Author: ["Tohru Ishitani","Tomoko Hirao","Maho Suzuki","Miho Isoda","Shizuka Ishitani","Kenichi Harigaya","Motoo Kitagawa","Kunihiro Matsumoto","Motoyuki Itoh"]
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Abstract
Notch-mediated transcriptional activation requires the formation of a ternary complex, consisting of NotchICD, CSL and a Mastermind family member. Nemo-like kinase is shown to negatively regulate Notch signalling and to promote neurogenesis in zebrafish by phosphoprylating Notch1ICD and reducing formation of the ternary complex. The Notch signalling pathway has a crucial function in determining cell fates in multiple tissues within metazoan organisms1. 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 member2,3,4,5. 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.Cite this article
Ishitani, T., Hirao, T., Suzuki, M. et al. Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex. Nat Cell Biol 12, 278–285 (2010). https://doi.org/10.1038/ncb2028 