Casein kinase Iε enhances the binding of Dvl-1 to Frat-1 and is essential for Wnt-3a-induced accumulation of β-catenin

We demonstrate that Dvl-1, casein kinase Iepsilon (CKIepsilon), and Frat-1 activate the Wnt signaling pathway cooperatively. The amino acid region 228-250 of Dvl-1 was necessary for its binding to Frat-1, and the interaction of Dvl-1 with Frat-1 was enhanced by CKIepsilon. Coexpression of Dvl-1 and Frat-1 caused accumulation of beta-catenin synergistically in L cells. Both proteins also activated the transcriptional activity of T-cell factor-4 (Tcf-4) synergistically in human embryonic kidney 293 cells, but coexpression of Dvl-1-(Delta228-250), which lacks the amino acid region 228-250 from Dvl-1, and Frat-1 did not. Dvl-1, but not Dvl-1-(Delta228-250), acted synergistically with CKIepsilon to activate Tcf-4. Depletion of CKIepsilon by double-stranded RNA interference in HeLa S3 cells led to the inhibition of Wnt-3a-induced phosphorylation of Dvl and the binding of Dvl-1 to Frat-1. Furthermore, depletion of CKIepsilon reduced the Wnt-3a-induced accumulation of beta-catenin, although it did not affect the basal level of beta-catenin. These results indicate that CKIepsilon-dependent phosphorylation of Dvl enhances the formation of a complex of Dvl-1 with Frat-1 and that this complex leads to the activation of the Wnt signaling pathway.