Hipk2 and PP1c Cooperate to Maintain Dvl Protein Levels Required for Wnt Signal Transduction

Nobuyuki Shimizu, Shizuka Ishitani, Atsushi Sato, Hiroshi Shibuya, Tohru Ishitani

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1391-1404
Number of pages14
JournalCell Reports
Volume8
Issue number5
DOIs
Publication statusPublished - Jan 1 2014

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Homeodomain Proteins
Protein Phosphatase 1
Catenins
Signal transduction
Protein Kinases
Signal Transduction
Cell Polarity
Proteins
Degradation
Phosphorylation
Ubiquitin-Protein Ligases
Ubiquitination
Phosphoproteins
Zebrafish
Embryonic Structures
Cell Count
Cells
Ligands
Feedback
Dishevelled Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Hipk2 and PP1c Cooperate to Maintain Dvl Protein Levels Required for Wnt Signal Transduction. / Shimizu, Nobuyuki; Ishitani, Shizuka; Sato, Atsushi; Shibuya, Hiroshi; Ishitani, Tohru.

In: Cell Reports, Vol. 8, No. 5, 01.01.2014, p. 1391-1404.

Research output: Contribution to journalArticle

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, vol. 8, no. 5, pp. 1391-1404. https://doi.org/10.1016/j.celrep.2014.07.040
Shimizu, Nobuyuki ; Ishitani, Shizuka ; Sato, Atsushi ; Shibuya, Hiroshi ; Ishitani, Tohru. / Hipk2 and PP1c Cooperate to Maintain Dvl Protein Levels Required for Wnt Signal Transduction. In: Cell Reports. 2014 ; Vol. 8, No. 5. pp. 1391-1404.
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