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WWP1 (WW domain containing E3 ubiquitin protein ligase 1)

Identity

Other namesAIP5 (Atropin-1-interacting protein 5)
Tiul1 (TGIF-interacting ubiquitin ligase 1)
HGNC (Hugo) WWP1
LocusID (NCBI) 11059
Location 8q21.3
Location_base_pair Starts at 87354994 and ends at 87480178 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
  Boxes represent Exons.
Description The WWP1 gene encompasses 26 exons which span approximatively 142 kb of DNA. BAC clone RPCI-459L5 contains the complete human WWP1 genome sequence.
Transcription WWP1 mRNA is strongly or modestly expressed in human heart, muscle, placenta, kidney, liver, pancreas and testis (Mosser EA, 1998; Komuro A, 2004). The size of the WWP1 mRNA is about 4.2 Kb (Chen C, 2007). There are multiple splicing isoforms in the breast cancer cell line T47D (Flasza M, 2002). The open reading frame for the full length WWP1 gene is 2766 bp. The transcription is increased by TGFb (Chen C, 2007).

Protein

 
  A: WWP1 protein
B: Exogenous WWP1 expression in the 22Rv1 prostate cancer cell line was detected under a confocal microscopy. The endosomes are indicated by GFP-Rab5.
C: Protein structure of WWP1
Description 922 amino acids; approximatively 110 kDa protein; The C2 domain at N-terminus is responsible for calcium-dependent phospholipid binding. The four WW domains in the middle are responsible for protein-protein interaction with PY motifs. The HECT domain at the C-terminus is responsible for the ubiquitin transfer. The Cystein 890 is the catalytic center. The underlined WWP1 substrates do not have a PY motif (PPXY). A smaller WWP1 protein isoform was detected in two prostate cancer cell lines PC-3 and LAPC-4 (Chen C, 2007).
Protein structure: The HECT domain of WWP1 (see Figure 2C.)(Verdecia MA., 2003).
Expression The WWP1 protein is lowly expressed in normal prostate and breast but is frequently upregulated in prostate and breast cancers due to the gene amplification.
Localisation Predominately on membrane structures in cytoplasm and occasionally in nucleus (see Figure 2B.).
Function WWP1 is an E3 ubiquitin ligase.
WWP1 negatively regulates the transforming growth factor-beta (TGF-b) signaling by targeting its molecular components, including TGF-beta receptor 1 (TbR1) (Komuro A, 2004), Smad2 (Seo SR, 2004), and Smad4 (Moren A., 2005) for ubiquitin mediated degradation.
In addition, WWP1 has been reported to target the epithelial Na+ channel (ENaC) (Malbert-Colas L, 2003), Notch (Shaye DD, 2005), Runx2 (Jones DC, 2006; Shen R, 2006), KLF2 (Zhang X, 2004), and KLF5 (Chen C, 2005) for ubiquitin-mediated proteolysis.
Recently, WWP1 has been demonstrated to inhibit p53 activity through exporting p53 from the nucleus after ubiquitination (Laine A,.2007). Overall, WWP1 may play a pro-survival role in several tumor types including breast (Chen C, 2007) and prostate (Chen C, 2007). WWP1 has also shown to promote virus budding (Martin-Serrano J, 2005; Heidecker G, 2007).
Homology WWP1 belongs to the C2-WW-HECT E3 family which contains 8 other members (Chen C, 2007). The WWP1 gene is highly-conserved among species (from human to c. elegant).

Mutations

Somatic The WWP1 gene is rarely mutated in human prostate cancer (Chen C, 2007). Two sequence alterations were detected in prostate cancer xenografts. One was 2393A-->T (Glu798Val) in CWR91 and the other was 721A-->T (Thr241Ser) in LuCaP35. Additionally, some mutations in the HECT domain decrease the E3 ligase activity (Verdecia MA., 2003).

Implicated in

Entity Prostate cancer
Disease The WWP1 gene is amplified in 31-44% prostate cancer cell lines/xenografts/tumors. Consistently, the WWP1 mRNA and protein is up-regulated in these samples compared to immortalized prostate epithelial cell lines. WWP1 knock-down increases the TGFb-induced CDK inhibitor p15 expression and decreases PC-3 prostate cancer cell growth in vitro. These results suggest that WWP1 may be an oncogene in prostate cancer.
  
