TY - JOUR
T1 - Hipk2 and PP1c Cooperate to Maintain Dvl Protein Levels Required for Wnt Signal Transduction
AU - Shimizu, Nobuyuki
AU - Ishitani, Shizuka
AU - Sato, Atsushi
AU - Shibuya, Hiroshi
AU - Ishitani, Tohru
N1 - Funding Information:
We thank R.T. Moon, J. Wrana, M. Hibi, A. Weissman, E. Nishida, and C.Y. Choi for providing plasmids, H. Hikasa for helpful discussion, E.M. Verheyen for providing the fly strain, T. Uemura for providing anti-Dsh, the Laboratory for Technical Support, MIB, Kyushu University, Y. Sado, and M. Matsuo for their technical support. This research was supported by the Inamori Foundation, the Nakajima Foundation, the Naito Foundation, the Takeda Foundation, and the Kaihara Morikazu Medical Science Promotion Foundation (T.I.), the Joint Usage/Research Program of the Medical Research Institute of Tokyo Medical and Dental University (T.I. and H.S.), JSPS Research Fellowships for Young Scientists (S.I.), Kyushu University P&P (N.S.), and a Grant-in-Aid for Scientific Research on Innovative Areas (25117720, 26114006) and Scientific Research (B) (25293072) (T.I.).
Publisher Copyright:
© 2014 The Authors.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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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U2 - 10.1016/j.celrep.2014.07.040
DO - 10.1016/j.celrep.2014.07.040
M3 - Article
C2 - 25159144
AN - SCOPUS:84922483614
SN - 2211-1247
VL - 8
SP - 1391
EP - 1404
JO - Cell Reports
JF - Cell Reports
IS - 5
ER -