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Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

Huang, Shih-Min and Mishina, Yuji and Liu, Shanming and Cheung, Atwood and Stegmeier, Frank and Michaud, Gregory and Charlat, Olga and Wiellette, Elizabeth and Zhang, Yue and Wiessner, Stephanie and Hild, Marc and Shi, Xiaoying and Wilson, Christopher and Mickanin, Craig and Myer, Vic and Fazal, Aleem and Tomlinson, Ronald and Serluca, Fabrizio and Shao, Wenlin and Cheng, Hong and Shultz, Michael and Rau, Christina and Schirle, Markus and Schlegl, Judith and Ghidelli, Sonja and Fawell, Stephen and Lu, Chris and Curtis, Daniel and Kirschner, Marc W. and Lengauer, Christoph and Finan, Peter and Tallarico, John and Bouwmeester, Antonius and Porter, Jeffrey and Bauer, Andreas and Cong, Feng (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature, 461 (7264). pp. 614-620. ISSN 0028-0836

Abstract

The stability of the Wnt pathway transcription factor -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 -catenin-mediated transcription. XAV939 stimulates -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.

Item Type: Article
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Additional Information: Author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2067

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