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首页> 外文期刊>Cellular Signalling >Wnt-3a utilizes a novel low dose and rapidly pathway that does not require casein kinase 1-mediated phosphorylation of Dvl to activate beta-catenin
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Wnt-3a utilizes a novel low dose and rapidly pathway that does not require casein kinase 1-mediated phosphorylation of Dvl to activate beta-catenin

机译：Wnt-3a利用新颖的低剂量和快速途径，不需要酪蛋白激酶1介导的Dv1磷酸化来激活β-连环蛋白

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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 APGGSK3 beta-axin-beta-catenin multiprotein complex, which subsequently dissociates. As a result beta-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 beta-catenin. Analysis of Wnt-3a time- and dose-responses in a dopaminergic cell line showed that beta-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 delta/epsilon (CK1 delta/epsilon) blocked the Wnt-3a-induced PS-Dvl. Interestingly, CK1 inhibition or siRNA for CK1 delta/epsilon did not ablate the activation of p-catenin by Wnt-3a, indicating that there is a PS-Dvl-independent path to activate beta-catenin. The increase in p-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 beta-catenin in the absence of PS-Dvl at low doses, while at high doses induce a full activation of p-catenin in a PS-DA-dependent manner. (c) 2006 Elsevier Inc. All rights reserved.
机译：当前Wnt信号的典型观点是Wnt与其受体（Frizzled-Lrp5 / 6）结合后，衣衫不整（Dvl）磷酸化过度，并且信号被转导至APGGSK3 beta-axin-beta-catenin多蛋白复合物，随后离解。结果，β-catenin没有被磷酸化，逃脱了蛋白体降解，并在易位至细胞核后激活了其靶基因。在这里，我们分析了Wnt-3a诱导的磷酸化和Dvl（PS-Dvl）电泳迁移中转移对于激活β-catenin的重要性。对多巴胺能细胞系中Wnt-3a的时间和剂量反应的分析表明，β-catenin可以在几分钟内以低剂量（1 ng / ml）快速激活（在几分钟之内）。出人意料的是，PS-Dvl仅在30分钟后以更大剂量（> = 20 ng / ml）的Wnt-3a出现。而且，我们发现酪蛋白激酶1抑制剂（D4476）或酪蛋白激酶1δ/ε（CK1δ/ε）的siRNA阻断了Wnt-3a诱导的PS-Dvl。有趣的是，CK1δ/ε的CK1抑制或siRNA并未消除Wnt-3a对p-catenin的激活，表明存在不依赖PS-Dvl的路径来激活β-catenin。 Dickkopf1（Dkk1）阻止了Wnt-3a对p-catenin激活的增加（PS-Dvl依赖性或非依赖性），这表明Wnt-3a的作用在两种情况下均由Lrp5 / 6受体介导。因此，我们的结果表明，在不存在低剂量的PS-Dvl的情况下，Wnt-3a迅速诱导β-catenin的部分活化，而在高剂量时，PS-DA依赖性地诱导p-catenin的完全活化。 （c）2006 Elsevier Inc.保留所有权利。

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