2. Academic Validation
  3. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

  • Nature. 2009 Oct 1;461(7264):614-20. doi: 10.1038/nature08356.
Shih-Min A Huang 1,  Yuji M Mishina,  Shanming Liu,  Atwood Cheung,  Frank Stegmeier,  Gregory A Michaud,  Olga Charlat,  Elizabeth Wiellette,  Yue Zhang,  Stephanie Wiessner,  Marc Hild,  Xiaoying Shi,  Christopher J Wilson,  Craig Mickanin,  Vic Myer,  Aleem Fazal,  Ronald Tomlinson,  Fabrizio Serluca,  Wenlin Shao,  Hong Cheng,  Michael Shultz,  Christina Rau,  Markus Schirle,  Judith Schlegl,  Sonja Ghidelli,  Stephen Fawell,  Chris Lu,  Daniel Curtis,  Marc W Kirschner,  Christoph Lengauer,  Peter M Finan,  John A Tallarico,  Tewis Bouwmeester,  Jeffery A Porter,  Andreas Bauer,  Feng Cong
Affiliations

Affiliation

  • 1 Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
PMID: 19759537 DOI: 10.1038/nature08356
Abstract

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.

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