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]

WWP2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesWWP2, AIP2, WWp2-like, WW domain containing E3 ubiquitin protein ligase 2
External IDsOMIM: 602308; MGI: 1914144; HomoloGene: 48490; GeneCards: WWP2; OMA:WWP2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001270453
NM_001270454
NM_001270455
NM_007014
NM_199424

NM_025830

RefSeq (protein)

NP_001257382
NP_001257383
NP_001257384
NP_008945
NP_955456

NP_080106

Location (UCSC)Chr 16: 69.76 – 69.94 MbChr 8: 108.16 – 108.29 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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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

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WWP2 has been shown to interact with SCNN1B[6][9] and ATN1.[10]

Clinical significance

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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

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198373Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031930Ensembl, 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.
  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.
  6. ^ 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.
  7. ^ a b "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.
  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.
  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.
  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.

Further reading

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