Wnt ligand-dependent activation of the negative feedback regulator Nkd1.
Wnt ligand-dependent activation of the negative feedback regulator Nkd1.
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DOI：
10.1091/mbc.e14-12-1648
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发表时间：
2015-06-15
影响因子：
3.3
通讯作者：
Van Raay TJ
中科院分区：
文献类型：
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作者：
Larraguibel J;Weiss AR;Pasula DJ;Dhaliwal RS;Kondra R;Van Raay TJ
Nkd1是Wnt途径的负反馈调节因子，它与Dvl2一起定位于可能的Wnt信号体，在那里它被Wnt激活。激活的NKD1离开细胞膜，变得更加胞浆，在那里它与β-连环蛋白相互作用，以防止核聚集。Wnt信号的错误调节是许多疾病的根源，最明显的是结直肠癌，尽管我们了解该通路的激活，但我们对Wnt信号关闭的情况了解很少。Wnt信号的负反馈调节因子很多，但有两个是结构型和强制性的，它们是：Axin2和Nkd1。虽然Axin2在破坏复合体中的行为类似于Axin，但Nkd1更神秘。在这里，我们使用响应Wnt信号的斑马鱼囊胚细胞来证明Nkd1的活性特定地依赖于Wnt配体对受体的激活。此外，我们的结果支持这样的假设，即Nkd1与Dvl2一起被招募到Wnt信号体，在那里它被激活，进入细胞质与β-catenin相互作用，抑制其核积累。将这些结果与果蝇的NKD功能进行比较，得到了一个关于这种负反馈调节因子在Wnt信号调制中所起作用的统一而保守的模型。
Nkd1, a negative feedback regulator of the Wnt pathway, localizes with Dvl2 to the putative Wnt signalosome, where it becomes activated by Wnt. Activated Nkd1 moves away from the membrane to become more cytosolic, where it interacts with β-catenin to prevent nuclear accumulation. Misregulation of Wnt signaling is at the root of many diseases, most notably colorectal cancer, and although we understand the activation of the pathway, we have a very poor understanding of the circumstances under which Wnt signaling turns itself off. There are numerous negative feedback regulators of Wnt signaling, but two stand out as constitutive and obligate Wnt-induced regulators: Axin2 and Nkd1. Whereas Axin2 behaves similarly to Axin in the destruction complex, Nkd1 is more enigmatic. Here we use zebrafish blastula cells that are responsive Wnt signaling to demonstrate that Nkd1 activity is specifically dependent on Wnt ligand activation of the receptor. Furthermore, our results support the hypothesis that Nkd1 is recruited to the Wnt signalosome with Dvl2, where it becomes activated to move into the cytoplasm to interact with β-catenin, inhibiting its nuclear accumulation. Comparison of these results with Nkd function in Drosophila generates a unified and conserved model for the role of this negative feedback regulator in the modulation of Wnt signaling.