title: Inhibition of Wnt/β-catenin signaling by p38 MAP kinase inhibitors is explained by cross-reactivity with casein kinase Iδ/ɛ.
abstract: Wnt/β-catenin signaling plays essential roles in embryonic development, adult stem cell maintenance, and disease. Screening of a small molecule compound library with a β-galactosidase fragment complementation assay measuring β-catenin nuclear entry revealed TAK-715 and AMG-548 as inhibitors of Wnt-3a-stimulated β-catenin signaling. TAK-715 and AMG-548 are inhibitors of p38 mitogen-activated protein kinase, which has been suggested to regulate activation of Wnt/β-catenin signaling. However, two highly selective and equally potent p38 inhibitors, VX-745 and Scio-469, did not inhibit Wnt-3a-stimulated β-catenin signaling. Profiling of TAK-715 and AMG-548 against a panel of over 200 kinases revealed cross-reactivity with casein kinase Iδ and ɛ, which are known activators of Wnt/β-catenin signaling. Our data demonstrate that this cross-reactivity accounts for the inhibition of β-catenin signaling by TAK-715 and AMG-548 and argue against a role of p38 in Wnt/β-catenin signaling.
authors.affiliation: Merck Research Laboratories, Molecular Pharmacology & DMPK, 5340 BH Oss, The Netherlands.
authors.forename: Folkert
authors.initials: F
authors.lastname: Verkaar
authors.forename: Antoon A
authors.initials: AA
authors.lastname: van der Doelen
authors.forename: Jos F M
authors.initials: JF
authors.lastname: Smits
authors.forename: W Matthijs
authors.initials: WM
authors.lastname: Blankesteijn
authors.forename: Guido J R
authors.initials: GJ
authors.lastname: Zaman
mesh_terms: D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology; D048149:Casein Kinase 1 epsilon / Q000378:metabolism; D047389:Casein Kinase I / Q000378:metabolism*; D048148:Casein Kinase Idelta / Q000378:metabolism; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013379:Substrate Specificity; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000893:Anti-Inflammatory Agents; D047428:Protein Kinase Inhibitors; D051153:Wnt Proteins; D051176:beta Catenin; D048149:Casein Kinase 1 epsilon; D047389:Casein Kinase I; D048148:Casein Kinase Idelta; D048051:p38 Mitogen-Activated Protein Kinases