WWP1 (WW domain containing E3 ubiquitin protein ligase 1)
2008-01-01 Ceshi Chen AffiliationThe Center for Cell Biology, Cancer Research Albany Medical College MS355\\\/350, Mail code 165, 47 New Scotland Ave. Albany, NY 12208, USA
Identity
HGNC
LOCATION
8q21.3
LOCUSID
ALIAS
AIP5,Tiul1,hSDRP1
FUSION GENES
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).
Proteins
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).
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).
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 name
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 name
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 17726579 | 2007 | The Nedd4-like family of E3 ubiquitin ligases and cancer. | Chen C et al |
| 17016436 | 2007 | Ubiquitin E3 ligase WWP1 as an oncogenic factor in human prostate cancer. | Chen C et al |
| 17330240 | 2007 | The amplified WWP1 gene is a potential molecular target in breast cancer. | Chen C et al |
| 11779188 | 2002 | Alternative splicing determines the domain structure of WWP1, a Nedd4 family protein. | Flasza M et al |
| 17609263 | 2007 | The role of WWP1-Gag interaction and Gag ubiquitination in assembly and release of human T-cell leukemia virus type 1. | Heidecker G et al |
| 16728642 | 2006 | Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3. | Jones DC et al |
| 15221015 | 2004 | Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1). | Komuro A et al |
| 16924229 | 2007 | Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1. | Laine A et al |
| 12908109 | 2003 | Differential expression and localisation of WWP1, a Nedd4-like protein, in epithelia. | Malbert-Colas L et al |
| 15623582 | 2005 | HECT ubiquitin ligases link viral and cellular PPXY motifs to the vacuolar protein-sorting pathway. | Martin-Serrano J et al |
| 15817471 | 2005 | Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases. | Morén A et al |
| 9753456 | 1998 | Physical and functional interactions between the transactivation domain of the hematopoietic transcription factor NF-E2 and WW domains. | Mosser EA et al |
| 15359284 | 2004 | The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation. | Seo SR et al |
| 16236769 | 2005 | LIN-12/Notch trafficking and regulation of DSL ligand activity during vulval induction in Caenorhabditis elegans. | Shaye DD et al |
| 16299379 | 2006 | Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation. | Shen R et al |
| 12535537 | 2003 | Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase. | Verdecia MA et al |
| 15003522 | 2004 | WWP1-dependent ubiquitination and degradation of the lung Krüppel-like factor, KLF2. | Zhang X et al |
Other Information
Locus ID:
NCBI: 11059
MIM: 602307
HGNC: 17004
Ensembl: ENSG00000123124
Variants:
dbSNP: 11059
ClinVar: 11059
TCGA: ENSG00000123124
COSMIC: WWP1
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000123124 | ENST00000265428 | Q9H0M0 |
| ENSG00000123124 | ENST00000517970 | Q9H0M0 |
| ENSG00000123124 | ENST00000520453 | H0YBA4 |
| ENSG00000123124 | ENST00000520798 | H0YBS9 |
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 34388030 | 2022 | High Expression of WWP1 Associates with Tumor Progression in Papillary Thyroid Cancer. | 2 |
| 35154481 | 2022 | α-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer. | 9 |
| 34388030 | 2022 | High Expression of WWP1 Associates with Tumor Progression in Papillary Thyroid Cancer. | 2 |
| 35154481 | 2022 | α-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer. | 9 |
| 33470109 | 2021 | Ubiquitin Ligase Activities of WWP1 Germline Variants K740N and N745S. | 6 |
| 33516665 | 2021 | BAP1 antagonizes WWP1-mediated transcription factor KLF5 ubiquitination and inhibits autophagy to promote melanoma progression. | 13 |
| 33648498 | 2021 | CircWAC induces chemotherapeutic resistance in triple-negative breast cancer by targeting miR-142, upregulating WWP1 and activating the PI3K/AKT pathway. | 45 |
| 34035464 | 2021 | miR-19b enhances osteogenic differentiation of mesenchymal stem cells and promotes fracture healing through the WWP1/Smurf2-mediated KLF5/β-catenin signaling pathway. | 24 |
| 34139860 | 2021 | Targeting E3 Ubiquitin Ligase WWP1 Prevents Cardiac Hypertrophy Through Destabilizing DVL2 via Inhibition of K27-Linked Ubiquitination. | 24 |
| 34404733 | 2021 | AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation. | 1 |
| 34404764 | 2021 | WWP1 targeting MUC1 for ubiquitin-mediated lysosomal degradation to suppress carcinogenesis. | 4 |
| 34559578 | 2021 | Ubiquitin ligase Wwp1 gene deletion attenuates diastolic dysfunction in pressure-overload hypertrophy. | 3 |
| 34907909 | 2021 | WWP1 inactivation enhances efficacy of PI3K inhibitors while suppressing their toxicities in breast cancer models. | 6 |
| 33470109 | 2021 | Ubiquitin Ligase Activities of WWP1 Germline Variants K740N and N745S. | 6 |
| 33516665 | 2021 | BAP1 antagonizes WWP1-mediated transcription factor KLF5 ubiquitination and inhibits autophagy to promote melanoma progression. | 13 |
Citation
Ceshi Chen
WWP1 (WW domain containing E3 ubiquitin protein ligase 1)
Atlas Genet Cytogenet Oncol Haematol. 2008-01-01
Online version: http://atlasgeneticsoncology.org/gene/42993/wwp1
