Alternative titles; symbols
HGNC Approved Gene Symbol: WWP1
Cytogenetic location: 8q21.3 Genomic coordinates (GRCh38) : 8:86,342,547-86,468,503 (from NCBI)
WWP1 belongs to the NEDD4 (602278) protein family. NEDD4 family proteins function as E3 ubiquitin ligases and are involved in protein trafficking, particularly in the targeting of proteins to proteosomes and lysosomes (Flasza et al., 2002).
The WW domain is a 35- to 40-amino acid protein-protein interaction motif characterized by 4 conserved aromatic residues, 2 of which are tryptophan. Using COLT (cloning of ligand targets), Pirozzi et al. (1997) screened human bone marrow and brain cDNA expression libraries with putative WW domain peptide ligand sequences and recovered 3 distinct proteins, WWP1, WWP2 (602308), and WWP3 (602625). WWP1 contains 4 tandem WW domains and a partial HECT (homologous to the E6-associated protein carboxyl terminus) domain, which is associated with ubiquitin-protein ligase activity. Pirozzi et al. (1997) noted the similarities between WWP1 and NEDD4 and suggested that WWP1 and WWP2 belong to a family of NEDD4-like proteins.
By Northern blot analysis, Wood et al. (1998) detected a 4.5-kb WWP1 transcript, which they called AIP5, in heart, brain, placenta, lung, liver, muscle, kidney, and pancreas. Expression was particularly high in heart and skeletal muscle.
By RT-PCR of the T47D mammary carcinoma cell line, Flasza et al. (2002) cloned full-length WWP1 and 5 splice variants. The full-length 922-amino acid WWP1 isoform has an N-terminal C2 domain, which is a membrane lipid interaction motif, followed by the WW domains and C-terminal HECT domain. Three of the WWP1 splice variants encode isoforms with deletions of either the entire C2 domain or the C-terminal end of the C2 domain. The other 2 variants encode short isoforms that are truncated within or before the C2 domain. RT-PCR detected WWP1 expression in all adult and fetal tissues examined. Expression of full-length WWP1 and the 3 WWP1 variants encoding isoforms with C2 deletions appeared to be regulated in a tissue-specific fashion. The 2 WWP1 variants encoding truncated peptides were not detected in any normal human tissues examined.
Using immunofluorescence analysis, Seo et al. (2004) detected Wwp1, which they called Tiul1, in both the nucleus and cytoplasm of canine and mink epithelial cells.
Using in vitro assays, Pirozzi et al. (1997) showed that individual WW domains of WWP1, WWP2, and WWP3 could selectively bind particular peptide ligands.
Seo et al. (2004) detected an interaction between mouse Smad7 (602932) and human TIUL1 in a yeast 2-hybrid screen of a placenta cDNA library, and they confirmed the interaction using canine, mink, monkey, and human epithelial cell lines. Endogenous Smad7 and Tiul1 interacted independent of TGF-beta (TGFB1; 190180) signaling, and the interaction led to efficient ubiquitination of activated TGF-beta receptor-1 (TGFBR1; 190181), with subsequent receptor degradation. Endogenous TIUL1 also interacted with SMAD2 (601366)/SMAD3 (603109) and the nuclear corepressor TGIF (602630) following TGF-beta treatment of human embryonic kidney cells, and this interaction led to ubiquitination and degradation of SMAD2. Overexpression of human TIUL1 in canine kidney cells suppressed TGF-beta-induced growth arrest, and this suppression required the catalytic cysteine (cys890) in the HECT domain of TIUL1. Conversely, knockdown of endogenous Tiul1 expression by small interfering RNA increased the sensitivity of cells to TGF-beta. Seo et al. (2004) concluded that TIUL1 negatively regulates TGF-beta signaling by directing the degradation of active components of the TGF-beta network.
Carrano et al. (2009) identified Wwp1 as a positive regulator of life span in C. elegans in response to dietary restriction. Overexpression of Wwp1 in worms extended life span by up to 20% under conditions of ad libitum feeding. Conversely, reduction of Wwp1 completely suppressed the extended longevity of diet-restricted animals. The E2 ubiquitin-conjugating enzyme Ubc18, which is homologous to human UBE2L3 (603721), interacted with Wwp1 and was required for Wwp1 ubiquitin ligase activity and the extended longevity of worms overexpressing Wwp1. Carrano et al. (2009) concluded that Wwp1 and Ubc18 function to ubiquitinate substrates that regulate longevity induced by diet restriction.
