Novel WWP2 ubiquitin ligase isoforms as potential prognostic markers and molecular targets in cancer

Soond, Surinder M., Smith, Paul G., Wahl, Lloyd, Swingler, Tracey E., Clark, Ian M., Hemmings, Andrew M. and Chantry, Andrew (2013) Novel WWP2 ubiquitin ligase isoforms as potential prognostic markers and molecular targets in cancer. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1832 (12). pp. 2127-2135. ISSN 0925-4439

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Abstract

The WWP2 E3 ubiquitin ligase has previously been shown to regulate TGFβ/Smad signalling activity linked to epithelial–mesenchymal transition (EMT). Whilst inhibitory I-Smad7 was found to be the preferred substrate for full-length WWP2-FL and a WWP2-C isoform, WWP2-FL also formed a stable complex with an N-terminal WWP2 isoform (WWP2-N) in the absence of TGFβ, and rapidly stimulated activating Smad2/3 turnover. Here, using stable knockdown experiments we show that specific depletion of individual WWP2 isoforms impacts differentially on Smad protein levels, and in WWP2-N knockdown cells we unexpectedly find spontaneous expression of the EMT marker vimentin. Re-introduction of WWP2-N into WWP2-N knockout cells also repressed TGFβ-induced vimentin expression. In support of the unique role for WWP2-N in regulating TGFβ/Smad functional activity, we then show that a novel V717M-WWP2 mutant in the MZ7-mel melanoma cell line forms a stable complex with the WWP2-N isoform and promotes EMT by stabilizing Smad3 protein levels. Finally, we report the first analysis of WWP2 expression in cancer cDNA panel arrays using WWP2 isoform-specific probes and identify unique patterns of WWP2 isoform abundance associated with early/advanced disease stages. WWP2-N is significantly downregulated in stage IIIC melanoma and up-regulated in stage II/III prostate cancer, and we also find isolated examples of WWP2-FL and WWP2-C overexpression in early-stage breast cancer. Together, these data suggest that individual WWP2 isoforms, and particularly WWP2-N, could play central roles in tumourigenesis linked to aberrant TGFβ-dependent signalling function, and also have potential as both prognostic markers and molecular therapeutic targets.

Item Type: Article
Uncontrolled Keywords: tgfβ,smads,ubiquitin ligase,transcription,cancer,emt
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Science > School of Chemistry
Faculty of Science
Depositing User: Pure Connector
Date Deposited: 25 Nov 2013 16:28
Last Modified: 21 Apr 2020 22:17
URI: https://ueaeprints.uea.ac.uk/id/eprint/44909
DOI: 10.1016/j.bbadis.2013.08.001

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