Regulation of Casein Kinase Iϵ Activity by Wnt Signaling

The Wnt/β-catenin signaling pathway is important in both development and cancer. Casein kinase Iϵ (CKIϵ) is a positive regulator of the canonical Wnt pathway. CKIϵ itself can be regulated in vitro by inhibitory autophosphorylation, and recent data suggest that in vivo kinase activity can be regulate...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-03, Vol.279 (13), p.13011-13017
Main Authors: Swiatek, Wojciech, Tsai, I-Chun, Klimowski, Laura, Pepler, Andrea, Barnette, Janet, Yost, H. Joseph, Virshup, David M.
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Animals
Casein Kinases
Cell Line
Electrophoresis, Gel, Two-Dimensional
Gene Expression Regulation, Enzymologic
Genes, Reporter
Humans
Ligands
Luciferases - metabolism
Mice
Mutation
Phosphorylation
Plasmids - metabolism
Precipitin Tests
Protein Kinases - biosynthesis
Protein Kinases - genetics
Proto-Oncogene Proteins - metabolism
Signal Transduction
Time Factors
Transfection
Wnt Proteins
Xenopus
Xenopus Proteins
Zebrafish Proteins
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Summary:The Wnt/β-catenin signaling pathway is important in both development and cancer. Casein kinase Iϵ (CKIϵ) is a positive regulator of the canonical Wnt pathway. CKIϵ itself can be regulated in vitro by inhibitory autophosphorylation, and recent data suggest that in vivo kinase activity can be regulated by extracellular stimuli. We show here that the phosphorylation state and kinase activity of CKIϵ are directly regulated by Wnt signaling. Coexpression of XWnt-8 or addition of soluble Wnt-3a ligand led to a significant and rapid increase in the activity of endogenous CKIϵ. The increase in CKIϵ activity is the result of decreased inhibitory autophosphorylation because it is abolished by preincubation of immunoprecipitated kinase with ATP. Furthermore, mutation of CKIϵ inhibitory autophosphorylation sites creates a kinase termed CKIϵ(MM2) that is significantly more active than CKIϵ and is not activated further upon Wnt stimulation. Autoinhibition of CKIϵ is biologically relevant because CKIϵ(MM2) is more effective than CKIϵ at activating transcription from a Lef1-dependent promoter. Finally, CKIϵ(MM2) expression in Xenopus embryos induces both axis duplication and additional developmental abnormalities. The data suggest that Wnt signaling activates CKIϵ by causing transient dephosphorylation of critical inhibitory sites present in the carboxyl-terminal domain of the kinase. Activation of the Wnt pathway may therefore stimulate a cellular phosphatase to dephosphorylate and activate CKIϵ
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M304682200