Inhibition of Wnt/beta-Catenin Signaling by p38 MAP Kinase Inhibitors Is Explained by Cross-Reactivity with Casein Kinase I delta/epsilon

Folkert Verkaar, Antoon A. van der Doelen, Jos F. M. Smits, W. Matthijs Blankesteijn, Guido J. R. Zaman*

*Corresponding author for this work

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Wnt/beta-catenin signaling plays essential roles in embryonic development, adult stem cell maintenance, and disease. Screening of a small molecule compound library with a beta-galactosidase fragment complementation assay measuring beta-catenin nuclear entry revealed TAK-715 and AMG-548 as inhibitors of Wnt-3a-stimulated beta-catenin signaling. TAK-715 and AMG-548 are inhibitors of p38 mitogen-activated protein kinase, which has been suggested to regulate activation of Wnt/beta-catenin signaling. However, two highly selective and equally potent p38 inhibitors, VX-745 and Scio-469, did not inhibit Wnt-3a-stimulated beta-catenin signaling. Profiling of TAK-715 and AMG-548 against a panel of over 200 kinases revealed cross-reactivity with casein kinase I delta and epsilon, which are known activators of Wnt/beta-catenin signaling. Our data demonstrate that this cross-reactivity accounts for the inhibition of beta-catenin signaling by TAK-715 and AMG-548 and argue against a role of p38 in Wnt/beta-catenin signaling.
Original languageEnglish
Pages (from-to)485-494
JournalChemistry & Biology
Issue number4
Publication statusPublished - 22 Apr 2011

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