WWP1 (WW domain containing E3 ubiquitin protein ligase 1)

Identity

Other names	AIP5 (Atropin-1-interacting protein 5)
	Tiul1 (TGIF-interacting ubiquitin ligase 1)
HGNC	WWP1
Location	8q21.3

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).

Protein

	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).

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	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.

External links

	Nomenclature
HGNC	WWP1   17004
Entrez_Gene	WWP1  11059  WW domain containing E3 ubiquitin protein ligase 1
	Cards
Atlas	WWP1ID42993ch8q21
GeneCards	WWP1
Ensembl	WWP1 [Search_View]   ENSG00000123124 [Gene_View]
Genatlas	WWP1
GeneLynx	WWP1
eGenome	WWP1
euGene	11059
	Genomic and cartography
GoldenPath	WWP1  -  8q21.3   chr8:87424110-87549294 +  8q21   [Description]    (hg18-Mar_2006)
Ensembl	WWP1 - 8q21 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	WWP1
	Gene and transcription
Genbank	AK292800 [ ENTREZ ]
Genbank	AK310683 [ ENTREZ ]
Genbank	AL050082 [ ENTREZ ]
Genbank	AL136739 [ ENTREZ ]
Genbank	AW137654 [ ENTREZ ]
RefSeq	NM_007013 [ SRS ]    NM_007013 [ ENTREZ ]
RefSeq	AC_000051 [ SRS ]    AC_000051 [ ENTREZ ]
RefSeq	AC_000140 [ SRS ]    AC_000140 [ ENTREZ ]
RefSeq	NC_000008 [ SRS ]    NC_000008 [ ENTREZ ]
RefSeq	NT_008046 [ SRS ]    NT_008046 [ ENTREZ ]
RefSeq	NW_001839136 [ SRS ]    NW_001839136 [ ENTREZ ]
RefSeq	NW_923984 [ SRS ]    NW_923984 [ ENTREZ ]
AceView	WWP1 AceView - NCBI
Unigene	Hs.655189 [ SRS ]    Hs.655189 [ NCBI ]     HS655189 [ spliceNest ]
Fast-db	6456 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q5YLC1 [ SRS]    Q5YLC1 [ EXPASY ]     Q5YLC1 [ INTERPRO ]     Q5YLC1 [ UNIPROT ]
Prosite	PS50004 C2 [ SRS ]    PS50004 C2 [ Expasy ]
Prosite	PS50237 HECT [ SRS ]    PS50237 HECT [ Expasy ]
Prosite	PS01159 WW_DOMAIN_1 [ SRS ]    PS01159 WW_DOMAIN_1 [ Expasy ]
Prosite	PS50020 WW_DOMAIN_2 [ SRS ]    PS50020 WW_DOMAIN_2 [ Expasy ]
Interpro	IPR000008 C2_Ca-dep [ SRS ]    IPR000008 C2_Ca-dep [ EBI ]
Interpro	IPR000569 HECT [ SRS ]    IPR000569 HECT [ EBI ]
Interpro	IPR002349 WW [ SRS ]    IPR002349 WW [ EBI ]
Interpro	IPR001202 WW_Rsp5_WWP [ SRS ]    IPR001202 WW_Rsp5_WWP [ EBI ]
CluSTr	Q5YLC1
Pfam	PF00168 C2 [ SRS ]    PF00168 C2 [ Sanger ]    pfam00168 [ NCBI-CDD ]
Pfam	PF00632 HECT [ SRS ]    PF00632 HECT [ Sanger ]    pfam00632 [ NCBI-CDD ]
Pfam	PF00397 WW [ SRS ]    PF00397 WW [ Sanger ]    pfam00397 [ NCBI-CDD ]
Smart	SM00239 C2 [EMBL]
Smart	SM00119 HECTc [EMBL]
Smart	SM00456 WW [EMBL]
Blocks	Q5YLC1
HPRD	03811
	Protein Interaction databases
DIP	Q5YLC1
IntAct	Q5YLC1
	Polymorphism : SNP, mutations, diseases
OMIM	602307    [ map ]
GENECLINICS	602307
SNP	WWP1 [dbSNP-NCBI]
SNP	NM_007013 [SNP-NCI]
SNP	WWP1 [GeneSNPs - Utah]  WWP1] [HGBASE - SRS]
HAPMAP	WWP1 [HAPMAP]
COSMIC	WWP1 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	WWP1
	General knowledge
Family Browser	WWP1 [UCSC Family Browser]
SOURCE	NM_007013
SMD	Hs.655189
SAGE	Hs.655189
GO	ubiquitin ligase complex [Amigo]  ubiquitin ligase complex
GO	ubiquitin-protein ligase activity [Amigo]  ubiquitin-protein ligase activity
GO	protein binding [Amigo]  protein binding
GO	protein binding [Amigo]  protein binding
GO	intracellular [Amigo]  intracellular
GO	protein modification process [Amigo]  protein modification process
GO	signal transduction [Amigo]  signal transduction
GO	central nervous system development [Amigo]  central nervous system development
GO	negative regulation of transcription [Amigo]  negative regulation of transcription
GO	protein ubiquitination [Amigo]  protein ubiquitination
GO	ligase activity [Amigo]  ligase activity
GO	interspecies interaction between organisms [Amigo]  interspecies interaction between organisms
GO	entry of virus into host cell [Amigo]  entry of virus into host cell
KEGG	Ubiquitin mediated proteolysis
KEGG	Dentatorubropallidoluysian atrophy (DRPLA)
PubGene	WWP1
TreeFam	WWP1
CTD	11059 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	WWP1 Related clones (RZPD - Berlin)
	PubMed
PubMed	23 Pubmed reference(s) in LocusLink

Bibliography

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

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

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

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

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

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

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

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

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.

Morˆ©n A, Imamura T, Miyazono K, Heldin CH, Moustakas A

The Journal of biological chemistry. 2005 ; 280 (23) : 22115-22123.

PMID 15817471

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

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

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

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

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 p53 localization and transcription by the HECT domain E3 ligase WWP1.

Laine A, Ronai Z

Oncogene. 2007 ; 26 (10) : 1477-1483.

PMID 16924229

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Search in all EBI   NCBI

Contributor(s)

Written	01-2008	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

Citation

This paper should be referenced as such :

Chen C . WWP1 (WW domain containing E3 ubiquitin protein ligase 1). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/WWP1ID42993ch8q21.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:18:32 2008