Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

被引：1691

作者：

Huang, Shih-Min A. ^{[1
]}

Mishina, Yuji M. ^{[1
]}

Liu, Shanming ^{[1
]}

Cheung, Atwood ^{[1
]}

Stegmeier, Frank ^{[1
]}

Michaud, Gregory A. ^{[1
]}

Charlat, Olga ^{[1
]}

Wiellette, Elizabeth ^{[1
]}

Zhang, Yue ^{[1
]}

Wiessner, Stephanie ^{[1
]}

Hild, Marc ^{[1
]}

Shi, Xiaoying ^{[1
]}

Wilson, Christopher J. ^{[1
]}

Mickanin, Craig ^{[1
]}

Myer, Vic ^{[1
]}

Fazal, Aleem ^{[1
]}

Tomlinson, Ronald ^{[1
]}

Serluca, Fabrizio ^{[1
]}

Shao, Wenlin ^{[1
]}

Cheng, Hong ^{[1
]}

Shultz, Michael ^{[1
]}

Rau, Christina ^{[2
]}

Schirle, Markus ^{[2
]}

Schlegl, Judith ^{[2
]}

Ghidelli, Sonja ^{[2
]}

Fawell, Stephen ^{[1
]}

Lu, Chris ^{[1
]}

Curtis, Daniel ^{[1
]}

Kirschner, Marc W. ^{[3
]}

Lengauer, Christoph ^{[1
]}

Finan, Peter M. ^{[1
]}

Tallarico, John A. ^{[1
]}

Bouwmeester, Tewis ^{[2
]}

Porter, Jeffery A. ^{[1
]}

Bauer, Andreas ^{[2
]}

Cong, Feng ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[2] Cellzome AG, D-69117 Heidelberg, Germany

[3] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA

来源：

NATURE | 2009年 / 461卷 / 7264期

关键词：

BETA-CATENIN; COLORECTAL TUMORS; UBIQUITIN LIGASE; REGENERATION; PATHWAY; CANCER; APC; MUTATIONS; TELOMERES; COMPLEX;

D O I：

10.1038/nature08356

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：614 / 620

页数：7

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