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WW domain containing E3 ubiquitin protein ligase 2
Symbols WWP2 ; AIP2; WWp2-like
External IDs OMIM602308 MGI1914144 HomoloGene48490 GeneCards: WWP2 Gene
EC number 6.3.2.-
Species Human Mouse
Entrez 11060 66894
Ensembl ENSG00000198373 ENSMUSG00000031930
UniProt O00308 Q9DBH0
RefSeq (mRNA) NM_001270453 NM_025830
RefSeq (protein) NP_001257382 NP_080106
Location (UCSC) Chr 16:
69.8 – 69.98 Mb
Chr 8:
107.44 – 107.56 Mb
PubMed search [1] [2]

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]


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]


WWP2 has been shown to interact with SCNN1B[2][4] and ATN1.[5]

Clinical significance[edit]

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]


  1. ^ Pirozzi G, McConnell SJ, Uveges AJ, Carter JM, Sparks AB, Kay BK et al. (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. 
  2. ^ 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. 
  3. ^ a b "Entrez Gene: WWP2 WW domain containing E3 ubiquitin protein ligase 2". 
  4. ^ 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. 
  5. ^ Wood JD, Yuan J, Margolis RL, Colomer V, Duan K, Kushi J et al. (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. 
  6. ^ 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. PMID 21258410. Lay summaryBBC News. 

Further reading[edit]