WWP1 (WW domain containing E3 ubiquitin protein ligase 1)

	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).

Implicated in

Note
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.

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