Entity Breast cancer
Disease The WWP1 gene is amplified in 41-51% breast cancer cell lines/tumors. Consistently, the WWP1 mRNA and protein is up-regulated in breast cancer cells compared to immortalized breast epithelial cell lines. WWP1 knock-down induces growth arrest and apoptosis in MCF7 and HCC1500 breast cancer cell lines. Forced expression of WWP1 promotes MCF10A and 184B5 immortalized breast epithelial cell proliferation in an E3 ligase independent manner.
 
WWP1 protein expression in normal breast epithelial cells and breast cancer cells by immunohistochemical staining.
  

External links

Nomenclature
HGNC (Hugo)WWP1   17004
Cards
AtlasWWP1ID42993ch8q21
Entrez_Gene (NCBI)WWP1  11059  WW domain containing E3 ubiquitin protein ligase 1
GeneCards (Weizmann)WWP1
Ensembl (Hinxton)ENSG00000123124 [Gene_View]  chr8:87354994-87480178 [Contig_View]  WWP1 [Vega]
AceView (NCBI)WWP1
Genatlas (Paris)WWP1
WikiGenes11059
SOURCE (Princeton)NM_007013
Genomic and cartography
GoldenPath (UCSC)WWP1  -  8q21.3   chr8:87354994-87480178 +  8q21.3   [Description]    (hg19-Feb_2009)
EnsemblWWP1 - 8q21.3 [CytoView]
Mapping of homologs : NCBIWWP1 [Mapview]
OMIM602307   
Gene and transcription
Genbank (Entrez)AK292800 AK310683 AL050082 AL136739 AW137654
RefSeq transcript (Entrez)NM_007013
RefSeq genomic (Entrez)AC_000140 NC_000008 NC_018919 NT_008046 NW_001839136 NW_004929340
Consensus coding sequences : CCDS (NCBI)WWP1
Cluster EST : UnigeneHs.655189 [ NCBI ]
CGAP (NCI)Hs.655189
Alternative Splicing : Fast-db (Paris)GSHG0029127
Alternative Splicing GalleryENSG00000123124
Gene ExpressionWWP1 [ NCBI-GEO ]     WWP1 [ SEEK ]   WWP1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9H0M0 (Uniprot)
NextProtQ9H0M0  [Medical]
With graphics : InterProQ9H0M0
Splice isoforms : SwissVarQ9H0M0 (Swissvar)
Catalytic activity : Enzyme6.3.2.- [ Enzyme-Expasy ]   6.3.2.-6.3.2.- [ IntEnz-EBI ]   6.3.2.- [ BRENDA ]   6.3.2.- [ KEGG ]   
Domaine pattern : Prosite (Expaxy)C2 (PS50004)    HECT (PS50237)    WW_DOMAIN_1 (PS01159)    WW_DOMAIN_2 (PS50020)   
Domains : Interpro (EBI)C2_dom    E3_ub_ligase_SMURF1    HECT    WW_dom   
Related proteins : CluSTrQ9H0M0
Domain families : Pfam (Sanger)C2 (PF00168)    HECT (PF00632)    WW (PF00397)   
Domain families : Pfam (NCBI)pfam00168    pfam00632    pfam00397   
Domain families : Smart (EMBL)C2 (SM00239)  HECTc (SM00119)  WW (SM00456)  
DMDM Disease mutations11059
Blocks (Seattle)Q9H0M0
PDB (SRS)1ND7    2OP7   
PDB (PDBSum)1ND7    2OP7   
PDB (IMB)1ND7    2OP7   
PDB (RSDB)1ND7    2OP7   
Human Protein AtlasENSG00000123124
Peptide AtlasQ9H0M0
HPRD03811
IPIIPI00013009   IPI00328376   IPI00328377   IPI00328378   IPI01018613   IPI00980771   
Protein Interaction databases
DIP (DOE-UCLA)Q9H0M0
IntAct (EBI)Q9H0M0
FunCoupENSG00000123124
BioGRIDWWP1
InParanoidQ9H0M0
Interologous Interaction database Q9H0M0
IntegromeDBWWP1
STRING (EMBL)WWP1
Ontologies - Pathways
Ontology : AmiGOubiquitin ligase complex  ubiquitin-protein ligase activity  ubiquitin-protein ligase activity  protein binding  nucleus  cytoplasm  cytosol  plasma membrane  signal transduction  central nervous system development  protein ubiquitination  modulation by virus of host morphology or physiology  ion transmembrane transport  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  proteasome-mediated ubiquitin-dependent protein catabolic process  negative regulation of transcription, DNA-dependent  viral entry into host cell  transmembrane transport  
Ontology : EGO-EBIubiquitin ligase complex  ubiquitin-protein ligase activity  ubiquitin-protein ligase activity  protein binding  nucleus  cytoplasm  cytosol  plasma membrane  signal transduction  central nervous system development  protein ubiquitination  modulation by virus of host morphology or physiology  ion transmembrane transport  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  proteasome-mediated ubiquitin-dependent protein catabolic process  negative regulation of transcription, DNA-dependent  viral entry into host cell  transmembrane transport  
Pathways : KEGGUbiquitin mediated proteolysis    Endocytosis   
REACTOMEWWP1
Protein Interaction DatabaseWWP1
Wikipedia pathwaysWWP1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)WWP1
SNP (GeneSNP Utah)WWP1
SNP : HGBaseWWP1
Genetic variants : HAPMAPWWP1
1000_GenomesWWP1 
ICGC programENSG00000123124 
Somatic Mutations in Cancer : COSMICWWP1 
CONAN: Copy Number AnalysisWWP1 
Mutations and Diseases : HGMDWWP1
OMIM602307   
GENETestsWWP1
Disease Genetic AssociationWWP1
Huge Navigator WWP1 [HugePedia]  WWP1 [HugeCancerGEM]
Genomic VariantsWWP1  WWP1 [DGVbeta]
Exome VariantWWP1
dbVarWWP1
ClinVarWWP1
snp3D : Map Gene to Disease11059
General knowledge
Homologs : HomoloGeneWWP1
Homology/Alignments : Family Browser (UCSC)WWP1
Phylogenetic Trees/Animal Genes : TreeFamWWP1
Chemical/Protein Interactions : CTD11059
Chemical/Pharm GKB GenePA134960138
Clinical trialWWP1
Cancer Resource (Charite)ENSG00000123124
Other databases
Probes
Litterature
PubMed70 Pubmed reference(s) in Entrez
CoreMineWWP1
iHOPWWP1

