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

73 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 1 2010

Fingerprint

Phosphotransferases
Transcriptional Activation
Notch Receptors
Aptitude
Neurogenesis
Zebrafish
Ligands
Genes

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Ishitani, T., Hirao, T., Suzuki, M., Isoda, M., Ishitani, S., Harigaya, 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

Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex. / Ishitani, Tohru; Hirao, Tomoko; Suzuki, Maho; Isoda, Miho; Ishitani, Shizuka; Harigaya, Kenichi; Kitagawa, Motoo; Matsumoto, Kunihiro; Itoh, Motoyuki.

In: Nature Cell Biology, Vol. 12, No. 3, 01.03.2010, p. 278-285.

Research output: Contribution to journalArticle

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, vol. 12, no. 3, pp. 278-285. https://doi.org/10.1038/ncb2028
Ishitani, Tohru ; Hirao, Tomoko ; Suzuki, Maho ; Isoda, Miho ; Ishitani, Shizuka ; Harigaya, Kenichi ; Kitagawa, Motoo ; Matsumoto, Kunihiro ; Itoh, Motoyuki. / Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex. In: Nature Cell Biology. 2010 ; Vol. 12, No. 3. pp. 278-285.
@article{9bb49db08d544704ab5c81286f4fecf8,
title = "Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex",
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.",
author = "Tohru Ishitani and Tomoko Hirao and Maho Suzuki and Miho Isoda and Shizuka Ishitani and Kenichi Harigaya and Motoo Kitagawa and Kunihiro Matsumoto and Motoyuki Itoh",
year = "2010",
month = "3",
day = "1",
doi = "10.1038/ncb2028",
language = "English",
volume = "12",
pages = "278--285",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex

AU - Ishitani, Tohru

AU - Hirao, Tomoko

AU - Suzuki, Maho

AU - Isoda, Miho

AU - Ishitani, Shizuka

AU - Harigaya, Kenichi

AU - Kitagawa, Motoo

AU - Matsumoto, Kunihiro

AU - Itoh, Motoyuki

PY - 2010/3/1

Y1 - 2010/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77649273214&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77649273214&partnerID=8YFLogxK

U2 - 10.1038/ncb2028

DO - 10.1038/ncb2028

M3 - Article

VL - 12

SP - 278

EP - 285

JO - Nature Cell Biology

JF - Nature Cell Biology

SN - 1465-7392

IS - 3

ER -