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WWP1 (WW domain containing E3 ubiquitin protein ligase 1)

Written2008-01Ceshi Chen
The Center for Cell Biology, Cancer Research Albany Medical College MS355/350, Mail code 165, 47 New Scotland Ave. Albany, NY 12208, USA

(Note : for Links provided by Atlas : click)


Alias_symbol (synonym)AIP5
Other aliasAIP5 (Atropin-1-interacting protein 5)
Tiul1 (TGIF-interacting ubiquitin ligase 1)
HGNC (Hugo) WWP1
LocusID (NCBI) 11059
Atlas_Id 42993
Location 8q21.3  [Link to chromosome band 8q21]
Location_base_pair Starts at 86342765 and ends at 86467949 bp from pter ( according to hg19-Feb_2009)  [Mapping WWP1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
WWP1 (8q21.3) / CPB2 (13q14.13)WWP1 (8q21.3) / NUBPL (14q12)WWP1 (8q21.3) / WWP1 (8q21.3)


  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).


  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).


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.


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
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
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 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
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
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
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
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.
Morén A, Imamura T, Miyazono K, Heldin CH, Moustakas A
The Journal of biological chemistry. 2005 ; 280 (23) : 22115-22123.
PMID 15817471
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
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
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
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
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
WWP1-dependent ubiquitination and degradation of the lung Krüppel-like factor, KLF2.
Zhang X, Srinivasan SV, Lingrel JB
Biochemical and biophysical research communications. 2004 ; 316 (1) : 139-148.
PMID 15003522


This paper should be referenced as such :
Chen, C
WWP1 (WW domain containing E3 ubiquitin protein ligase 1)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(5):393-396.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  t(8;13)(q21;q14) WWP1/CPB2
t(8;14)(q21;q12) WWP1/NUBPL

