The casein kinase I family in Wnt signaling.
The canonical Wnt-signaling pathway is critical for many aspects of development, and mutations in components of the Wnt pathway are carcinogenic. Recently, sufficiency tests identified casein kinase Iepsilon (CKIepsilon) as a positive component of the canonical Wnt/beta-catenin pathway, and necessity tests showed that CKIepsilon is required in vertebrates to transduce Wnt signals. In addition to CKIepsilon, the CKI family includes several other isoforms (alpha, beta, gamma, and delta) and their role in Wnt sufficiency tests had not yet been clarified. However, in Caenorhabditis elegans studies, loss-of-function of a CKI isoform most similar to alpha produced the mom phenotype, indicative of loss-of-Wnt signaling. In this report, we examine the ability of the various CKI isoforms to activate Wnt signaling and find that all the wild-type CKI isoforms do so. Dishevelled (Dsh), another positive component of the Wnt pathway, becomes phosphorylated in response to Wnt signals. All the CKI isoforms, with the exception of gamma, increase the phosphorylation of Dsh in vivo. In addition, CKI directly phosphorylates Dsh in vitro. Finally, we find that CKI is required in vivo for the Wnt-dependent phosphorylation of Dsh. These studies advance our understanding of the mechanism of Wnt action and suggest that more than one CKI isoform is capable of transducing Wnt signals in vivo.
McKay
R M
RM
Center for Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9133, USA.
Peters
J M
JM
Graff
J M
JM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D017173:Caenorhabditis elegans; D047388:Casein Kinases; D002417:Cattle; D002454:Cell Differentiation; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D000072261:Dishevelled Proteins; D017353:Gene Deletion; D006801:Humans; D005810:Multigene Family; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators; D020798:Two-Hybrid System Techniques; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D001616:beta-Galactosidase / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D012313:RNA; D011494:Protein Kinases; D047388:Casein Kinases; D001616:beta-Galactosidase