Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex

Tohru Ishitani, Tomoko Hirao, Maho Suzuki, Miho Isoda, Shizuka Ishitani, Kenichi Harigaya, Motoo Kitagawa, Kunihiro Matsumoto, Motoyuki Itoh

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

The Notch signalling pathway has a crucial function in determining cell fates in multiple tissues within metazoan organisms. 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. 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.

Original languageEnglish
Pages (from-to)278-285
Number of pages8
JournalNature Cell Biology
Volume12
Issue number3
DOIs
Publication statusPublished - Mar 2010

All Science Journal Classification (ASJC) codes

  • Cell Biology

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    Ishitani, T., Hirao, T., Suzuki, M., Isoda, M., Ishitani, S., Harigaya, K., Kitagawa, M., Matsumoto, K., & Itoh, M. (2010). Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex. Nature Cell Biology, 12(3), 278-285. https://doi.org/10.1038/ncb2028