2009-10-05Nature：新的Wnt信号通路药物靶点

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来源 Nature 2009-10-5 14:55:05 + }/ A5 d2 ~. j4 q

0 W  g! V7 l% _Nature：新的Wnt信号通路药物靶点
# J. A' K. {# d; s' UWnt信号通路（胚胎形成及活细胞中很多其他过程中所涉及的一个信号系统）的失调已被发现与很多癌症有关，这使得它成为抗癌疗法的一个有吸引力的目标。但虽然Notch和Hedgehog信号通路的抑制药物已进入临床试验阶段，Wnt抑制药物可发挥作用的目标却难以确定。* u: W- _  f/ p  ^% C

1 ?& s+ Y0 l" g) D现在，研究人员利用一种化学遗传学方法发现了Wnt信号通路的一个小分子抑制药物，并且对其直接目标和作用机制做了定性。XAV939能通过稳定Axin（Beta-catenin降解复合物的一个浓度限制因子）高效抑制Wnt信号作用。这项工作除了提出新的药物作用目标外，还为了解Wnt信号通路的生理调控方式提供了见解。
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Nature 461, 614-620 (1 October 2009) | doi:10.1038/nature08356. I5 V& f- t0 }# K
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Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling
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+ ^* \1 Z$ j5 G! K9 iShih-Min A. Huang1, Yuji M. Mishina1, Shanming Liu1, Atwood Cheung1, Frank Stegmeier1, Gregory A. Michaud1, Olga Charlat1, Elizabeth Wiellette1, Yue Zhang1, Stephanie Wiessner1, Marc Hild1, Xiaoying Shi1, Christopher J. Wilson1, Craig Mickanin1, Vic Myer1, Aleem Fazal1, Ronald Tomlinson1, Fabrizio Serluca1, Wenlin Shao1, Hong Cheng1, Michael Shultz1, Christina Rau2, Markus Schirle2,4, Judith Schlegl2, Sonja Ghidelli2, Stephen Fawell1, Chris Lu1, Daniel Curtis1, Marc W. Kirschner3, Christoph Lengauer1,4, Peter M. Finan1, John A. Tallarico1, Tewis Bouwmeester2,4, Jeffery A. Porter1, Andreas Bauer2,4 & Feng Cong1- u! _) j, ]& X. t; s

" Z, Q) P  y1 _/ f, d1 Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
5 G; s4 ]: G$ r" l# s2 Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
! n0 Z1 W- @, ]$ b$ c( `! j3 qDepartment of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
4 P6 ?- Z5 Z/ t: d2 D3 Present addresses: Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland (T.B., A.B.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA (M. Sc.); Sanofi-Aventis, 94403 Vitry-sur-Seine, France (C.L.).. l: U2 C7 X0 q; ?, F
Correspondence to: Feng Cong1 Correspondence and requests for materials should be addressed to F.C.
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% T9 o& n! x5 Z( C. ~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.

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