Introduction to Notch

NOTCH SIGNALING IN DEVELOPMENT AND DISEASE

The Notch pathway is an evolutionarily conserved cell-cell signaling system that operates in most multicellular organisms. Notch signaling is also important for cell differentiation processes in most cell types in an organism, and is frequently used reiteratively during cell lineage progressions. Notch thus ranks as one of the “ivy league” signaling pathways, and mutations or dysregulation of Notch signaling is increasingly linked to disease, including cancer. In its core form, Notch signaling has a simple molecular architecture, yet it is able to control differentiation processes in a wide variety of cell types. Mechanistically, cell-bound ligands on the signal-sending cell activate cell-bound receptors at the signal-receiving cell. The ligand-receptor interaction leads to proteolytic processing of the receptor and ultimately release of the Notch intracellular domain, which traverses from the plasma membrane to the nucleus. In the nucleus, the Notch intracellular domain interacts with the DNA-binding protein CSL (RBP-Jk) to orchestrate a transcriptional response. In addition to this canonical mode of Notch signaling, there are emerging data that Notch signaling also uses alternate, non-canonical, modes of signaling.