PUBLICATION
Hipk2 and PP1c Cooperate to Maintain Dvl Protein Levels Required for Wnt Signal Transduction
- Authors
- Shimizu, N., Ishitani, S., Sato, A., Shibuya, H., Ishitani, T.
- ID
- ZDB-PUB-140828-6
- Date
- 2014
- Source
- Cell Reports 8(5): 1391-404 (Journal)
- Registered Authors
- Ishitani, Shizuka, Ishitani, Tohru, Sato, Atsushi, Shimizu, Nobuyuki
- Keywords
- none
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/chemistry
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism*
- Animals
- Base Sequence
- Carrier Proteins/genetics
- Carrier Proteins/metabolism*
- HeLa Cells
- Humans
- Molecular Sequence Data
- Phosphoproteins/chemistry
- Phosphoproteins/genetics
- Phosphoproteins/metabolism*
- Protein Phosphatase 1/genetics
- Protein Phosphatase 1/metabolism*
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism*
- Protein Structure, Tertiary
- Proteolysis
- Wnt Signaling Pathway*
- Wnt3A Protein/genetics
- Wnt3A Protein/metabolism
- Zebrafish
- PubMed
- 25159144 Full text @ Cell Rep.
Citation
Shimizu, N., Ishitani, S., Sato, A., Shibuya, H., Ishitani, T. (2014) Hipk2 and PP1c Cooperate to Maintain Dvl Protein Levels Required for Wnt Signal Transduction. Cell Reports. 8(5):1391-404.
Abstract
The phosphoprotein Dishevelled (Dvl) is a common essential component of Wnt/β-catenin and Wnt/planar cell polarity (PCP) signaling pathways. However, the regulation and significance of Dvl phosphorylation are not fully understood. Here, we show that homeodomain-interacting protein kinase 2 (Hipk2) facilitates protein phosphatase 1 catalytic subunit (PP1c)-mediated dephosphorylation of Dvl via its C-terminal domain and that this dephosphorylation blocks ubiquitination and consequent degradation mediated by the E3 ubiquitin ligase Itch, which targets the phosphorylated form of Dvl proteins. Inhibition of Hipk2 or PP1c function reduces Dvl protein levels and suppresses Wnt/β-catenin and Wnt/PCP pathway-dependent events in mammalian cells and zebrafish embryos, suggesting that Hipk2 and PP1c are essential for maintaining Dvl protein levels that are sufficient to activate Wnt signaling. We also show that Wnt-3a, a Wnt/β-catenin ligand, induces dissociation of the Dvl-Hipk2-PP1c complex and Dvl degradation under high-cell-density conditions. This regulation may be a negative feedback mechanism that fine-tunes Wnt/β-catenin signaling.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping