Sequential Activation and Inactivation of Dishevelled in the Wnt/β-Catenin Pathway by Casein Kinases

• Published in: The Journal of biological chemistry Vol. 286; no. 12; pp. 10396 - 10410
• Main Authors: Bernatik, Ondrej, Ganji, Ranjani Sri, Dijksterhuis, Jacomijn P., Konik, Peter, Cervenka, Igor, Polonio, Tilman, Krejci, Pavel, Schulte, Gunnar, Bryja, Vitezslav
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.03.2011; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; beta Catenin - genetics; beta Catenin - metabolism; Casein Kinase Idelta - genetics; Casein Kinase Idelta - metabolism; Casein Kinase Iepsilon - genetics; Casein Kinase Iepsilon - metabolism; Casein Kinase II - genetics; Casein Kinase II - metabolism; Cell Biology; Dishevelled; Dishevelled Proteins; HEK293 Cells; Humans; Medicin och hälsovetenskap; Mice; Peptide Mapping; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation - physiology; Protein Kinases; Protein Phosphorylation; Protein-Protein Interactions; Receptor, PAR-1 - genetics; Receptor, PAR-1 - metabolism; Signal Transduction; Signal Transduction - physiology; Wnt Pathway; Wnt Proteins - genetics; Wnt Proteins - metabolism; Dishevelled; Protein Phosphorylation; Protein Kinases; Signal Transduction; Wnt Pathway; Protein-Protein Interactions
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M110.169870

Dishevelled (Dvl) is a key component in the Wnt/β-catenin signaling pathway. Dvl can multimerize to form dynamic protein aggregates, which are required for the activation of downstream signaling. Upon pathway activation by Wnts, Dvl becomes phosphorylated to yield phosphorylated and shifted (PS) Dvl. Both activation of Dvl in Wnt/β-catenin signaling and Wnt-induced PS-Dvl formation are dependent on casein kinase 1 (CK1) δ/ϵ activity. However, the overexpression of CK1 was shown to dissolve Dvl aggregates, and endogenous PS-Dvl forms irrespective of whether or not the activating Wnt triggers the Wnt/β-catenin pathway. Using a combination of gain-of-function, loss-of-function, and domain mapping approaches, we attempted to solve this discrepancy regarding the role of CK1ϵ in Dvl biology. We analyzed mutual interaction of CK1δ/ϵ and two other Dvl kinases, CK2 and PAR1, in the Wnt/β-catenin pathway. We show that CK2 acts as a constitutive kinase whose activity is required for the further action of CK1ϵ. Furthermore, we demonstrate that the two consequences of CK1ϵ phosphorylation are separated both spatially and functionally; first, CK1ϵ-mediated induction of TCF/LEF-driven transcription (associated with dynamic recruitment of Axin1) is mediated via a PDZ-proline-rich region of Dvl. Second, CK1ϵ-mediated formation of PS-Dvl is mediated by the Dvl3 C terminus. Furthermore, we demonstrate with several methods that PS-Dvl has decreased ability to polymerize with other Dvls and could, thus, act as the inactive signaling intermediate. We propose a multistep and multikinase model for Dvl activation in the Wnt/β-catenin pathway that uncovers a built-in de-activation mechanism that is triggered by activating phosphorylation of Dvl by CK1δ/ϵ.