Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

Nature. 2009 Oct 1;461(7264):614-20. doi: 10.1038/nature08356. Epub 2009 Sep 16.


The stability of the Wnt pathway transcription factor beta-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.

MeSH terms

  • Axin Protein
  • Cell Division / drug effects
  • Cell Line
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / metabolism
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Proteomics
  • Repressor Proteins / chemistry
  • Repressor Proteins / metabolism*
  • Signal Transduction / drug effects*
  • Tankyrases / antagonists & inhibitors*
  • Tankyrases / metabolism
  • Transcription, Genetic / drug effects
  • Ubiquitin / metabolism
  • Ubiquitination
  • Wnt Proteins / antagonists & inhibitors*
  • Wnt Proteins / metabolism
  • beta Catenin / antagonists & inhibitors
  • beta Catenin / metabolism


  • Axin Protein
  • Heterocyclic Compounds, 3-Ring
  • Repressor Proteins
  • Ubiquitin
  • Wnt Proteins
  • XAV939
  • beta Catenin
  • Tankyrases
  • Proteasome Endopeptidase Complex