# WWP2

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Protein-coding gene in the species Homo sapiens

WWP2 Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4Y07 Identifiers Aliases WWP2, AIP2, WWp2-like, WW domain containing E3 ubiquitin protein ligase 2 External IDs OMIM: 602308; MGI: 1914144; HomoloGene: 48490; GeneCards: WWP2; OMA:WWP2 - orthologs Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16q22.1 Start 69,762,328 bp[1] End 69,941,741 bp[1] Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8|8 D3 Start 108,162,997 bp[2] End 108,285,227 bp[2] RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in tibia tendon of biceps brachii ascending aorta Descending thoracic aorta sural nerve right coronary artery popliteal artery tibial arteries pancreatic ductal cell endothelial cell Top expressed in facial skeleton sphenoid bone basisphenoid splanchnocranium thumb membranous bone index finger phalanx of index finger tunica media of zone of aorta bones of pectoral girdle More reference expression data BioGPS n/a Gene ontology Molecular function transcription factor binding ubiquitin-protein transferase activity protein binding transferase activity ubiquitin protein ligase activity Cellular component membrane ubiquitin ligase complex extracellular exosome nucleus cytoplasm cytosol Biological process regulation of membrane potential regulation of ion transmembrane transport negative regulation of transcription by RNA polymerase II transcription by RNA polymerase II negative regulation of DNA-binding transcription factor activity negative regulation of gene expression negative regulation of protein transport regulation of potassium ion transmembrane transporter activity viral entry into host cell viral process negative regulation of transcription, DNA-templated negative regulation of transporter activity positive regulation of transcription by RNA polymerase II proteasome-mediated ubiquitin-dependent protein catabolic process protein autoubiquitination ubiquitin-dependent protein catabolic process protein K63-linked ubiquitination extracellular transport protein ubiquitination protein polyubiquitination positive regulation of protein catabolic process negative regulation of Notch signaling pathway Sources:Amigo / QuickGO Orthologs Species Human Mouse Entrez 11060 66894 Ensembl ENSG00000198373 ENSMUSG00000031930 UniProt O00308 Q9DBH0 RefSeq (mRNA) NM_001270453 NM_001270454 NM_001270455 NM_007014 NM_199424 NM_025830 RefSeq (protein) NP_001257382 NP_001257383 NP_001257384 NP_008945 NP_955456 NP_080106 Location (UCSC) Chr 16: 69.76 – 69.94 Mb Chr 8: 108.16 – 108.29 Mb PubMed search [3] [4] Wikidata View/Edit Human View/Edit Mouse

**NEDD4-like E3 ubiquitin-protein ligase WWP2** also known as **atrophin-1-interacting protein 2** (AIP2) or **WW domain-containing protein 2** (WWP2) is an [enzyme](/source/Enzyme) that in humans is encoded by the *WWP2* [gene](/source/Gene).[5][6][7]

## Function

This gene encodes a member of the NEDD4-like protein family. The family of proteins is known to possess [ubiquitin-protein ligase](/source/Ubiquitin_ligase) activity. The encoded protein contains 4 tandem [WW domains](/source/WW_domain). The WW domain is a protein motif consisting of 35 to 40 amino acids and is characterized by 4 conserved aromatic residues. The WW domain may mediate specific protein–protein interactions. Three alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[7] In neurons, murine ortholog Wwp2 and its homolog Wwp1 control polarity acquisition, formation, and branching of axons, as well as migration of newly born nerve cells into the cortical plate.[8]

## Interactions

WWP2 has been shown to [interact](/source/Protein%E2%80%93protein_interaction) with [SCNN1B](/source/SCNN1B)[6][9] and [ATN1](/source/ATN1).[10]