Using immunoprecipitation followed by mass spectrometry analysis, Lee et al. (2019) identified the HECT-type E3 ubiquitin ligase WWP1 as a physical PTEN (601728) interactor and found that WWP1 specifically triggers nondegradative K27-linked polyubiquitination of PTEN to suppress its dimerization, membrane recruitment, and tumor suppressive functions both in vivo and in vitro. WWP1 is genetically amplified and frequently overexpressed in multiple cancers, including those of prostate, breast, and liver, which lead to pleiotropic inactivation of PTEN. Lee et al. (2019) found that WWP1 may be transcriptionally activated by the MYC (190080) protooncogene and that genetic depletion of Wwp1 in both Myc- driven mouse models of prostate cancer in vivo and cancer cells in vitro reactivates PTEN function, leading to inhibition of the PI3K-AKT pathway and MYC-driven tumorigenesis. Structural simulation and biochemical analyses showed that indole-3-carbinol (I3C), a derivative of cruciferous vegetables, was a natural and potent WWP1 inhibitor. Lee et al. (2019) concluded that the MYC-WWP1 axis is a fundamental and evolutionary conserved regulatory pathway for PTEN and PI3K signaling.
Using FISH, Flasza et al. (2002) mapped the WWP1 gene to chromosome 8q21. They identified a WWP1 pseudogene on chromosome 3.
Associations Pending Confirmation
Lee et al. (2020) enrolled 431 patients with wildtype PTEN (601728) who met at least the relaxed diagnostic criteria of the International Cowden Consortium and screened them for WWP1 germline variants. From the original cohort, the authors selected 83 probands based on clinical manifestations, high phenotypic burden, and/or pathognomonic features such as Lhermitte-Duclos disease. A large 3-generation family (family CCF02632) segregating autosomal dominant oligopolyposis and early-onset colon cancer carried a lys740-to-asn (K740N) variant in the WWP1 gene. The proband was a female with GI polyposis, desmoid tumor, and basal cell cancer. A sister and brother had died of colon cancer at 33 and 43 years of age, respectively, and were not tested. Her father with GI polyposis and numerous skin lesions and a brother with GI polyposis carried the same variant. A healthy brother and a brother with testicular cancer at age 55 but no colon cancer, polyps, or skin lesions did not inherit the WWP1 variant. Five other probands were identified as carrying deleterious variants in the WWP1 gene. The second proband (CCF03506) was a 65-year-old male with macrocephaly and 15 GI polyps (first polyp at age 61). The third proband (CCF04145) was a 51-year-old female with 28 GI polyps (first polyp at age 48). The fourth proband (CCF04959) was a 69-year-old female with 8 GI polyps (first polyp at age 59), ascending colon cancer (age 62), and ovarian cancer (age 48). The fifth proband (CCF01687) was a 63-year-old female with follicular papillary thyroid cancer (age 62), invasive breast cancer (age 63), fibrocystic breast disease, uterine fibroids, and 8 GI polyps. The sixth proband (CCF03258) was a 70-year old male with 7 polyps (first polyp at age 67) and bladder cancer at age 70; he had an asn745-to-ser (N745S) substitution in the WWP1 gene.
Using purified proteins and in vitro enzymatic assays, Jiang et al. (2021) investigated the possibility that the WWP1 K740N and N745S variants possess enhanced ubiquitin ligase activity and demonstrated that the variants are similar to wildtype in both autoubiquitination and PTEN ubiquitination. Furthermore, both variants showed dependencies similar to those of wildtype in terms of allosteric activation by an engineered ubiquitin variant, upstream E2 concentration, and substrate ubiquitin concentration. Transfected WWP1 wildtype and mutants demonstrated comparable effects on cellular PTEN levels. These findings called into question the idea that the K740N and N745S variants promote cancer by enhanced PTEN ubiquitination. Gonzalez-Abuin et al. (2024) also called into question the pathogenicity of the WWP1 variants identified by Lee et al. (2020) in gastrointestinal polyposis and other phenotypes suggestive of PTEN hamartoma tumor syndrome. They noted the absence of disease phenotypes in multiple heterozygotes and the relatively high frequency of the most promising variants in the general population.
