Wnt-3a utilizes a novel low dose and rapid pathway that does not require casein kinase 1-mediated phosphorylation of Dvl to activate β-catenin
- 作者：Ví ; tě ; zslav Bryja ; Gunnar Schulte ; Ernest Arenas
- 关键词：Wnt-3a ; Dishevelled ; Dopaminergic cells ; Casein kinase 1 ; Activation of β ; -catenin ; Canonical Wnt signalling
- 刊名：Cellular Signalling
- 出版年：2007
- 期刊代码：42_08986568
- 类别：bio
- 出版时间：March 2007
- 卷：19
- 期：3
- 页码：610-616
- 文件大小：977 K
摘要
The current view of canonical Wnt signalling is that following Wnt binding to its receptors (Frizzled-Lrp5/6), dishevelled (Dvl) becomes hyperphosphorylated, and the signal is transduced to the APC-GSK3β-axin-β-catenin multiprotein complex, which subsequently dissociates. As a result β-catenin is not phosphorylated, escapes proteosomal degradation and activates its target genes after translocation to the nucleus. Here, we analyzed the importance of the Wnt-3a-induced phosphorylation and shift in electrophoretic migration of Dvl (PS-Dvl) for the activation of β-catenin. Analysis of Wnt-3a time- and dose-responses in a dopaminergic cell line showed that β-catenin is activated rapidly (within minutes) and at a low dose of Wnt-3a (1 ng/ml). Surprisingly, PS-Dvl appeared only after 30 min and at greater doses (≥ 20 ng/ml) of Wnt-3a. Moreover, we found that a casein kinase 1 inhibitor (D4476) or siRNA for casein kinase 1 δ/ε (CK1δ/ε) blocked the Wnt-3a-induced PS-Dvl. Interestingly, CK1 inhibition or siRNA for CK1δ/ε did not ablate the activation of β-catenin by Wnt-3a, indicating that there is a PS-Dvl-independent path to activate β-catenin. The increase in β-catenin activation by Wnt-3a (PS-Dvl-dependent or -independent) were blocked by Dickkopf1 (Dkk1), suggesting that the effect of Wnt-3a is in both cases mediated by Lrp5/6 receptors. Thus, our results show that Wnt-3a rapidly induce a partial activation of β-catenin in the absence of PS-Dvl at low doses, while at high doses induce a full activation of β-catenin in a PS-Dvl-dependent manner.