooper JA, Borisy GG, Gertler FB.
Cell. 2002 May 17;109(4):509-21.
PMID 12086607
 
Critical roles of phosphorylation and actin binding motifs, but not the central proline-rich region, for Ena/vasodilator-stimulated phosphoprotein (VASP) function during cell migration.
Loureiro JJ, Rubinson DA, Bear JE, Baltus GA, Kwiatkowski AV, Gertler FB.
Mol Biol Cell. 2002 Jul;13(7):2533-46.
PMID 12134088
 
Ena/VASP proteins: regulators of the actin cytoskeleton and cell migration.
Krause M, Dent EW, Bear JE, Loureiro JJ, Gertler FB.
Annu Rev Cell Dev Biol. 2003;19:541-64. (Review)
PMID 14570581
 
Abl interactor 1 promotes tyrosine 296 phosphorylation of mammalian enabled (Mena) by c-Abl kinase.
Tani K, Sato S, Sukezane T, Kojima H, Hirose H, Hanafusa H, Shishido T.
J Biol Chem. 2003 Jun 13;278(24):21685-92.
PMID 12672821
 
Human Mena protein, a serex-defined antigen overexpressed in breast cancer eliciting both humoral and CD8+ T-cell immune response.
Di Modugno F, Bronzi G, Scanlan MJ, Del Bello D, Cascioli S, Venturo I, Botti C, Nicotra MR, Mottolese M, Natali PG, Santoni A, Jager E, Nistico P.
Int J Cancer. 2004 May 10;109(6):909-18.
PMID 15027125
 
The VASP tetramerization domain is a right-handed coiled coil based on a 15-residue repeat.
Kuhnel K, Jarchau T, Wolf E, Schlichting I, Walter U, Wittinghofer A, Strelkov SV.
Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17027-32.
PMID 15569942
 
Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors.
Wang W, Goswami S, Lapidus K, Wells AL, Wyckoff JB, Sahai E, Singer RH, Segall JE, Condeelis JS.
Cancer Res. 2004 Dec 1;64(23):8585-94.
PMID 15574765
 
Ena/VASP proteins enhance actin polymerization in the presence of barbed end capping proteins.
Barzik M, Kotova TI, Higgs HN, Hazelwood L, Hanein D, Gertler FB, Schafer DA.
J Biol Chem. 2005 Aug 5;280(31):28653-62.
PMID 15939738
 
The cytoskeleton regulatory protein hMena (ENAH) is overexpressed in human benign breast lesions with high risk of transformation and human epidermal growth factor receptor-2-positive/hormonal receptor-negative tumors.
Di Modugno F, Mottolese M, Di Benedetto A, Conidi A, Novelli F, Perracchio L, Venturo I, Botti C, Jager E, Santoni A, Natali PG, Nistico P.
Clin Cancer Res. 2006 Mar 1;12(5):1470-8.
PMID 16533770
 
Ena/VASP proteins can regulate distinct modes of actin organization at cadherin-adhesive contacts.
Scott JA, Shewan AM, den Elzen NR, Loureiro JJ, Gertler FB, Yap AS.
Mol Biol Cell. 2006 Mar;17(3):1085-95.
PMID 16371509
 
Characterization of human Enah gene.
Urbanelli L, Massini C, Emiliani C, Orlacchio A, Bernardi G, Orlacchio A.
Biochim Biophys Acta. 2006 Jan-Feb;1759(1-2):99-107.
PMID 16494957
 
Tes, a specific Mena interacting partner, breaks the rules for EVH1 binding.
Boeda B, Briggs DC, Higgins T, Garvalov BK, Fadden AJ, McDonald NQ, Way M.
Mol Cell. 2007 Dec 28;28(6):1071-82.
PMID 18158903
 
Molecular cloning of hMena (ENAH) and its splice variant hMena+11a: epidermal growth factor increases their expression and stimulates hMena+11a phosphorylation in breast cancer cell lines.
Di Modugno F, DeMonte L, Balsamo M, Bronzi G, Nicotra MR, Alessio M, Jager E, Condeelis JS, Santoni A, Natali PG, Nistico P.
Cancer Res. 2007 Mar 15;67(6):2657-65.
PMID 17363586
 
Human Mena+11a isoform serves as a marker of epithelial phenotype and sensitivity to epidermal growth factor receptor inhibition in human pancreatic cancer cell lines.
Pino MS, Balsamo M, Di Modugno F, Mottolese M, Alessio M, Melucci E, Milella M, McConkey DJ, Philippar U, Gertler FB, Natali PG, Nistico P.
Clin Cancer Res. 2008 Aug 1;14(15):4943-50.
PMID 18676769
 
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Contributor(s)

Written08-2008Paola Nisticò, Francesca Di Modugno
Regina Elena Cancer Institute, Department of Experimental Oncology, via delle Messi d'Oro 156, 00158 Rome, Italy

Citation

This paper should be referenced as such :
Nisticò , P ; Di, Modugno F
ENAH (enabled homolog (Drosophila))
Atlas Genet Cytogenet Oncol Haematol. 2009;13(7):474-476.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/ENAHID44148ch1q42.html

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indexed on : Wed Jul 30 16:55:59 CEST 2014

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