CKIɛ/discs overgrown Promotes Both Wnt-Fz/β-Catenin and Fz/PCP Signaling in Drosophila

The related Wnt-Frizzled(Fz)/b-catenin and Fz/planar cell polarity (PCP) pathways are essential for the regulation of numerous developmental processes and are deregulated in many human diseases. Both pathways require members of the Dishevelled (Dsh or Dvl) family of cytoplasmic factors for signal transduction downstream of the Fz receptors. Dsh family members have been studied extensively, but their activation and regulation remains largely unknown. In particular, very little is known about how Dsh differentially signals to the two pathways. Recent work in cell culture has suggested that phosphorylation of Dsh by Casein Kinase I epsilon (CKI3) may act as a molecular ‘‘switch,’’ promoting Wnt/b-catenin while inhibiting Fz/PCP signaling [1]. Here, we demonstrate in vivo in Drosophila through a series of loss-of-function and coexpression assays that CKI3 acts positively for signaling in both pathways, rather than as a switch. Our data suggest that the kinase activity of CKI3 is required for peak levels of Wnt/b-catenin signaling. In contrast, CKI3 is a mandatory signaling factor in the Fz/PCP pathway, possibly through a kinase-independent mechanism. Furthermore, we have identified the primary kinase target residue of CKI3 on Dsh. Thus, our data suggest that CKI3 modulates Wnt/b-catenin and Fz/PCP signaling pathways via kinase-dependent and -independent mechanisms.