Casein Kinase Iε Modulates the Signaling Specificities of Dishevelled

Abstract

Wnt signaling is critical to many aspects of development, and aberrant activation of the Wnt signaling pathway can cause cancer. Dishevelled (Dvl) protein plays a central role in this pathway by transducing the signal from the Wnt receptor complex to the β-catenin destruction complex. Dvl also plays a pivotal role in the planar cell polarity pathway that involves the c-Jun N-terminal kinase (JNK). How functions of Dvl are regulated in these two distinct pathways is not clear. We show that deleting the C-terminal two-thirds of Dvl, which includes the PDZ and DEP domains and is essential for Dvl-induced JNK activation, rendered the molecule a much more potent activator of the β-catenin pathway. We also found that casein kinase Iε (CKIε), a previously identified positive regulator of Wnt signaling, stimulated Dvl activity in the Wnt pathway, but dramatically inhibited Dvl activity in the JNK pathway. Consistent with this, overexpression of CKIε in Drosophila melanogaster stimulated Wnt signaling and disrupted planar cell polarity. We also observed a correlation between the localization and the signaling activity of Dvl in the β-catenin pathway and the JNK pathway. Furthermore, by using RNA interference, we demonstrate that the Drosophila CKIε homologue Double time positively regulates the β-catenin pathway through Dvl and negatively regulates the Dvl-induced JNK pathway. We suggest that CKIε functions as a molecular switch to direct Dvl from the JNK pathway to the β-catenin pathway, possibly by altering the conformation of the C terminus of Dvl.

We thank Lewis Williams, Dianqing Wu, Shin-ichi Yanagawa, Rudolf Grosschedl, Peter Vogt, Michael Forte, Richard Young, Po Chen, Myriam Zecca, Virginia Cox, and Mary Baylies for providing reagents critical to this work. We also thank William Pao and Suzanne Ortiz for reading the manuscript.

F.C. is supported by a postdoctoral fellowship from the Susan G. Komen Breast Cancer Foundation.