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 ␤-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 ␤-catenin pathway. We also found that casein kinase I (CKI), 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 CKI 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 ␤-catenin pathway and the JNK pathway. Furthermore, by using RNA interference, we demonstrate that the Drosophila CKI homologue Double time positively regulates the ␤-catenin pathway through Dvl and negatively regulates the Dvl-induced JNK pathway. We suggest that CKI functions as a molecular switch to direct Dvl from the JNK pathway to the ␤-catenin pathway, possibly by altering the conformation of the C terminus of Dvl.The Wnt family of glycoproteins regulate cell growth and cell fate determination in a wide range of metazoan organisms, including Drosophila melanogaster and mammals. Wnts play pivotal roles in diverse developmental processes, such as segmentation in D. melanogaster, control of asymmetric division in Caenorhabditis elegans, and axis formation and patterning of the central nervous system in vertebrates (10,56).Genetic experiments in D. melanogaster and biochemical studies in Xenopus and mammalian cells have established a framework for the Wnt signaling pathway (15, 39). In the absence of a Wnt signal, cytoplasmic ␤-catenin is bound to Axin and constitutively phosphorylated at several N-terminal Ser and Thr residues by glycogen synthase kinase 3 (GSK3); phosphorylated ␤-catenin is then recognized by ␤-TrCP and degraded by the ubiquitin-proteasome system. Wnt signaling is initiated by the binding of secreted Wnt protein to its receptors, Frizzled and LRP5/6, activating Dishevelled (Dvl) by an unknown mechanism. Dvl induces the dissociation of the Axin-GSK3-␤-catenin complex and the stabilization of ␤-catenin, presumably through the inactivation of GSK3 and failure to phosphorylate ␤-catenin. Accumulated ␤-catenin enters the nucleus, binds to members of LEF/TCF family of transcription factors, and alters the transcription of Wnt target genes.Deregulated Wnt signaling contributes to tumorigenesis. Wnt-1, the founding member of the Wnt family, was first identified as a gene activated b...

Phosphorylation of nm23-H1 by CKI induces its complex formation with h-prune and promotes cell motility

“…Our findings show that IC261 impairs cell motility, thus raising the hypothesis that h-prune, nm23 and CKIe, the last of which has already been found to be involved in the modulation of the signaling of dishevelled (Cong et al, 2004), have roles in the Wnt pathway. These hypotheses might thus open up new aspects of the migration-based mechanism that involves h-prune as an important actor and of the physiopathological functions of h-prune within the complex with nm23 in cancer metastasis formation.…”

Myristoylated Naked2 Antagonizes Wnt-β-Catenin Activity by Degrading Dishevelled-1 at the Plasma Membrane

“…Although most of the studies on post-translational modifications of Dvl have focused on phosphorylation (27)(28)(29)(30), it is instructive to consider proteins that interact with Dvl and lead to its degradation. Inversin and Dapper1 interact with and degrade Dvl-1 via either proteasomal or lysosomal degradation, respectively (31,32).…”

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

“…However, evidence exists that the DEP domain influences b-catenin signaling (Wong et al 2000;Simons et al 2009;Tauriello et al 2012). DVL associates with kinases such as CK11 and CK2, and becomes hyperphosphorylated upon Wnt signaling (Willert et al 1997;Peters et al 1999;Kishida et al 2001;Cong et al 2004a;Klein et al 2006). These kinases, in particular CK11, have been documented to have activating roles in Wnt/b-catenin signaling, but the role of DVL phosphorylation remains unclear.…”