Coordinated Action of CK1 Isoforms in Canonical Wnt Signaling

Activation of the Wnt pathway promotes the progressive phosphorylation of coreceptor LRP5/6 (low-density lipoprotein receptor-related proteins 5 and 6), creating a phosphorylated motif that inhibits glycogen synthase kinase 3 beta (GSK-3 beta), which in turn stabilizes beta-catenin, increasing the transcription of beta-catenin target genes. Casein kinase 1 (CK1) kinase family members play a complex role in this pathway, either as inhibitors or as activators. In this report, we have dissected the roles of CK1 isoforms in the early steps of Wnt signaling. CK1 epsilon is constitutively bound to LRP5/6 through its interaction with p120-catenin and E-cadherin or N-cadherin and is activated upon Wnt3a stimulation. CK1 alpha also associates with the LRP5/6/p120-catenin complex but, differently from CK1 epsilon, only after Wnt3a addition. Binding of CK1 alpha is dependent on CK1 epsilon and occurs in a complex with axin. The two protein kinases function sequentially: whereas CK1 epsilon is required for early responses to Wnt3a stimulation, such as recruitment of Dishevelled 2 (Dvl-2), CK1 alpha participates in the release of p120-catenin from the complex, which activates p120-catenin for further actions on this pathway. Another CK1, CK1 gamma, acts at an intermediate level, since it is not necessary for Dvl-2 recruitment but for LRP5/6 phosphorylation at Thr1479 and axin binding. Therefore, our results indicate that CK1 isoforms work coordinately to promote the full response to Wnt stimulus.