Molecular Mechanisms of Notch Signaling

Franz Oswald, Rhett A. Kovall

The highly conserved Notch signal transduction pathway orchestrates fundamental cellular processes including, differentiation, proliferation, and apoptosis during embryonic development and in the adult organism. Dysregulated Notch signaling underlies the etiology of a variety of human diseases, such as certain types of cancers, developmental disorders and cardiovascular disease. Ligand binding induces proteolytic cleavage of the Notch receptor and nuclear translocation of the Notch intracellular domain (NICD), which forms a ternary complex with the transcription factor CSL and the coactivator MAML to upregulate transcription of Notch target genes. The DNA-binding protein CSL is the centrepiece of transcriptional regulation in the Notch pathway, acting as a molecular hub for interactions with either corepressors or coactivators to repress or activate, respectively, transcription. Here we review previous structure-function studies of CSL-associated coregulator complexes and discuss the molecular insights gleaned from this research. We discuss the functional consequences of both activating and repressing binding partners using the same interaction platforms on CSL. We also emphasize that although there has been a significant uptick in structural information over the past decade, it is still under debate how the molecular switch from repression to activation mediated by CSL occurs at Notch target genes and whether it will be possible to manipulate these transcription complexes therapeutically in the future.