Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex
Copyright policy )Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex
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.
- Kyushu University Japan
- Nagoya University Japan
- Chiba University Japan
Homeodomain Proteins, Embryo, Nonmammalian, Neurogenesis, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, ELAV-Like Protein 3, Nerve Tissue Proteins, DNA, Oligonucleotides, Antisense, Models, Biological, Mice, Amino Acid Substitution, ELAV Proteins, Gene Expression Regulation, Cell Line, Tumor, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Basic Helix-Loop-Helix Transcription Factors, Animals, Humans, Mitogen-Activated Protein Kinases
Homeodomain Proteins, Embryo, Nonmammalian, Neurogenesis, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, ELAV-Like Protein 3, Nerve Tissue Proteins, DNA, Oligonucleotides, Antisense, Models, Biological, Mice, Amino Acid Substitution, ELAV Proteins, Gene Expression Regulation, Cell Line, Tumor, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Basic Helix-Loop-Helix Transcription Factors, Animals, Humans, Mitogen-Activated Protein Kinases
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