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; Feng Cong

doi:10.1038/nature08356

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 ChengMichael 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

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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.

Original language	English (US)
Pages (from-to)	614-620
Number of pages	7
Journal	Nature
Volume	461
Issue number	7264
DOIs	https://doi.org/10.1038/nature08356
State	Published - Oct 1 2009
Externally published	Yes

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Huang, S. M. A., Mishina, Y. M., Liu, S., Cheung, A., Stegmeier, F., Michaud, G. A., Charlat, O., Wiellette, E., Zhang, Y., Wiessner, S., Hild, M., Shi, X., Wilson, C. J., Mickanin, C., Myer, V., Fazal, A., Tomlinson, R., Serluca, F., Shao, W., ... Cong, F. (2009). Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature, 461(7264), 614-620. https://doi.org/10.1038/nature08356

Huang, SMA, Mishina, YM, Liu, S, Cheung, A, Stegmeier, F, Michaud, GA, Charlat, O, Wiellette, E, Zhang, Y, Wiessner, S, Hild, M, Shi, X, Wilson, CJ, Mickanin, C, Myer, V, Fazal, A, Tomlinson, R, Serluca, F, Shao, W, Cheng, H, Shultz, M, Rau, C, Schirle, M, Schlegl, J, Ghidelli, S, Fawell, S, Lu, C, Curtis, D, Kirschner, MW, Lengauer, C, Finan, PM, Tallarico, JA, Bouwmeester, T, Porter, JA, Bauer, A & Cong, F 2009, 'Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling', Nature, vol. 461, no. 7264, pp. 614-620. https://doi.org/10.1038/nature08356

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title = "Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling",

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.",

author = "Huang, {Shih Min A} and Mishina, {Yuji M.} and Shanming Liu and Atwood Cheung and Frank Stegmeier and Michaud, {Gregory A.} and Olga Charlat and Elizabeth Wiellette and Yue Zhang and Stephanie Wiessner and Marc Hild and Xiaoying Shi and Wilson, {Christopher J.} and Craig Mickanin and Vic Myer and Aleem Fazal and Ronald Tomlinson and Fabrizio Serluca and Wenlin Shao and Hong Cheng and Michael Shultz and Christina Rau and Markus Schirle and Judith Schlegl and Sonja Ghidelli and Stephen Fawell and Chris Lu and Daniel Curtis and Kirschner, {Marc W.} and Christoph Lengauer and Finan, {Peter M.} and Tallarico, {John A.} and Tewis Bouwmeester and Porter, {Jeffery A.} and Andreas Bauer and Feng Cong",

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AU - Mishina, Yuji M.

AU - Liu, Shanming

AU - Cheung, Atwood

AU - Stegmeier, Frank

AU - Michaud, Gregory A.

AU - Charlat, Olga

AU - Wiellette, Elizabeth

AU - Zhang, Yue

AU - Wiessner, Stephanie

AU - Hild, Marc

AU - Shi, Xiaoying

AU - Wilson, Christopher J.

AU - Mickanin, Craig

AU - Myer, Vic

AU - Fazal, Aleem

AU - Tomlinson, Ronald

AU - Serluca, Fabrizio

AU - Shao, Wenlin

AU - Cheng, Hong

AU - Shultz, Michael

AU - Rau, Christina

AU - Schirle, Markus

AU - Schlegl, Judith

AU - Ghidelli, Sonja

AU - Fawell, Stephen

AU - Lu, Chris

AU - Curtis, Daniel

AU - Kirschner, Marc W.

AU - Lengauer, Christoph

AU - Finan, Peter M.

AU - Tallarico, John A.

AU - Bouwmeester, Tewis

AU - Porter, Jeffery A.

AU - Bauer, Andreas

AU - Cong, Feng

PY - 2009/10/1

Y1 - 2009/10/1

N2 - 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.

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Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

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