Biology:WWP2
 Generic protein structure example |
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.[1][2][3]
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.[3] 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.[4]
Interactions
WWP2 has been shown to interact with SCNN1B[2][5] and ATN1.[6]
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.[7]
References
- ↑ "Identification of novel human WW domain-containing proteins by cloning of ligand targets". J Biol Chem 272 (23): 14611–6. Jun 1997. doi:10.1074/jbc.272.23.14611. PMID 9169421.
- ↑ 2.0 2.1 "Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel". Am J Physiol Renal Physiol 283 (3): F431–6. Aug 2002. doi:10.1152/ajprenal.00080.2002. PMID 12167593.
- ↑ 3.0 3.1 "Entrez Gene: WWP2 WW domain containing E3 ubiquitin protein ligase 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=11060.
- ↑ "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. December 2018. doi:10.1016/j.neuron.2018.10.008. PMID 30392800.
- ↑ "The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel". J. Biol. Chem. 276 (11): 8597–601. March 2001. doi:10.1074/jbc.C000906200. PMID 11244092.
- ↑ "Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins". Mol. Cell. Neurosci. 11 (3): 149–60. June 1998. doi:10.1006/mcne.1998.0677. PMID 9647693.
- ↑ "Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT". Oncogene 30 (21): 2451–62. 2011. doi:10.1038/onc.2010.617. PMID 21258410.
- Lay summary in: "Blocking a gene stops cancer cells spreading". January 24, 2011. https://www.bbc.co.uk/news/health-12254242.
Further reading
- "Identification of a human cDNA clone that mediates adherence of pathogenic Neisseria to non-binding cells.". FEMS Microbiol. Lett. 162 (1): 25–30. 1998. doi:10.1111/j.1574-6968.1998.tb12974.x. PMID 9595660.
- "Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins.". Mol. Cell. Neurosci. 11 (3): 149–60. 1998. doi:10.1006/mcne.1998.0677. PMID 9647693.
- "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. 2000. doi:10.1128/MCB.20.22.8526-8535.2000. PMID 11046148.
- "N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein.". J. Biol. Chem. 277 (11): 9307–17. 2002. doi:10.1074/jbc.M110443200. PMID 11748237. https://espace.library.uq.edu.au/view/UQ:63244/UQ63244_OA.pdf.
- "Adenovirus protein involved in virus internalization recruits ubiquitin-protein ligases.". Biochemistry 41 (48): 14299–305. 2003. doi:10.1021/bi020125b. PMID 12450395.
- "Functional proteomics mapping of a human signaling pathway.". Genome Res. 14 (7): 1324–32. 2004. doi:10.1101/gr.2334104. PMID 15231748.
- "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. 2005. doi:10.1242/jcs.01212. PMID 15252135.
- "Molecular determinants of voltage-gated sodium channel regulation by the Nedd4/Nedd4-like proteins.". Am. J. Physiol., Cell Physiol. 288 (3): C692–701. 2005. doi:10.1152/ajpcell.00460.2004. PMID 15548568.
- "Towards a proteome-scale map of the human protein-protein interaction network.". Nature 437 (7062): 1173–8. 2005. doi:10.1038/nature04209. PMID 16189514. Bibcode: 2005Natur.437.1173R.
- "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.". Cell 125 (4): 801–14. 2006. doi:10.1016/j.cell.2006.03.032. PMID 16713569.
- "A probability-based approach for high-throughput protein phosphorylation analysis and site localization.". Nat. Biotechnol. 24 (10): 1285–92. 2006. doi:10.1038/nbt1240. PMID 16964243.
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