Muscular dystrophy in chickens is transmitted codominantly by a single gene, but the phenotype is modified by other background genes. Matsumoto et al. (2008) identified a mutation in the Wwp1 gene that led to an arg441-to-glu (R441Q) substitution in dystrophic chickens. Full-length chicken Wwp1 shares 83% amino acid identity with human WWP1 and contains a C2 domain, followed by 3 WW domains and a C-terminal HECT domain. The R441Q substitution occurred between WW domains 1 and 2 within a region highly conserved among tetrapods and snakes, including 100% conservation of the 20 amino acids immediately surrounding R441.
Carrano, A. C., Liu, Z., Dillin, A., Hunter, T. A conserved ubiquitination pathway determines longevity in response to diet restriction. Nature 460: 396-399, 2009. [PubMed: 19553937] [Full Text: https://doi.org/10.1038/nature08130]
Flasza, M., Gorman, P., Roylance, R., Canfield, A. E., Baron, M. Alternative splicing determines the domain structure of WWP1, a Nedd4 family protein. Biochem. Biophys. Res. Commun. 290: 431-437, 2002. [PubMed: 11779188] [Full Text: https://doi.org/10.1006/bbrc.2001.6206]
Gonzalez-Abuin, N., Pons, T., Fuster, T., Quintana, I., Terradas, M., Aiza, G., Brunet, J., Capella, G., Hampel, H., Valle, L. Lack of evidence for germline WWP1 pathogenic variants in gastrointestinal polyposis and other phenotypes suggestive of PTEN-hamartoma-tumor syndrome. Genes Dis. 11: 524-527, 2024. [PubMed: 37692519] [Full Text: https://doi.org/10.1016/j.gendis.2023.03.011]
Jiang, H., Dempsey, D. R., Cole, P. A. Ubiquitin ligase activities of WWP1 germline variants K740N and N745S. Biochemistry 60: 357-364, 2021. [PubMed: 33470109] [Full Text: https://doi.org/10.1021/acs.biochem.0c00869]
Lee, Y. R., Yehia, L., Kishikawa, T., Ni, Y., Leach, B., Zhang, J., Panch, N., Liu, J., Wei, W., Eng, C., Pandolfi, P. P. WWP1 gain-of-function inactivation of PTEN in cancer predisposition. New Eng. J. Med. 382: 2103-2116, 2020. [PubMed: 32459922] [Full Text: https://doi.org/10.1056/NEJMoa1914919]
Lee, Y.-R., Chen, M., Lee, J. D., Zhang, J., Lin, S.-Y., Fu, T.-M., Chen, H., Ishikawa, T., Chiang, S.-Y., Katon, J., Zhang, Y., Shulga, Y. V., and 15 others. Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. Science 364: eaau0159, 2019. Note: Electronic Article. [PubMed: 31097636] [Full Text: https://doi.org/10.1126/science.aau0159]
Matsumoto, H., Maruse, H., Inaba, Y., Yoshizawa, K., Sasazaki, S., Fujiwara, A., Nishibori, M., Nakamura, A., Takeda, S., Ichihara, N., Kikuchi, T., Mukai, F., Mannen, H. The ubiquitin ligase gene (WWP1) is responsible for the chicken muscular dystrophy. FEBS Lett. 582: 2212-2218, 2008. [PubMed: 18501710] [Full Text: https://doi.org/10.1016/j.febslet.2008.05.013]
Pirozzi, G., McConnell, S. J., Uveges, A. J., Carter, J. M., Sparks, A. B., Kay, B. K., Fowlkes, D. M. Identification of novel human WW domain-containing proteins by cloning of ligand targets. J. Biol. Chem. 272: 14611-14616, 1997. [PubMed: 9169421] [Full Text: https://doi.org/10.1074/jbc.272.23.14611]
Seo, S. R., 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. 23: 3780-3792, 2004. [PubMed: 15359284] [Full Text: https://doi.org/10.1038/sj.emboj.7600398]
Wood, J. D., Yuan, J., Margolis, R. L., Colomer, V., Duan, K., Kushi, J., Kaminsky, Z., Kleiderlein, J. J., Jr., Sharp, A. H., Ross, C. A. Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins. Molec. Cell. Neurosci. 11: 149-160, 1998. [PubMed: 9647693] [Full Text: https://doi.org/10.1006/mcne.1998.0677]