Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

Shih-Min A. Huang, 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 and Feng Cong ()
Additional contact information
Shih-Min A. Huang: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Yuji M. Mishina: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Shanming Liu: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Atwood Cheung: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Frank Stegmeier: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Gregory A. Michaud: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Olga Charlat: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Elizabeth Wiellette: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Yue Zhang: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Stephanie Wiessner: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Marc Hild: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Xiaoying Shi: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Christopher J. Wilson: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Craig Mickanin: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Vic Myer: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Aleem Fazal: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Ronald Tomlinson: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Fabrizio Serluca: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Wenlin Shao: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Hong Cheng: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Michael Shultz: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Christina Rau: Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
Markus Schirle: Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
Judith Schlegl: Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
Sonja Ghidelli: Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
Stephen Fawell: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Chris Lu: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Daniel Curtis: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Marc W. Kirschner: Harvard Medical School, Boston, Massachusetts 02115, USA
Christoph Lengauer: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Peter M. Finan: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
John A. Tallarico: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Tewis Bouwmeester: Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
Jeffery A. Porter: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Andreas Bauer: Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
Feng Cong: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

Nature, 2009, vol. 461, issue 7264, 614-620

Abstract: Abstract 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.

Date: 2009
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DOI: 10.1038/nature08356

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