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Inhibition of Wnt/β-catenin Signaling by p38 MAP Kinase Inhibitors Is Explained by Cross-Reactivity With Casein Kinase Iδ/ɛ

Inhibition of Wnt/β-catenin Signaling by p38 MAP Kinase Inhibitors Is Explained by Cross-Reactivity With Casein Kinase Iδ/ɛ

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

Chem Biol. 2011 Apr 22;18(4):485-94.

PMID: 21513885

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP303162790	TAK-715		303162-79-0	Price

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