Bibliography

Physical and functional interactions between the transactivation domain of the hematopoietic transcription factor NF-E2 and WW domains.
Mosser EA, Kasanov JD, Forsberg EC, Kay BK, Ney PA, Bresnick EH
Biochemistry. 1998 ; 37 (39) : 13686-13695.
PMID 9753456
 
Alternative splicing determines the domain structure of WWP1, a Nedd4 family protein.
Flasza M, Gorman P, Roylance R, Canfield AE, Baron M
Biochemical and biophysical research communications. 2002 ; 290 (1) : 431-437.
PMID 11779188
 
Differential expression and localisation of WWP1, a Nedd4-like protein, in epithelia.
Malbert-Colas L, Fay M, Cluzeaud F, Blot-Chabaud M, Farman N, Dhermy D, Lecomte MC
Pflugers Archiv : European journal of physiology. 2003 ; 447 (1) : 35-43.
PMID 12908109
 
Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase.
Verdecia MA, Joazeiro CA, Wells NJ, Ferrer JL, Bowman ME, Hunter T, Noel JP
Molecular cell. 2003 ; 11 (1) : 249-259.
PMID 12535537
 
Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1).
Komuro A, Imamura T, Saitoh M, Yoshida Y, Yamori T, Miyazono K, Miyazawa K
Oncogene. 2004 ; 23 (41) : 6914-6923.
PMID 15221015
 
