| RRC ID |
65587
|
| 著者 |
Shimizu N, Ishitani S, Sato A, Shibuya H, Ishitani T.
|
| タイトル |
Hipk2 and PP1c cooperate to maintain Dvl protein levels required for Wnt signal transduction.
|
| ジャーナル |
Cell Rep
|
| 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.
|
| 巻・号 |
8(5)
|
| ページ |
1391-404
|
| 公開日 |
2014-9-11
|
| DOI |
10.1016/j.celrep.2014.07.040
|
| PII |
S2211-1247(14)00624-X
|
| PMID |
25159144
|
| MeSH |
Adaptor Proteins, Signal Transducing / chemistry
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Base Sequence
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Dishevelled Proteins
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
|
| IF |
8.109
|
| リソース情報 |
| ゼブラフィッシュ |
Tg(6xTcf/LefBS-miniP:d2EGFP)isi04 |
