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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
	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
	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
	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.
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