β-arrestin is a necessary component of Wnt/β-catenin signaling in vitro and in vivo
β-arrestin is a necessary component of Wnt/β-catenin signaling in vitro and in vivo
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DOI：
10.1073/pnas.0611356104
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发表时间：
2007-04-17
影响因子：
11.1
通讯作者：
Schulte, Gunnar
中科院分区：
文献类型：
--
作者：
Bryja, Vitezslav;Gradl, Dietmar;Schulte, Gunnar
Wnt/ β -连环蛋白信号通路对胚胎正常发育和组织稳态至关重要。磷酸化蛋白disheveled （Dvl）是Wnt信号的一个组成部分，最近被证明与多功能支架蛋白-阻滞蛋白相互作用。利用Dvl缺失结构，我们发现p -阻滞蛋白结合了Dvl PDZ结构域的n端区域，该区域包含酪蛋白激酶1 （CK1）磷酸化位点。CKII抑制剂对Wnt信号的抑制降低了β -抑制素与Dvl的结合。此外，缺乏β -阻滞蛋白的小鼠胚胎成纤维细胞能够磷酸化LRP6以响应Wnt-3a，但降低了Dvl的激活并阻断了β -连环蛋白信号传导。此外，我们发现β -阻滞蛋白可以结合轴蛋白并与轴蛋白和Dvl形成三聚体复合物。此外，β -抑制素morpholinos处理非洲爪蟾胚胎可降低内源性β -catenin的激活，降低P-catenin靶基因Xnr3的表达，并阻断X-Wnt-8、CK1 epsilon或Dsh Delta DEP诱导的轴复制，但β -catenin没有作用。因此，我们的研究结果确定β -阻滞蛋白是Wnt/ β -连环蛋白信号传导的必要组成部分，连接DO和轴蛋白，并为与其他β -阻滞蛋白依赖的信号传导途径的串扰开辟了大量的信号传导途径和可能性。
The Wnt/beta-catenin signaling pathway is crucial for proper embryonic development and tissue homeostasis. The phosphoprotein dishevelled (Dvl) is an integral part of Wnt signaling and has recently been shown to interact with the multifunctional scaffolding protein beta-arrestin. Using Dvl deletion constructs, we found that P-arrestin binds a region N-terminal of the PDZ domain of Dvl, which contains casein kinase 1 (CK1) phosphorylation sites. Inhibition of Wnt signaling by CKII inhibitors reduced the binding of beta-arrestin to Dvl. Moreover, mouse embryonic fibroblasts lacking beta-arrestins were able to phosphorylate LRP6 in response to Wnt-3a but decreased the activation of Dvl and blocked beta-catenin signaling. In addition, we found that beta-arrestin can bind axin and forms a trimeric complex with axin and Dvl. Furthermore, treatment of Xenopus laevis embryos with beta-arrestin morpholinos reduced the activation of endogenous beta-catenin, decreased the expression of the P-catenin target gene, Xnr3, and blocked axis duplication induced by X-Wnt-8, CK1 epsilon, or Dsh Delta DEP, but not by beta-catenin. Thus, our results identify beta-arrestin as a necessary component for Wnt/ beta-catenin signaling, linking DO and axin, and open a vast array of signaling avenues and possibilities for cross-talk with other beta-arrestin-dependent signaling pathways.