## Clinical significance

Full-length WWP2 (WWP2-FL), together with [N-terminal](/source/N-terminus), (WWP2-N); [C-terminal](/source/C-terminus) (WWP2-C) isoforms bind to [SMAD](/source/SMAD_(protein)) proteins. WWP2-FL interacts with [SMAD2](/source/Mothers_against_decapentaplegic_homolog_2), [SMAD3](/source/Mothers_against_decapentaplegic_homolog_3) and [SMAD7](/source/Mothers_against_decapentaplegic_homolog_7) in the [TGF-β pathway](/source/TGF_beta_signaling_pathway). The WWP2-N isoform interacts with SMAD2 and SMAD3, whereas WWP2-C interacts only with SMAD7. Disruption of interactions between WWP2 and SMAD7 can stabilize SMAD7 protein levels and prevent TGF-β induced [Epithelial-mesenchymal transition](/source/Epithelial-mesenchymal_transition). Hence inhibiting WWP2 may in turn lead to the disabling of an inhibitor that normally controls cell growth and [tumorogenesis](/source/Tumorogenesis). In tissue cultures lacking the inhibitor [SMAD7](/source/SMAD7), cancer cells spread rapidly, so that silencing WWP2 prevented the spread.[11]

## References

1. ^ [***a***](#cite_ref-refGRCh38Ensembl_1-0) [***b***](#cite_ref-refGRCh38Ensembl_1-1) [***c***](#cite_ref-refGRCh38Ensembl_1-2) [GRCh38: Ensembl release 89: ENSG00000198373](http://May2017.archive.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000198373) – [Ensembl](/source/Ensembl_genome_database_project), May 2017

1. ^ [***a***](#cite_ref-refGRCm38Ensembl_2-0) [***b***](#cite_ref-refGRCm38Ensembl_2-1) [***c***](#cite_ref-refGRCm38Ensembl_2-2) [GRCm38: Ensembl release 89: ENSMUSG00000031930](http://May2017.archive.ensembl.org/Mus_musculus/Gene/Summary?db=core;g=ENSMUSG00000031930) – [Ensembl](/source/Ensembl_genome_database_project), May 2017

1. **[^](#cite_ref-3)** ["Human PubMed Reference:"](https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Link&LinkName=gene_pubmed&from_uid=11060). *National Center for Biotechnology Information, U.S. National Library of Medicine*.

1. **[^](#cite_ref-4)** ["Mouse PubMed Reference:"](https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Link&LinkName=gene_pubmed&from_uid=66894). *National Center for Biotechnology Information, U.S. National Library of Medicine*.

1. **[^](#cite_ref-pmid9169421_5-0)** Pirozzi G, McConnell SJ, Uveges AJ, Carter JM, Sparks AB, Kay BK, Fowlkes DM (Jun 1997). ["Identification of novel human WW domain-containing proteins by cloning of ligand targets"](https://cdr.lib.unc.edu/downloads/1g05fm824). *J Biol Chem*. **272** (23): 14611–6. [doi](/source/Doi_(identifier)):[10.1074/jbc.272.23.14611](https://doi.org/10.1074%2Fjbc.272.23.14611). [PMID](/source/PMID_(identifier)) [9169421](https://pubmed.ncbi.nlm.nih.gov/9169421).

1. ^ [***a***](#cite_ref-pmid12167593_6-0) [***b***](#cite_ref-pmid12167593_6-1) McDonald FJ, Western AH, McNeil JD, Thomas BC, Olson DR, Snyder PM (Aug 2002). "Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel". *Am J Physiol Renal Physiol*. **283** (3): F431–6. [doi](/source/Doi_(identifier)):[10.1152/ajprenal.00080.2002](https://doi.org/10.1152%2Fajprenal.00080.2002). [PMID](/source/PMID_(identifier)) [12167593](https://pubmed.ncbi.nlm.nih.gov/12167593).

1. ^ [***a***](#cite_ref-entrez_7-0) [***b***](#cite_ref-entrez_7-1) ["Entrez Gene: WWP2 WW domain containing E3 ubiquitin protein ligase 2"](https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=11060).

