Cong Feng, Schweizer Liang, Varmus Harold
Program in Cell Biology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Mol Cell Biol. 2004 Mar;24(5):2000-11. doi: 10.1128/MCB.24.5.2000-2011.2004.
Wnt signaling is critical to many aspects of development, and aberrant activation of the Wnt signaling pathway can cause cancer. Dishevelled (Dvl) protein plays a central role in this pathway by transducing the signal from the Wnt receptor complex to the beta-catenin destruction complex. Dvl also plays a pivotal role in the planar cell polarity pathway that involves the c-Jun N-terminal kinase (JNK). How functions of Dvl are regulated in these two distinct pathways is not clear. We show that deleting the C-terminal two-thirds of Dvl, which includes the PDZ and DEP domains and is essential for Dvl-induced JNK activation, rendered the molecule a much more potent activator of the beta-catenin pathway. We also found that casein kinase Iepsilon (CKIepsilon), a previously identified positive regulator of Wnt signaling, stimulated Dvl activity in the Wnt pathway, but dramatically inhibited Dvl activity in the JNK pathway. Consistent with this, overexpression of CKIepsilon in Drosophila melanogaster stimulated Wnt signaling and disrupted planar cell polarity. We also observed a correlation between the localization and the signaling activity of Dvl in the beta-catenin pathway and the JNK pathway. Furthermore, by using RNA interference, we demonstrate that the Drosophila CKIepsilon homologue Double time positively regulates the beta-catenin pathway through Dvl and negatively regulates the Dvl-induced JNK pathway. We suggest that CKIepsilon functions as a molecular switch to direct Dvl from the JNK pathway to the beta-catenin pathway, possibly by altering the conformation of the C terminus of Dvl.
Wnt信号传导对发育的许多方面都至关重要，Wnt信号通路的异常激活可导致癌症。散乱蛋白（Dvl）在该通路中起着核心作用，它将信号从Wnt受体复合物传递至β-连环蛋白破坏复合物。Dvl在涉及c-Jun氨基末端激酶（JNK）的平面细胞极性通路中也起着关键作用。Dvl的功能在这两条不同的通路中是如何被调控的尚不清楚。我们发现，删除Dvl的C末端三分之二，其中包括PDZ和DEP结构域，而这对于Dvl诱导的JNK激活至关重要，结果使该分子成为β-连环蛋白通路更有效的激活剂。我们还发现，酪蛋白激酶Iε（CKIε），一种先前确定的Wnt信号的正向调节因子，刺激Wnt通路中的Dvl活性，但显著抑制JNK通路中的Dvl活性。与此一致的是，在果蝇中过表达CKIε会刺激Wnt信号传导并破坏平面细胞极性。我们还观察到Dvl在β-连环蛋白通路和JNK通路中的定位与信号活性之间存在相关性。此外，通过RNA干扰，我们证明果蝇CKIε同源物双倍时间蛋白通过Dvl正向调节β-连环蛋白通路，并负向调节Dvl诱导的JNK通路。我们认为CKIε作为一个分子开关，可能通过改变Dvl C末端的构象，将Dvl从JNK通路导向β-连环蛋白通路。
