Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α.
Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α.
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DOI：
10.1038/nchembio.453
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发表时间：
2010-11
影响因子：
14.8
通讯作者：
Lee, Ethan
中科院分区：
文献类型：
--
作者：
Thorne, Curtis A.;Hanson, Alison J.;Schneider, Judsen;Tahinci, Emilios;Orton, Darren;Cselenyi, Christopher S.;Jernigan, Kristin K.;Meyers, Kelly C.;Hang, Brian I.;Waterson, Alex G.;Kim, Kwangho;Melancon, Bruce;Ghidu, Victor P.;Sulikowski, Gary A.;LaFleur, Bonnie;Salic, Adrian;Lee, Laura A.;Miller, David M., III;Lee, Ethan
Wnt/β-catenin信号传导在后生动物发育、干细胞维持和人类疾病中起着关键作用。使用非洲爪蟾卵提取物筛选既稳定Axin又促进β-连环蛋白周转的化合物，我们鉴定了FDA批准的药物pyrvinium作为Wnt信号传导的有效抑制剂（EC 50约为10 nM）。我们表明，pyrvinium结合所有酪蛋白激酶1（CK 1）家族成员在体外低纳摩尔浓度和pyrvinium选择性增强酪蛋白激酶1α（CK 1 α）激酶活性。CK 1 α敲低消除了pyrvinium对Wnt途径的影响。除了其对轴蛋白和β-连环蛋白水平的影响之外，pyrvinium还促进Pygopus（一种Wnt转录组分）的降解。吡咯烷铵处理具有结肠腺瘤性息肉病（APC）或β-连环蛋白基因突变的结肠癌细胞抑制Wnt信号传导和增殖。我们的研究结果揭示了CK 1 α的变构激活是抑制Wnt信号传导的有效机制，并强调了针对Wnt通路的靶向治疗的新策略。
Wnt/β-catenin signaling is critically involved in metazoan development, stem cell maintenance and human disease. Using Xenopus laevis egg extract to screen for compounds that both stabilize Axin and promote β-catenin turnover, we identified an FDA-approved drug, pyrvinium, as a potent inhibitor of Wnt signaling (EC50 of ~10 nM). We show pyrvinium binds all casein kinase 1 (CK1) family members in vitro at low nanomolar concentrations and pyrvinium selectively potentiates casein kinase 1α (CK1α) kinase activity. CK1α knockdown abrogates the effects of pyrvinium on the Wnt pathway. In addition to its effects on Axin and β-catenin levels, pyrvinium promotes degradation of Pygopus, a Wnt transcriptional component. Pyrvinium treatment of colon cancer cells with mutation of the gene for adenomatous polyposis coli (APC) or β-catenin inhibits both Wnt signaling and proliferation. Our findings reveal allosteric activation of CK1α as an effective mechanism to inhibit Wnt signaling and highlight a new strategy for targeted therapeutics directed against the Wnt pathway.
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影响因子：
64.5
作者：
Kramps, T;Peter, O;Basler, K
通讯作者：
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