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 WWP2gene.[1][2][3]
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]
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.[6]
References
↑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. PMID9169421.
↑ 2.02.1McDonald 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. PMID12167593.
↑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. PMID11244092.
↑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. PMID9647693.
↑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. PMID21258410. 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. PMID9595660.
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. PMID9647693.
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". J. Biol. Chem. 277 (11): 9307–17. doi:10.1074/jbc.M110443200. PMID11748237.
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. PMID12450395.
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. PMID15252135.
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. PMID15548568.
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. PMID16189514.
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. PMID16713569.
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. PMID16964243.
