Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex
Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex
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DOI：
10.1038/ncb2028
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发表时间：
2010-03-01
影响因子：
21.3
通讯作者：
Itoh, Motoyuki
中科院分区：
文献类型：
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作者：
Ishitani, Tohru;Hirao, Tomoko;Itoh, Motoyuki
Notch信号通路在决定后生动物生物体内多个组织中的细胞命运方面具有至关重要的功能（1）。在与配体结合时，Notch受体被蛋白水解切割并释放其细胞内结构域（NotchICD）。NotchICD进入细胞核并与其他因子协同作用以刺激靶基因的转录。高水平的Notch介导的转录激活需要形成由NotchICD、CSL（CBF-1，无毛抑制因子，LAG-1）和Mastermind家族成员组成的三元复合物（2-5）。然而，目前还不清楚三元复合物的形成是如何调节的。在这里，我们表明，Nemo样激酶（NLK）负调控Notch依赖的转录激活，通过减少这种三元复合物的形成。使用生物化学筛选，我们确定Notch为NLK的新底物。NLK-磷酸化Notch 1 ICD形成转录活性三元复合物的能力受损。此外，NLK的敲低导致Notch信号转导的过度激活，从而减少斑马鱼的神经发生。我们的研究结果既定义了NLK的新功能，又揭示了Notch信号通路中先前未识别的调节模式。
The Notch signalling pathway has a crucial function in determining cell fates in multiple tissues within metazoan organisms(1). On binding to ligands, the Notch receptor is cleaved proteolytically and releases its intracellular domain (NotchICD). The NotchICD enters the nucleus and acts cooperatively with other factors to stimulate the transcription of target genes. High levels of Notch-mediated transcriptional activation require the formation of a ternary complex consisting of NotchICD, CSL (CBF-1, suppressor of hairless, LAG-1) and a Mastermind family member(2-5). However, it is still not clear how the formation of the ternary complex is regulated. Here we show that Nemo-like kinase (NLK) negatively regulates Notch-dependent transcriptional activation by decreasing the formation of this ternary complex. Using a biochemical screen, we identified Notch as a new substrate of NLK. NLK-phosphorylated Notch1ICD is impaired in its ability to form a transcriptionally active ternary complex. Furthermore, knockdown of NLK leads to hyperactivation of Notch signalling and consequently decreases neurogenesis in zebrafish. Our results both define a new function for NLK and reveal a previously unidentified mode of regulation in the Notch signalling pathway.