1. **[^](#cite_ref-8)** Ambrozkiewicz MC, Schwark M, Kishimoto-Suga M, Borisova E, Hori K, Salazar-Lázaro A, Rusanova A, Altas B, Piepkorn L, Bessa P, Schaub T, Zhang X, Rabe T, Ripamonti S, Rosário M, Akiyama H, Jahn O, Kobayashi T, Hoshino M, Tarabykin V, Kawabe H (December 2018). ["Polarity Acquisition in Cortical Neurons Is Driven by Synergistic Action of Sox9-Regulated Wwp1 and Wwp2 E3 Ubiquitin Ligases and Intronic miR-140"](https://doi.org/10.1016%2Fj.neuron.2018.10.008). *Neuron*. **100** (5): 1097–1115.e15. [doi](/source/Doi_(identifier)):[10.1016/j.neuron.2018.10.008](https://doi.org/10.1016%2Fj.neuron.2018.10.008). [PMID](/source/PMID_(identifier)) [30392800](https://pubmed.ncbi.nlm.nih.gov/30392800).

1. **[^](#cite_ref-pmid11244092_9-0)** Harvey KF, Dinudom A, Cook DI, Kumar S (March 2001). ["The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel"](https://doi.org/10.1074%2Fjbc.C000906200). *J. Biol. Chem*. **276** (11): 8597–601. [doi](/source/Doi_(identifier)):[10.1074/jbc.C000906200](https://doi.org/10.1074%2Fjbc.C000906200). [PMID](/source/PMID_(identifier)) [11244092](https://pubmed.ncbi.nlm.nih.gov/11244092).

1. **[^](#cite_ref-pmid9647693_10-0)** Wood JD, Yuan J, Margolis RL, Colomer V, Duan K, Kushi J, Kaminsky Z, Kleiderlein JJ, Sharp AH, Ross CA (June 1998). ["Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins"](https://doi.org/10.1006%2Fmcne.1998.0677). *Mol. Cell. Neurosci*. **11** (3): 149–60. [doi](/source/Doi_(identifier)):[10.1006/mcne.1998.0677](https://doi.org/10.1006%2Fmcne.1998.0677). [PMID](/source/PMID_(identifier)) [9647693](https://pubmed.ncbi.nlm.nih.gov/9647693). [S2CID](/source/S2CID_(identifier)) [20003277](https://api.semanticscholar.org/CorpusID:20003277).

1. **[^](#cite_ref-Soond_2011_11-0)** Soond SM, Chantry A (2011). ["Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073228). *Oncogene*. **30** (21): 2451–62. [doi](/source/Doi_(identifier)):[10.1038/onc.2010.617](https://doi.org/10.1038%2Fonc.2010.617). [PMC](/source/PMC_(identifier)) [4073228](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073228). [PMID](/source/PMID_(identifier)) [21258410](https://pubmed.ncbi.nlm.nih.gov/21258410). - Lay summary in: Gallagher J (January 24, 2011). ["Blocking a gene stops cancer cells spreading"](https://www.bbc.co.uk/news/health-12254242). *BBC News*.

## Further reading

- Jonsson AB (1998). ["Identification of a human cDNA clone that mediates adherence of pathogenic Neisseria to non-binding cells"](https://doi.org/10.1111%2Fj.1574-6968.1998.tb12974.x). *FEMS Microbiol. Lett*. **162** (1): 25–30. [doi](/source/Doi_(identifier)):[10.1111/j.1574-6968.1998.tb12974.x](https://doi.org/10.1111%2Fj.1574-6968.1998.tb12974.x). [PMID](/source/PMID_(identifier)) [9595660](https://pubmed.ncbi.nlm.nih.gov/9595660).

- Wood JD, Yuan J, Margolis RL, Colomer V, Duan K, Kushi J, Kaminsky Z, Kleiderlein JJ, Sharp AH, Ross CA (1998). ["Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins"](https://doi.org/10.1006%2Fmcne.1998.0677). *Mol. Cell. Neurosci*. **11** (3): 149–60. [doi](/source/Doi_(identifier)):[10.1006/mcne.1998.0677](https://doi.org/10.1006%2Fmcne.1998.0677). [PMID](/source/PMID_(identifier)) [9647693](https://pubmed.ncbi.nlm.nih.gov/9647693). [S2CID](/source/S2CID_(identifier)) [20003277](https://api.semanticscholar.org/CorpusID:20003277).

