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Nat Chem Biol
2010 Nov 01;611:829-36. doi: 10.1038/nchembio.453.
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Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α.
Thorne CA, Hanson AJ, Schneider J, Tahinci E, Orton D, Cselenyi CS, Jernigan KK, Meyers KC, Hang BI, Waterson AG, Kim K, Melancon B, Ghidu VP, Sulikowski GA, LaFleur B, Salic A, Lee LA, Miller DM, Lee E.
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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 (EC(50) 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.
Aoki,
Nuclear endpoint of Wnt signaling: neoplastic transformation induced by transactivating lymphoid-enhancing factor 1.
1999, Pubmed
Aoki,
Nuclear endpoint of Wnt signaling: neoplastic transformation induced by transactivating lymphoid-enhancing factor 1.
1999,
Pubmed Barker,
Mining the Wnt pathway for cancer therapeutics.
2006,
Pubmed Bhanot,
A new member of the frizzled family from Drosophila functions as a Wingless receptor.
1996,
Pubmed Bidère,
Casein kinase 1alpha governs antigen-receptor-induced NF-kappaB activation and human lymphoma cell survival.
2009,
Pubmed Chen,
Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer.
2009,
Pubmed Clevers,
Wnt/beta-catenin signaling in development and disease.
2006,
Pubmed Cselenyi,
LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3's phosphorylation of beta-catenin.
2008,
Pubmed
,
Xenbase de la Roche,
The function of BCL9 in Wnt/beta-catenin signaling and colorectal cancer cells.
2008,
Pubmed De Robertis,
Dorsal-ventral patterning and neural induction in Xenopus embryos.
2004,
Pubmed
,
Xenbase Downey,
Efficacy of pyrvinium pamoate against Cryptosporidium parvum infection in vitro and in a neonatal mouse model.
2008,
Pubmed Esumi,
Antitumor activity of pyrvinium pamoate, 6-(dimethylamino)-2-[2-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)ethenyl]-1-methyl-quinolinium pamoate salt, showing preferential cytotoxicity during glucose starvation.
2004,
Pubmed Faux,
Restoration of full-length adenomatous polyposis coli (APC) protein in a colon cancer cell line enhances cell adhesion.
2004,
Pubmed Gao,
Casein kinase I phosphorylates and destabilizes the beta-catenin degradation complex.
2002,
Pubmed
,
Xenbase Gille,
ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation.
1995,
Pubmed Gleason,
Activation of Wnt signaling bypasses the requirement for RTK/Ras signaling during C. elegans vulval induction.
2002,
Pubmed Goenka,
Selective potentiation of Stat-dependent gene expression by collaborator of Stat6 (CoaSt6), a transcriptional cofactor.
2006,
Pubmed Hämmerlein,
A second protein kinase CK1-mediated step negatively regulates Wnt signalling by disrupting the lymphocyte enhancer factor-1/beta-catenin complex.
2005,
Pubmed He,
Identification of c-MYC as a target of the APC pathway.
1998,
Pubmed Hempelmann,
Hemozoin biocrystallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors.
2007,
Pubmed Huang,
Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.
2009,
Pubmed Inoki,
TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth.
2006,
Pubmed Jho,
Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway.
2002,
Pubmed Jones,
Non-competitive androgen receptor inhibition in vitro and in vivo.
2009,
Pubmed Kinzler,
Identification of FAP locus genes from chromosome 5q21.
1991,
Pubmed Klaus,
Wnt signalling and its impact on development and cancer.
2008,
Pubmed Knight,
Features of selective kinase inhibitors.
2005,
Pubmed Knippschild,
The casein kinase 1 family: participation in multiple cellular processes in eukaryotes.
2005,
Pubmed Kofron,
Wnt11/beta-catenin signaling in both oocytes and early embryos acts through LRP6-mediated regulation of axin.
2007,
Pubmed
,
Xenbase Korswagen,
The Axin-like protein PRY-1 is a negative regulator of a canonical Wnt pathway in C. elegans.
2002,
Pubmed Kramps,
Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex.
2002,
Pubmed Larabell,
Establishment of the dorso-ventral axis in Xenopus embryos is presaged by early asymmetries in beta-catenin that are modulated by the Wnt signaling pathway.
1997,
Pubmed
,
Xenbase Lewis,
The genetics of levamisole resistance in the nematode Caenorhabditis elegans.
1980,
Pubmed Liu,
Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism.
2002,
Pubmed
,
Xenbase Lustig,
Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors.
2002,
Pubmed Matschinsky,
Assessing the potential of glucokinase activators in diabetes therapy.
2009,
Pubmed Mithani,
Smad3 has a critical role in TGF-beta-mediated growth inhibition and apoptosis in colonic epithelial cells.
2004,
Pubmed Miyamoto,
The kinesin Eg5 drives poleward microtubule flux in Xenopus laevis egg extract spindles.
2004,
Pubmed
,
Xenbase Parker,
Pygopus, a nuclear PHD-finger protein required for Wingless signaling in Drosophila.
2002,
Pubmed Pierre,
Multisite phosphorylation of tau proteins from rat brain.
1983,
Pubmed Polakis,
Wnt signaling and cancer.
2000,
Pubmed Price,
CKI, there's more than one: casein kinase I family members in Wnt and Hedgehog signaling.
2006,
Pubmed Rosenbluth,
A gene signature-based approach identifies mTOR as a regulator of p73.
2008,
Pubmed Salic,
Control of beta-catenin stability: reconstitution of the cytoplasmic steps of the wnt pathway in Xenopus egg extracts.
2000,
Pubmed
,
Xenbase Sparks,
Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer.
1998,
Pubmed Thompson,
A new nuclear component of the Wnt signalling pathway.
2002,
Pubmed Tolwinski,
Wg/Wnt signal can be transmitted through arrow/LRP5,6 and Axin independently of Zw3/Gsk3beta activity.
2003,
Pubmed Whangbo,
A Wnt signaling system that specifies two patterns of cell migration in C. elegans.
1999,
Pubmed Xu,
Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair.
2004,
Pubmed Yamamoto,
Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability.
1999,
Pubmed Yu,
Pyrvinium targets the unfolded protein response to hypoglycemia and its anti-tumor activity is enhanced by combination therapy.
2008,
Pubmed