External links

HGNC (Hugo)WWP1   17004
Entrez_Gene (NCBI)WWP1  11059  WW domain containing E3 ubiquitin protein ligase 1
AliasesAIP5; Tiul1; hSDRP1
GeneCards (Weizmann)WWP1
Ensembl hg19 (Hinxton)ENSG00000123124 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000123124 [Gene_View]  ENSG00000123124 [Sequence]  chr8:86342765-86467949 [Contig_View]  WWP1 [Vega]
ICGC DataPortalENSG00000123124
TCGA cBioPortalWWP1
AceView (NCBI)WWP1
Genatlas (Paris)WWP1
SOURCE (Princeton)WWP1
Genetics Home Reference (NIH)WWP1
Genomic and cartography
GoldenPath hg38 (UCSC)WWP1  -     chr8:86342765-86467949 +  8q21.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)WWP1  -     8q21.3   [Description]    (hg19-Feb_2009)
GoldenPathWWP1 - 8q21.3 [CytoView hg19]  WWP1 - 8q21.3 [CytoView hg38]
Mapping of homologs : NCBIWWP1 [Mapview hg19]  WWP1 [Mapview hg38]
Gene and transcription
Genbank (Entrez)AK292800 AK310683 AL050082 AL136739 AW137654
RefSeq transcript (Entrez)NM_007013
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)WWP1
Cluster EST : UnigeneHs.655189 [ NCBI ]
CGAP (NCI)Hs.655189
Alternative Splicing GalleryENSG00000123124
Gene ExpressionWWP1 [ NCBI-GEO ]   WWP1 [ EBI - ARRAY_EXPRESS ]   WWP1 [ SEEK ]   WWP1 [ MEM ]
Gene Expression Viewer (FireBrowse)WWP1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)11059
GTEX Portal (Tissue expression)WWP1
Human Protein AtlasENSG00000123124-WWP1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9H0M0   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9H0M0  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9H0M0
Splice isoforms : SwissVarQ9H0M0
Domaine pattern : Prosite (Expaxy)C2 (PS50004)    HECT (PS50237)    WW_DOMAIN_1 (PS01159)    WW_DOMAIN_2 (PS50020)   
Domains : Interpro (EBI)C2_dom    C2_domain_sf    E3_ub_ligase_SMURF1    HECT_dom    Hect_E3_ubiquitin_ligase    WW_dom    WW_dom_sf   
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)  
Conserved Domain (NCBI)WWP1
DMDM Disease mutations11059
Blocks (Seattle)WWP1
PDB (RSDB)1ND7    2OP7    5HPS    5HPT   
PDB Europe1ND7    2OP7    5HPS    5HPT   
PDB (PDBSum)1ND7    2OP7    5HPS    5HPT   
PDB (IMB)1ND7    2OP7    5HPS    5HPT   
Structural Biology KnowledgeBase1ND7    2OP7    5HPS    5HPT   
SCOP (Structural Classification of Proteins)1ND7    2OP7    5HPS    5HPT   
CATH (Classification of proteins structures)1ND7    2OP7    5HPS    5HPT   
Human Protein Atlas [tissue]ENSG00000123124-WWP1 [tissue]
Peptide AtlasQ9H0M0
IPIIPI00013009   IPI00328376   IPI00328377   IPI00328378   IPI01018613   IPI00980771   
Protein Interaction databases
IntAct (EBI)Q9H0M0
Ontologies - Pathways
Ontology : AmiGOubiquitin ligase complex  protein polyubiquitination  ubiquitin-protein transferase activity  protein binding  nucleus  cytoplasm  cytosol  plasma membrane  ubiquitin-dependent protein catabolic process  signal transduction  central nervous system development  protein ubiquitination  protein ubiquitination  ion transmembrane transport  proteasome-mediated ubiquitin-dependent protein catabolic process  positive regulation of protein catabolic process  negative regulation of transcription, DNA-templated  viral entry into host cell  ubiquitin protein ligase activity  extracellular exosome  
Ontology : EGO-EBIubiquitin ligase complex  protein polyubiquitination  ubiquitin-protein transferase activity  protein binding  nucleus  cytoplasm  cytosol  plasma membrane  ubiquitin-dependent protein catabolic process  signal transduction  central nervous system development  protein ubiquitination  protein ubiquitination  ion transmembrane transport  proteasome-mediated ubiquitin-dependent protein catabolic process  positive regulation of protein catabolic process  negative regulation of transcription, DNA-templated  viral entry into host cell  ubiquitin protein ligase activity  extracellular exosome  
Pathways : KEGGUbiquitin mediated proteolysis    Endocytosis   
REACTOMEQ9H0M0 [protein]
REACTOME PathwaysR-HSA-983168 [pathway]   
NDEx NetworkWWP1
Atlas of Cancer Signalling NetworkWWP1
Wikipedia pathwaysWWP1
Orthology - Evolution
GeneTree (enSembl)ENSG00000123124
Phylogenetic Trees/Animal Genes : TreeFamWWP1
Homologs : HomoloGeneWWP1
Homology/Alignments : Family Browser (UCSC)WWP1
Gene fusions - Rearrangements
Fusion : MitelmanWWP1/CPB2 [8q21.3/13q14.13]  
Fusion : MitelmanWWP1/NUBPL [8q21.3/14q12]  [t(8;14)(q21;q12)]  
Fusion PortalWWP1 8q21.3 CPB2 13q14.13 BRCA
Fusion PortalWWP1 8q21.3 NUBPL 14q12 BRCA
Fusion : FusionGDB17259    17753    42118    42119    42120    42121    42122    42123    42124    42125    42126   
Fusion : Fusion_HubASAP1--WWP1    DUSP2--WWP1    EML4--WWP1    FAT4--WWP1    ISCA1--WWP1    RFX3--WWP1    SF3B1--WWP1    SLC30A9--WWP1    SPIDR--WWP1    WWP1--CNBD1    WWP1--CPB2    WWP1--CPNE3    WWP1--DHX34    WWP1--ESRP1    WWP1--FOXP2   
WWP1--KAT6A    WWP1--LRRCC1    WWP1--MATN2    WWP1--MBP    WWP1--MYBPC1    WWP1--MYO6    WWP1--NDUFAF6    WWP1--NUBPL    WWP1--PSIP1    WWP1--PTTG1    WWP1--UBA2    WWP1--UTP23    WWP1--WLS    WWP1--WWP1    WWP1--ZNF704   
Fusion : QuiverWWP1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerWWP1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)WWP1
Exome Variant ServerWWP1
ExAC (Exome Aggregation Consortium)ENSG00000123124
GNOMAD BrowserENSG00000123124
Varsome BrowserWWP1
Genetic variants : HAPMAP11059
Genomic Variants (DGV)WWP1 [DGVbeta]
DECIPHERWWP1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisWWP1 
ICGC Data PortalWWP1 
TCGA Data PortalWWP1 
Broad Tumor PortalWWP1
OASIS PortalWWP1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICWWP1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DWWP1
Mutations and Diseases : HGMDWWP1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch WWP1
DgiDB (Drug Gene Interaction Database)WWP1
DoCM (Curated mutations)WWP1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)WWP1 (select a term)
NCG5 (London)WWP1
Cancer3DWWP1(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry WWP1
NextProtQ9H0M0 [Medical]
Target ValidationWWP1
Huge Navigator WWP1 [HugePedia]
snp3D : Map Gene to Disease11059
BioCentury BCIQWWP1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD11059
Chemical/Pharm GKB GenePA134960138
Clinical trialWWP1
canSAR (ICR)WWP1 (select the gene name)
DataMed IndexWWP1
PubMed114 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Nov 13 22:10:54 CET 2019

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