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

Surinder M. Soond, Paul G. Smith, Lloyd Wahl, Tracey E. Swingler, Ian M. Clark, Andrew M. Hemmings, Andrew Chantry

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)2127-2135
Number of pages39
JournalBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Volume1832
Issue number12
DOIs
Publication statusPublished - 1 Dec 2013

Keywords

  • TGFβ
  • Smads
  • Ubiquitin ligase
  • Transcription
  • Cancer
  • EMT

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