WWP2

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 that in humans is encoded by the WWP2 gene.[5][6][7]

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
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16q22.1 Start 69,762,306 bp[1] End 69,941,741 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8|8 D3 Start 107,436,365 bp[2] End 107,558,595 bp[2]
Gene ontology Molecular function • RNA polymerase II transcription factor binding • transcription factor binding • ubiquitin-protein transferase activity • GO:0001948 protein binding • transferase activity • GO:1904264, GO:1904822, GO:0090622, GO:0090302 ubiquitin protein ligase activity Cellular component • membrane • ubiquitin ligase complex • extracellular exosome • cell nucleus • cytoplasm • cytosol Biological process • regulation of membrane potential • regulation of ion transmembrane transport • negative regulation of transcription from RNA polymerase II promoter • transcription from RNA polymerase II promoter • negative regulation of sequence-specific DNA binding transcription factor activity • negative regulation of gene expression • cellular protein modification process • negative regulation of protein transport • regulation of potassium ion transmembrane transporter activity • viral entry • GO:0022415 viral process • negative regulation of transcription, DNA-templated • negative regulation of transporter activity • positive regulation of transcription from RNA polymerase II promoter • 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: 107.44 – 107.56 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

This gene encodes a member of the NEDD4-like protein family. The family of proteins is known to possess ubiquitin-protein ligase activity. The encoded protein contains 4 tandem WW domains. 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 with SCNN1B[6][9] and ATN1.[10]

Clinical significance

Full-length WWP2 (WWP2-FL), together with N-terminal, (WWP2-N); C-terminal (WWP2-C) isoforms bind to SMAD proteins. WWP2-FL interacts with SMAD2, SMAD3 and SMAD7 in the TGF-β 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. Hence inhibiting WWP2 may in turn lead to the disabling of an inhibitor that normally controls cell growth and tumorogenesis. In tissue cultures lacking the inhibitor SMAD7, cancer cells spread rapidly, so that silencing WWP2 prevented the spread.[11]

References

1. GRCh38: Ensembl release 89: ENSG00000198373 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000031930 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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". J Biol Chem. 272 (23): 14611–6. doi:10.1074/jbc.272.23.14611. PMID 9169421.
6. 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:10.1152/ajprenal.00080.2002. PMID 12167593.
7. "Entrez Gene: WWP2 WW domain containing E3 ubiquitin protein ligase 2".
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". Neuron. 100 (5): 1097–1115.e15. doi:10.1016/j.neuron.2018.10.008. PMID 30392800.
9. Harvey KF, Dinudom A, Cook DI, Kumar S (March 2001). "The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel". J. Biol. Chem. 276 (11): 8597–601. doi:10.1074/jbc.C000906200. PMID 11244092.
10. 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". Mol. Cell. Neurosci. 11 (3): 149–60. doi:10.1006/mcne.1998.0677. PMID 9647693.
11. Soond SM, Chantry A (2011). "Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT". Oncogene. 30 (21): 2451–62. doi:10.1038/onc.2010.617. PMC 4073228. PMID 21258410. Lay summary – BBC News.

Further reading

• Jonsson AB (1998). "Identification of a human cDNA clone that mediates adherence of pathogenic Neisseria to non-binding cells". FEMS Microbiol. Lett. 162 (1): 25–30. doi:10.1111/j.1574-6968.1998.tb12974.x. PMID 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". Mol. Cell. Neurosci. 11 (3): 149–60. doi:10.1006/mcne.1998.0677. PMID 9647693.
• 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". Mol. Cell. Biol. 20 (22): 8526–35. doi:10.1128/MCB.20.22.8526-8535.2000. PMC 102158. PMID 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" (PDF). J. Biol. Chem. 277 (11): 9307–17. doi:10.1074/jbc.M110443200. PMID 11748237.
• 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:10.1021/bi020125b. PMID 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". Genome Res. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC 442148. PMID 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". J. Cell Sci. 117 (Pt 16): 3679–89. doi:10.1242/jcs.01212. PMID 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:10.1152/ajpcell.00460.2004. PMID 15548568.
• 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, 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. doi:10.1038/nature04209. PMID 16189514.
• 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". Cell. 125 (4): 801–14. doi:10.1016/j.cell.2006.03.032. PMID 16713569.
• 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:10.1038/nbt1240. PMID 16964243.