Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

• Published in: Nature 2009-10, Vol.461 (7264), p.614-620
• Main Authors: Bauer, Andreas, Myer, Vic, Fawell, Stephen, Ghidelli, Sonja, Shi, Xiaoying, Rau, Christina, Schirle, Markus, Serluca, Fabrizio, Zhang, Yue, Bouwmeester, Tewis, Charlat, Olga, Mickanin, Craig, Curtis, Daniel, Stegmeier, Frank, Hild, Marc, Cong, Feng, Mishina, Yuji M, Wilson, Christopher J, Liu, Shanming, Wiessner, Stephanie, Tomlinson, Ronald, Fazal, Aleem, Shao, Wenlin, Shultz, Michael, Wiellette, Elizabeth, Michaud, Gregory A, Cheng, Hong, Schlegl, Judith, Finan, Peter M, Porter, Jeffery A, Lu, Chris, Cheung, Atwood, Lengauer, Christoph, Tallarico, John A, Kirschner, Marc W, Huang, Shih-Min A
• Format: Article
• Language: English
• Subjects: Axin Protein; beta Catenin - antagonists & inhibitors; beta Catenin - metabolism; Biological and medical sciences; Biotechnology; Cell Division - drug effects; Cell Line; Cell Line, Tumor; Cells; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Fundamental and applied biological sciences. Psychology; Health. Pharmaceutical industry; Heterocyclic Compounds, 3-Ring - pharmacology; Humanities and Social Sciences; Humans; Industrial applications and implications. Economical aspects; Kinases; multidisciplinary; Other active biomolecules; Production of active biomolecules; Properties; Protease inhibitors; Proteasome Endopeptidase Complex - metabolism; Protein Binding; Protein kinases; Proteins; Proteomics; Repressor Proteins - chemistry; Repressor Proteins - metabolism; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Tankyrases - antagonists & inhibitors; Tankyrases - metabolism; Transcription, Genetic - drug effects; Ubiquitin - metabolism; Ubiquitination; Wnt proteins; Wnt Proteins - antagonists & inhibitors; Wnt Proteins - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08356

The stability of the Wnt pathway transcription factor β-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 β-catenin-mediated transcription. XAV939 stimulates β-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. Target for Wnt inhibitors Deregulation of the Wnt pathway, a signalling system involved in embryogenesis and in many other processes in living cells, has been implicated in many cancers, making it an attractive target for anticancer therapies. But while inhibitors of Notch and Hedgehog pathways have reached the clinical trial stage, 'drugable' targets for Wnt inhibitors have proved elusive. Now, using a chemical genetics approach, a small molecule inhibitor of the Wnt pathway has been identified and its direct target and mechanism of action characterized. XAV939 inhibits Wnt signalling with high specificity via the stabilization of axin, a concentration-limiting factor of the β-catenin degradation complex. As well as suggesting new drug targets, this work provides insights into how the Wnt pathway is physiologically regulated. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. Here, a small molecule inhibitor of the Wnt pathway is identified and its direct target and mechanism of action are characterized, providing new insights into the physiological regulation of the Wnt pathway and new possibilities for targeted Wnt pathway therapeutics.