- Winberg G, Matskova L, Chen F, Plant P, Rotin D, Gish G, Ingham R, Ernberg I, Pawson T (2000). ["Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3 protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC102158). *Mol. Cell. Biol*. **20** (22): 8526–35. [doi](/source/Doi_(identifier)):[10.1128/MCB.20.22.8526-8535.2000](https://doi.org/10.1128%2FMCB.20.22.8526-8535.2000). [PMC](/source/PMC_(identifier)) [102158](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC102158). [PMID](/source/PMID_(identifier)) [11046148](https://pubmed.ncbi.nlm.nih.gov/11046148).

- Harvey KF, Shearwin-Whyatt LM, Fotia A, Parton RG, Kumar S (2002). ["N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein"](https://espace.library.uq.edu.au/view/UQ:63244/UQ63244_OA.pdf) (PDF). *J. Biol. Chem*. **277** (11): 9307–17. [doi](/source/Doi_(identifier)):[10.1074/jbc.M110443200](https://doi.org/10.1074%2Fjbc.M110443200). [PMID](/source/PMID_(identifier)) [11748237](https://pubmed.ncbi.nlm.nih.gov/11748237). [S2CID](/source/S2CID_(identifier)) [37817970](https://api.semanticscholar.org/CorpusID:37817970).

- Galinier R, Gout E, Lortat-Jacob H, Wood J, Chroboczek J (2003). "Adenovirus protein involved in virus internalization recruits ubiquitin-protein ligases". *Biochemistry*. **41** (48): 14299–305. [doi](/source/Doi_(identifier)):[10.1021/bi020125b](https://doi.org/10.1021%2Fbi020125b). [PMID](/source/PMID_(identifier)) [12450395](https://pubmed.ncbi.nlm.nih.gov/12450395).

- Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM (2004). ["Functional proteomics mapping of a human signaling pathway"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC442148). *Genome Res*. **14** (7): 1324–32. [doi](/source/Doi_(identifier)):[10.1101/gr.2334104](https://doi.org/10.1101%2Fgr.2334104). [PMC](/source/PMC_(identifier)) [442148](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC442148). [PMID](/source/PMID_(identifier)) [15231748](https://pubmed.ncbi.nlm.nih.gov/15231748).

- Shearwin-Whyatt LM, Brown DL, Wylie FG, Stow JL, Kumar S (2005). ["N4WBP5A (Ndfip2), a Nedd4-interacting protein, localizes to multivesicular bodies and the Golgi, and has a potential role in protein trafficking"](https://doi.org/10.1242%2Fjcs.01212). *J. Cell Sci*. **117** (Pt 16): 3679–89. [doi](/source/Doi_(identifier)):[10.1242/jcs.01212](https://doi.org/10.1242%2Fjcs.01212). [hdl](/source/Hdl_(identifier)):[2440/9578](https://hdl.handle.net/2440%2F9578). [PMID](/source/PMID_(identifier)) [15252135](https://pubmed.ncbi.nlm.nih.gov/15252135).

- Rougier JS, van Bemmelen MX, Bruce MC, Jespersen T, Gavillet B, Apothéloz F, Cordonier S, Staub O, Rotin D, Abriel H (2005). "Molecular determinants of voltage-gated sodium channel regulation by the Nedd4/Nedd4-like proteins". *Am. J. Physiol., Cell Physiol*. **288** (3): C692–701. [doi](/source/Doi_(identifier)):[10.1152/ajpcell.00460.2004](https://doi.org/10.1152%2Fajpcell.00460.2004). [PMID](/source/PMID_(identifier)) [15548568](https://pubmed.ncbi.nlm.nih.gov/15548568). [S2CID](/source/S2CID_(identifier)) [5342436](https://api.semanticscholar.org/CorpusID:5342436).

- Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, [Zoghbi HY](/source/Huda_Zoghbi), Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (2005). "Towards a proteome-scale map of the human protein-protein interaction network". *Nature*. **437** (7062): 1173–8. [Bibcode](/source/Bibcode_(identifier)):[2005Natur.437.1173R](https://ui.adsabs.harvard.edu/abs/2005Natur.437.1173R). [doi](/source/Doi_(identifier)):[10.1038/nature04209](https://doi.org/10.1038%2Fnature04209). [PMID](/source/PMID_(identifier)) [16189514](https://pubmed.ncbi.nlm.nih.gov/16189514). [S2CID](/source/S2CID_(identifier)) [4427026](https://api.semanticscholar.org/CorpusID:4427026).

- Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY (2006). ["A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration"](https://doi.org/10.1016%2Fj.cell.2006.03.032). *Cell*. **125** (4): 801–14. [doi](/source/Doi_(identifier)):[10.1016/j.cell.2006.03.032](https://doi.org/10.1016%2Fj.cell.2006.03.032). [PMID](/source/PMID_(identifier)) [16713569](https://pubmed.ncbi.nlm.nih.gov/16713569). [S2CID](/source/S2CID_(identifier)) [13709685](https://api.semanticscholar.org/CorpusID:13709685).

- Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP (2006). "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". *Nat. Biotechnol*. **24** (10): 1285–92. [doi](/source/Doi_(identifier)):[10.1038/nbt1240](https://doi.org/10.1038%2Fnbt1240). [PMID](/source/PMID_(identifier)) [16964243](https://pubmed.ncbi.nlm.nih.gov/16964243). [S2CID](/source/S2CID_(identifier)) [14294292](https://api.semanticscholar.org/CorpusID:14294292).

v t e Enzymes: CO CS and CN ligases (EC 6.1-6.3) 6.1: Carbon-Oxygen Aminoacyl tRNA synthetase Alanine Arginine Asparagine Aspartate Cysteine D-Alanine—poly(phosphoribitol) ligase Glutamate Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Proline Serine Threonine Tryptophan Tyrosine Valine 6.2: Carbon-Sulfur (2,2,3-trimethyl-5-oxocyclopent-3-enyl)acetyl-CoA synthase 2-furoate—CoA ligase 3-alpha,7-alpha-dihydroxy-5-beta-cholestanate—CoA ligase 3-hydroxybenzoate—CoA ligase 3-hydroxypropionyl-CoA synthase 4-chlorobenzoate—CoA ligase 4-Coumarate-CoA ligase 4-hydroxybenzoate—CoA ligase 6-carboxyhexanoate—CoA ligase Acetate—ACP ligase Acetate—CoA ligase (ADP-forming) Acetoacetate—CoA ligase Acetyl—CoA synthetase Acid—CoA ligase (GDP-forming) Anthranilate—CoA ligase Arachidonate—CoA ligase Benzoate—CoA ligase Biotin—CoA ligase (butirosin acyl-carrier protein)—L-glutamate ligase Butyrate—CoA ligase Cholate—CoA ligase Citrate—CoA ligase (citrate (pro-3S)-lyase) ligase Dicarboxylate—CoA ligase Glutarate—CoA ligase Long-chain-fatty-acid—ACP ligase Long-chain-fatty-acid—CoA ligase Malate—CoA ligase Malonate—CoA ligase o-Succinylbenzoate—CoA ligase Oxalate—CoA ligase Phenylacetate—CoA ligase Phytanate—CoA ligase Propionate—CoA ligase Succinate—CoA ligase (ADP-forming) Succinate—CoA ligase (GDP-forming) Succinyl—CoA synthetase trans-Feruloyl—CoA synthase 6.3: Carbon-Nitrogen Glutamine synthetase Ubiquitin ligase Cullin Von Hippel–Lindau tumor suppressor UBE3A Mdm2 Anaphase-promoting complex UBR1 Glutathione synthetase CTP synthetase Adenylosuccinate synthase Argininosuccinate synthase Holocarboxylase synthetase GMP synthase Asparagine synthetase Carbamoyl phosphate synthetase I II Glutamate–cysteine ligase

v t e Enzymes Activity Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis Regulation Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator Classification EC number Enzyme superfamily Enzyme family List of enzymes Kinetics Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics Types EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

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Adapted from the Wikipedia article [WWP2](https://en.wikipedia.org/wiki/WWP2) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/WWP2?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.