Journal article
Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α
Nature chemical biology, Vol.6(11), pp.829-836
11/01/2010
DOI: 10.1038/NCHEMBIO.453
PMCID: PMC3681608
PMID: 20890287
Abstract
Wnt/beta-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 beta-catenin turnover, we identified an FDA-approved drug, pyrvinium, as a potent inhibitor of Wnt signaling (EC(50) of similar to 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 1 alpha (CK1 alpha) kinase activity. CK1 alpha knockdown abrogates the effects of pyrvinium on the Wnt pathway. In addition to its effects on Axin and beta-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 beta-catenin inhibits both Wnt signaling and proliferation. Our findings reveal allosteric activation of CK1 alpha as an effective mechanism to inhibit Wnt signaling and highlight a new strategy for targeted therapeutics directed against the Wnt pathway.
Details
- Title: Subtitle
- Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α
- Creators
- Curtis A. Thorne - Vanderbilt UniversityAlison J. Hanson - Vanderbilt UniversityJudsen Schneider - Vanderbilt UniversityEmilios Tahinci - Vanderbilt UniversityDarren Orton - Vanderbilt UniversityChristopher S. Cselenyi - Vanderbilt UniversityKristin K. Jernigan - Vanderbilt UniversityKelly C. Meyers - Vanderbilt UniversityBrian I. Hang - Vanderbilt UniversityAlex G. Waterson - Vanderbilt UniversityKwangho Kim - Vanderbilt UniversityBruce Melancon - Vanderbilt UniversityVictor P. Ghidu - Vanderbilt UniversityGary A. Sulikowski - Vanderbilt UniversityBonnie LaFleur - Vanderbilt UniversityAdrian Salic - Harvard UniversityLaura A. Lee - Vanderbilt UniversityDavid M. Miller - Vanderbilt UniversityEthan Lee - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- Nature chemical biology, Vol.6(11), pp.829-836
- DOI
- 10.1038/NCHEMBIO.453
- PMID
- 20890287
- PMCID
- PMC3681608
- NLM abbreviation
- Nat Chem Biol
- ISSN
- 1552-4450
- eISSN
- 1552-4469
- Publisher
- Springer Nature
- Number of pages
- 8
- Grant note
- 0615279B; 0615162B / American Heart Association (AHA); American Heart Association T32 GM007347 / US National Institute of General Medical Studies RSG-05-126-01; IRG-58-009-46 / American Cancer Society GI SPORE P50 CA95103 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 5 T 32 DK007563 / Molecular Endocrinology 5 T32 HD007502 / Training Program in Developmental Biology (National Institute of Child Health and Human Development); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) Pew Scholarship in the Biomedical Sciences 0615279B; 0615162B / American Heart Association 5U01 CA084239 / Mouse Models of Human Cancers Consortium 1 R01 GM081635-01; 1 R01 NS26115; T32 CA09592 / US National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 11/01/2010
- Academic Unit
- Psychiatry
- Record Identifier
- 9984823122802771
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