Distinct domains of mouse dishevelled are responsible for the c-Jun N-terminal kinase/stress-activated protein kinase activation and the axis formation in vertebrates
Distinct domains of mouse dishevelled are responsible for the c-Jun N-terminal kinase/stress-activated protein kinase activation and the axis formation in vertebrates
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DOI：
10.1074/jbc.274.43.30957
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发表时间：
1999-10-22
影响因子：
4.8
通讯作者：
Nishida, E
中科院分区：
文献类型：
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作者：
Moriguchi, T;Kawachi, K;Nishida, E
最近的研究表明，果蝇disheveled （Dsh）作为果蝇无翅信号转导的重要组成部分，也通过果蝇c-Jun n -末端激酶(JNK)/应激激活蛋白激酶（SAPK）通路参与平面极性信号转导。在这里，我们发现在NIH3T3细胞中表达Dsh的小鼠同源物（mdl -1）可以激活JNK/SAPK及其激活剂MKK7。mDvl-1的c端一半包含DEP结构域足以激活JNK/SAPK，而mDvl-1的n端一半以及DEP结构域则需要刺激TCF/ lef -1依赖的转录激活，这是一个β -连环蛋白依赖的过程。DEP结构域（mDvl-1 (KM)）内的单氨基酸取代（Met取代Lys）可消除mDvl-1的JNK/ sapk激活活性，但不影响激活lef -1依赖性转录的活性。异位表达mDvl-1 （KM）或mDvl-1的n端一半，而不是c端，能够诱导爪蟾胚胎的次级轴。由于次级轴的形成依赖于Wnt/ β -catenin信号通路，这些结果表明，mdl -1的不同结构域负责脊椎动物的两个下游信号通路，β -catenin通路和JNK/SAPK通路。
Recent studies have shown that Drosophila Dishevelled (Dsh), an essential component of the wingless signal transduction, is also involved in planar polarity signaling through the c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) pathway in Drosophila. Here, we show that expression of a mouse homolog of Dsh (mDvl-1) in NIH3T3 cells activates JNK/SAPK, and its activator MKK7. A C-terminal half of mDvl-1 which contains the DEP domain was sufficient for the activation of JNK/SAPK, whereas an N-terminal half of mDvl-1 as well as the DEP domain is required for stimulation of the TCF/LEF-1-dependent transcriptional activation, a beta-catenin-dependent process. A single amino acid substitution (Met for Lys) within the DEP domain (mDvl-1 (KM)) abolished the JNK/SAPK-activating activity of mDvl-1, but did not affect the activity to activate the LEF-1-dependent transcription. Ectopic expression of mDvl-1 (KM) or an N-terminal half of mDvl-1, but not the C-terminal, was able to induce secondary axis in Xenopus embryos. Because the secondary axis formation is dependent on the Wnt/beta-catenin signaling pathway, these results suggest that distinct domains of mDvl-1 are responsible for the two downstream signaling pathways, the beta-catenin pathway and the JNK/SAPK pathway in vertebrates.