The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation.
Seo SR, Lallemand F, Ferrand N, Pessah M, L'Hoste S, Camonis J, Atfi A
The EMBO journal. 2004 ; 23 (19) : 3780-3792.
PMID 15359284
 
WWP1-dependent ubiquitination and degradation of the lung Krˆºppel-like factor, KLF2.
Zhang X, Srinivasan SV, Lingrel JB
Biochemical and biophysical research communications. 2004 ; 316 (1) : 139-148.
PMID 15003522
 
Human Kruppel-like factor 5 is a target of the E3 ubiquitin ligase WWP1 for proteolysis in epithelial cells.
Chen C, Sun X, Guo P, Dong XY, Sethi P, Cheng X, Zhou J, Ling J, Simons JW, Lingrel JB, Dong JT
The Journal of biological chemistry. 2005 ; 280 (50) : 41553-41561.
PMID 16223724
 
HECT ubiquitin ligases link viral and cellular PPXY motifs to the vacuolar protein-sorting pathway.
Martin-Serrano J, Eastman SW, Chung W, Bieniasz PD
The Journal of cell biology. 2005 ; 168 (1) : 89-101.
PMID 15623582
 
Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases.
Morˆ©n A, Imamura T, Miyazono K, Heldin CH, Moustakas A
The Journal of biological chemistry. 2005 ; 280 (23) : 22115-22123.
PMID 15817471
 
LIN-12/Notch trafficking and regulation of DSL ligand activity during vulval induction in Caenorhabditis elegans.
Shaye DD, Greenwald I
Development (Cambridge, England). 2005 ; 132 (22) : 5081-5092.
PMID 16236769
 
Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3.
Jones DC, Wein MN, Oukka M, Hofstaetter JG, Glimcher MJ, Glimcher LH
Science (New York, N.Y.). 2006 ; 312 (5777) : 1223-1227.
PMID 16728642
 
Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation.
Shen R, Chen M, Wang YJ, Kaneki H, Xing L, O'keefe RJ, Chen D
The Journal of biological chemistry. 2006 ; 281 (6) : 3569-3576.
PMID 16299379
 
The Nedd4-like family of E3 ubiquitin ligases and cancer.
Chen C, Matesic LE
Cancer metastasis reviews. 2007 ; 26 (3-4) : 587-604.
PMID 17726579
 
Ubiquitin E3 ligase WWP1 as an oncogenic factor in human prostate cancer.
Chen C, Sun X, Guo P, Dong XY, Sethi P, Zhou W, Zhou Z, Petros J, Frierson HF Jr, Vessella RL, Atfi A, Dong JT
Oncogene. 2007 ; 26 (16) : 2386-2394.
PMID 17016436
 
The amplified WWP1 gene is a potential molecular target in breast cancer.
Chen C, Zhou Z, Ross JS, Zhou W, Dong JT
International journal of cancer. Journal international du cancer. 2007 ; 121 (1) : 80-87.
PMID 17330240
 
The role of WWP1-Gag interaction and Gag ubiquitination in assembly and release of human T-cell leukemia virus type 1.
Heidecker G, Lloyd PA, Soheilian F, Nagashima K, Derse D
Journal of virology. 2007 ; 81 (18) : 9769-9777.
PMID 17609263
 
Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1.
Laine A, Ronai Z
Oncogene. 2007 ; 26 (10) : 1477-1483.
PMID 16924229
 
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Contributor(s)

Written01-2008Ceshi Chen
The Center for Cell Biology and Cancer Research Albany Medical College MS355/350, Mail code 165, 47 New Scotland Ave. Albany, NY 12208, USA

Citation

This paper should be referenced as such :
Chen C . WWP1 (WW domain containing E3 ubiquitin protein ligase 1). Atlas Genet Cytogenet Oncol Haematol. January 2008 .
URL : http://AtlasGeneticsOncology.org/Genes/WWP1ID42993ch8q21.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/38581/1/01-2008-WWP1ID42993ch8q21.pdf   [ Bibliographic record ]

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indexed on : Wed Apr 16 11:16:46 CEST 2014

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