The Notch Signaling Pathway: Mechanistic Insights in Health and Disease

Abstract

The Notch signaling pathway is evolutionarily conserved across metazoan species and plays key roles in many physiological processes. The Notch receptor is activated by two families of canonical ligands (Delta and Serrate/Jagged) where both ligands and receptors are single-pass transmembrane proteins usually with large extracellular domains, relative to their intracellular portions. Upon interaction of the core binding regions, presented on opposing cell surfaces, formation of the receptor/ligand complex initiates force-mediated proteolysis, ultimately releasing the transcriptionally-active Notch intracellular domain. This review focuses on structural features of the extracellular receptor/ligand complex, the role of post-translational modifications in tuning this complex, the contribution of the cell membrane to ligand function, and insights from acquired and genetic diseases.