Download Gene Section WWP1 (WW domain containing E3 ubiquitin protein ligase 1)

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WWP1 (WW domain containing E3 ubiquitin
protein ligase 1)
Ceshi 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
Published in Atlas Database: January 2008
Online updated version: http://AtlasGeneticsOncology.org/Genes/WWP1ID42993ch8q21.html
DOI: 10.4267/2042/38581
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
breast cancer cell line T47D (Flasza et al., 2002). The
open reading frame for the full length WWP1 gene is
2766 bp. The transcription is increased by TGFb (Chen
et al., 2007).
Identity
Hugo: WWP1
Other names: AIP5 (Atropin-1-interacting protein 5);
Tiul1 (TGIF-interacting ubiquitin ligase 1)
Location: 8q21.3
Protein
Description
DNA/RNA
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 proteinprotein 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 et al., 2007a).
Protein structure: The HECT domain of WWP1 (see
Figure 2C.) (Verdecia et al., 2003).
Description
The WWP1 gene encompasses 26 exons which span
approximatively 142 kb of DNA. BAC clone RPCI459L5 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 et al., 1998; Komuro et al., 2004).
The size of the WWP1 mRNA is about 4.2 kb (Chen et
al., 2007). There are multiple splicing isoforms in the
Figure 1. Boxes represent exons.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(5)
393
WWP1 (WW domain containing E3 ubiquitin protein ligase 1)
Chen C
Figure 2A: WWP1 protein.
Figure 2B: Exogenous WWP1 expression in the 22Rv1 prostate cancer cell line was detected under a confocal microscopy. The
endosomes are indicated by GFP-Rab5.
Figure 2C: Protein structure of WWP1.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(5)
394
WWP1 (WW domain containing E3 ubiquitin protein ligase 1)
Chen C
Expression
Mutations
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.
Somatic
The WWP1 gene is rarely mutated in human prostate
cancer (Chen et al., 2007a). 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 et al., 2003).
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 et al., 2004), Smad2 (Seo et al., 2004), and
Smad4 (Moren et al., 2005) for ubiquitin mediated
degradation.
In addition, WWP1 has been reported to target the
epithelial Na+ channel (ENaC) (Malbert-Colas et al.,
2003), Notch (Shaye and Greenwald, 2005), Runx2
(Jones et al., 2006; Shen et al., 2006), KLF2 (Zhang et
al., 2004), and KLF5 (Chen et al., 2005) for ubiquitinmediated proteolysis.
Recently, WWP1 has been demonstrated to inhibit p53
activity through exporting p53 from the nucleus after
ubiquitination (Laine and Ronai, 2007). Overall,
WWP1 may play a pro-survival role in several tumor
types including breast (Chen et al., 2007b) and prostate
(Chen et al., 2007a). WWP1 has also shown to promote
virus budding (Martin-Serrano et al., 2005; Heidecker
et al., 2007).
Implicated in
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 TGFbinduced 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.
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.
Homology
WWP1 belongs to the C2-WW-HECT E3 family which
contains 8 other members (Chen and Matesic, 2007).
The WWP1 gene is highly-conserved among species
(from human to c. elegant).
Figure 3. WWP1 protein expression in normal breast epithelial cells and breast cancer cells by immunohistochemical staining.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(5)
395
WWP1 (WW domain containing E3 ubiquitin protein ligase 1)
Chen C
Morén A, Imamura T, Miyazono K, Heldin CH, Moustakas A.
Degradation of the tumor suppressor Smad4 by WW and
HECT
domain
ubiquitin
ligases.
J
Biol
Chem
2005;280(23):22115-22123.
References
Mosser EA, Kasanov JD, Forsberg EC, Kay BK, Ney PA,
Bresnick EH. Physical and functional interactions between the
transactivation domain of the hematopoietic transcription factor
NF-E2 and WW domains. Biochemistry 1998;37(39):1368613695.
