Abstract
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 language | English |
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Pages (from-to) | 485-494 |
Journal | Chemistry & Biology |
Volume | 18 |
Issue number | 4 |
DOIs | |
Publication status | Published - 22 Apr 2011 |