ZFIN ID: ZDB-PUB-140828-6
Hipk2 and PP1c Cooperate to Maintain Dvl Protein Levels Required for Wnt Signal Transduction
Shimizu, N., Ishitani, S., Sato, A., Shibuya, H., Ishitani, T.
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 Structure, Tertiary
  • Protein-Serine-Threonine Kinases/genetics
  • Protein-Serine-Threonine Kinases/metabolism*
  • Proteolysis
  • Wnt Signaling Pathway*
  • Wnt3A Protein/genetics
  • Wnt3A Protein/metabolism
  • Zebrafish
PubMed: 25159144 Full text @ Cell Rep.
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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.
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