Inhibition of the Wnt/beta-catenin pathway by the WWOX tumor suppressor protein

Oncogene. 2009 Jul 16;28(28):2569-80. doi: 10.1038/onc.2009.120. Epub 2009 May 25.


The WWOX gene encodes a candidate tumor suppressor protein (WWOX) implicated in a variety of human diseases such as cancer. To better understand the molecular mechanisms of WWOX action, we investigated novel partners of this protein. Using the two-hybrid system and a coimmunoprecipitation assay, we observed a physical association between WWOX and the Dishevelled protein (Dvl) family signaling elements involved in the Wnt/beta-catenin pathway. We found that enforced WWOX expression inhibited, and inhibition of endogenous WWOX expression stimulated the transcriptional activity of the Wnt/beta-catenin pathway. Inhibition of endogenous WWOX expression also enhanced the effect of Wnt-3a on beta-catenin stability. Moreover, we observed the sequestration of Dvl-2 wild type and Dvl-2NESm, a mutated form of Dvl-2 predominantly localized in the nucleus, in the cytoplasm compartment by WWOX. Our results indicate that WWOX is a novel inhibitor of the Wnt/beta-catenin pathway. WWOX would act, at least in part, by preventing the nuclear import of the Dvl proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Compartmentation
  • Cell Line
  • Cytoplasm / metabolism
  • Dishevelled Proteins
  • Genes, Tumor Suppressor*
  • Humans
  • Immunoprecipitation
  • LDL-Receptor Related Proteins / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Oxidoreductases / physiology*
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Signal Transduction
  • Transcription, Genetic
  • Tumor Suppressor Proteins / physiology*
  • Two-Hybrid System Techniques
  • WW Domain-Containing Oxidoreductase
  • Wnt Proteins / antagonists & inhibitors*
  • Wnt Proteins / metabolism
  • beta Catenin / antagonists & inhibitors*
  • beta Catenin / metabolism


  • Adaptor Proteins, Signal Transducing
  • DVL2 protein, human
  • Dishevelled Proteins
  • LDL-Receptor Related Proteins
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Phosphoproteins
  • Tumor Suppressor Proteins
  • Wnt Proteins
  • beta Catenin
  • Oxidoreductases
  • WW Domain-Containing Oxidoreductase
  • WWOX protein, human