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ZFIN ID: ZDB-PUB-100202-21
Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex
Ishitani, T., Hirao, T., Suzuki, M., Isoda, M., Ishitani, S., Harigaya, K., Kitagawa, M., Matsumoto, K., and Itoh, M.
Date: 2010
Source: Nature cell biology   12(3): 278-285 (Journal)
Registered Authors: Ishitani, Tohru, Itoh, Motoyuki
Keywords: none
MeSH Terms:
  • Amino Acid Substitution/physiology
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors/genetics
  • Basic Helix-Loop-Helix Transcription Factors/metabolism
  • Cell Line, Tumor
  • DNA/metabolism
  • ELAV Proteins/metabolism
  • ELAV-Like Protein 3
  • Embryo, Nonmammalian/metabolism
  • Gene Expression Regulation/physiology*
  • Homeodomain Proteins/genetics
  • Homeodomain Proteins/metabolism
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism
  • Intracellular Signaling Peptides and Proteins/genetics
  • Intracellular Signaling Peptides and Proteins/metabolism*
  • Mice
  • Mitogen-Activated Protein Kinases/genetics
  • Mitogen-Activated Protein Kinases/metabolism*
  • Models, Biological
  • Nerve Tissue Proteins/genetics
  • Nerve Tissue Proteins/metabolism
  • Neurogenesis/physiology
  • Nuclear Proteins/genetics
  • Nuclear Proteins/metabolism
  • Oligonucleotides, Antisense/genetics
  • Phosphorylation/physiology
  • Protein Binding/physiology
  • Protein Interaction Domains and Motifs/physiology
  • Protein-Serine-Threonine Kinases/genetics
  • Protein-Serine-Threonine Kinases/metabolism*
  • RNA, Small Interfering/genetics
  • Receptor, Notch1/genetics
  • Receptor, Notch1/metabolism
  • Receptors, Notch/genetics
  • Receptors, Notch/metabolism*
  • Signal Transduction/physiology*
  • Transcription Factors/genetics
  • Transcription Factors/metabolism
  • Transfection
  • Xenopus
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 20118921 Full text @ Nat. Cell Biol.
FIGURES
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.
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