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| | 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 |
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| 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). |
| Physical and functional interactions between the transactivation domain of the hematopoietic transcription factor NF-E2 and WW domains. |
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| PMID 9753456 |
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| Alternative splicing determines the domain structure of WWP1, a Nedd4 family protein. |
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| Biochemical and biophysical research communications. 2002 ; 290 (1) : 431-437. |
| PMID 11779188 |
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| 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 |
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| 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 |
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| 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 |
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| The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation. |
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| The EMBO journal. 2004 ; 23 (19) : 3780-3792. |
| PMID 15359284 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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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