WWP2

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)
End	69,941,741 bp
Gene location (Mouse)
Chr.	Chromosome 8 (mouse)
End	108,285,227 bp
RNA expression pattern
	Top expressed in
	Top expressed in
	More reference expression data
	n/a
Gene ontology
Molecular function
Cellular component
Biological process
	Sources:Amigo / QuickGO
Orthologs
	11060
	66894
	ENSG00000198373
	ENSMUSG00000031930
	O00308
	Q9DBH0
	NM_001270453; NM_001270454; NM_001270455; NM_007014; NM_199424
	NM_025830
	NP_001257382; NP_001257383; NP_001257384; NP_008945; NP_955456
	NP_080106
	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 that in humans is encoded by the WWP2 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 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

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000198373 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000031930 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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.
^ ^a ^b 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.
^ ^a ^b "Entrez Gene: WWP2 WW domain containing E3 ubiquitin protein ligase 2".
^ 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.
^ 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.
^ 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. S2CID 20003277.
^
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 in: Gallagher J (January 24, 2011). "Blocking a gene stops cancer cells spreading". BBC News.

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. S2CID 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". 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. S2CID 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: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. hdl:2440/9578. 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. S2CID 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, 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:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 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". Cell. 125 (4): 801–14. doi:10.1016/j.cell.2006.03.032. PMID 16713569. S2CID 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:10.1038/nbt1240. PMID 16964243. S2CID 14294292.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000198373 – Ensembl, May 2017

[refGRCm38Ensembl-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.

[pmid9169421-5] 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.

[pmid12167593-6] 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.

[entrez-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.

[pmid11244092-9] 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.

[pmid9647693-10] 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. S2CID 20003277.

[Soond_2011-11] 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 in: Gallagher J (January 24, 2011). "Blocking a gene stops cancer cells spreading". BBC News.

[12] Lay summary in: Gallagher J (January 24, 2011). "Blocking a gene stops cancer cells spreading". BBC News.

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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	Succinyl coenzyme A synthetase Acetyl—CoA synthetase Long-chain-fatty-acid—CoA ligase
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

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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