Shaye DD, Greenwald I. LIN-12/Notch trafficking and
regulation of DSL ligand activity during vulval induction in
Caenorhabditis elegans. Development 2005;132(22):50815092.
Flasza M, Gorman P, Roylance R, Canfield AE, Baron M.
Alternative splicing determines the domain structure of WWP1,
a Nedd4 family protein. Biochem Biophys Res Commun
2002;290(1):431-437.
Jones DC, Wein MN, Oukka M, Hofstaetter JG, Glimcher MJ,
Glimcher LH. Regulation of adult bone mass by the zinc finger
adapter protein Schnurri-3. Science 2006;312(5777):12231227.
Malbert-Colas L, Fay M, Cluzeaud F, Blot-Chabaud M, Farman
N, Dhermy D, Lecomte MC. Differential expression and
localisation of WWP1, a Nedd4-like protein, in epithelia.
Pflugers Arch 2003;447(1):35-43.
Shen R, Chen M, Wang YJ, Kaneki H, Xing L, O'keefe RJ,
Chen D. Smad6 interacts with Runx2 and mediates Smad
ubiquitin regulatory factor 1-induced Runx2 degradation. J Biol
Chem 2006;281(6):3569-3576.
Verdecia MA, Joazeiro CA, Wells NJ, Ferrer JL, Bowman ME,
Hunter T, Noel JP. Conformational flexibility underlies ubiquitin
ligation mediated by the WWP1 HECT domain E3 ligase. Mol
Cell 2003;11(1):249-259.
Chen C, Matesic LE. The Nedd4-like family of E3 ubiquitin
ligases and cancer. Cancer Metastasis Rev 2007;26(3-4):587604.
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.
Ubiquitin E3 ligase WWP1 as an oncogenic factor in human
prostate cancer. Oncogene 2007;26(16):2386-2394.
Komuro A, Imamura T, Saitoh M, Yoshida Y, Yamori T,
Miyazono K, Miyazawa K. Negative regulation of transforming
growth factor-beta (TGF-beta) signaling by WW domaincontaining protein 1 (WWP1). Oncogene 2004;23(41):69146923.
Chen C, Zhou Z, Ross JS, Zhou W, Dong JT. The amplified
WWP1 gene is a potential molecular target in breast cancer.
Int J Cancer 2007;121(1):80-87.
Seo SR, Lallemand F, Ferrand N, Pessah M, L'Hoste S,
Camonis J, Atfi A. The novel E3 ubiquitin ligase Tiul1
associates with TGIF to target Smad2 for degradation. EMBO
J 2004;23(19):3780-3792.
Heidecker G, Lloyd PA, Soheilian F, Nagashima K, Derse D.
The Role of WWP1-Gag Interaction and Gag Ubiquitination in
Assembly and Release of Human T-Cell Leukemia Virus Type
1. J Virol 2007;81(18):9769-9777.
Zhang X, Srinivasan SV, Lingrel JB. WWP1-dependent
ubiquitination and degradation of the lung Kruppel-like factor,
KLF2. Biochem Biophys Res Commun 2004;316(1):139-148.
Laine A, Ronai Z. Regulation of p53 localization and
transcription by the HECT domain E3 ligase WWP1. Oncogene
2007;26(10):1477-1483.
Chen C, Sun X, Guo P, Dong XY, Sethi P, Cheng X, Zhou J,
Ling J, Simons JW, Lingrel JB, Dong JT. Human Kruppel-like
factor 5 is a target of the E3 ubiquitin ligase WWP1 for
proteolysis in epithelial cells. J Biol Chem 2005;280(50):4155341561.
This article 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.
Martin-Serrano J, Eastman SW, Chung W, Bieniasz PD. HECT
ubiquitin ligases link viral and cellular PPXY motifs to the
vacuolar protein-sorting pathway. J Cell Biol 2005;168(1):89101.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(5)
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