NOTCH1
NOTCH1 is a cell-surface receptor that implements direct cell-to-cell communication: contact with a neighboring cell’s ligand converts NOTCH1 into a transcription factor inside the receiving cell.
Function
NOTCH1 is synthesized as a single-chain precursor, cleaved in the Golgi into a heterodimer, and displayed at the surface. When a Delta or Jagged ligand on an adjacent cell binds, the mechanical pull exposes a site for ADAM protease and then γ-secretase, which releases the Notch intracellular domain (NICD). NICD enters the nucleus, binds RBPJ, converts it from a repressor to an activator, and turns on HES/HEY transcription factors. The signal travels only between touching cells, which is how NOTCH implements lateral inhibition — the mechanism that spaces out stem cells, differentiates neighbors, and patterns tissues.
In cancer
NOTCH1’s role in cancer is tissue-dependent in a way few oncogenes are: activating mutations drive T-cell acute lymphoblastic leukemia (where NOTCH1 is the dominant oncogene) and chronic lymphocytic leukemia, while in squamous carcinomas of the skin and head-and-neck NOTCH1 mutations are loss-of-function, making the receptor a tumor suppressor there. γ-secretase inhibitors, developed for Alzheimer’s, were repurposed against NOTCH1-driven leukemia; their gut toxicity follows from the pathway’s role in intestinal stem cells.
Notes
- Human gene symbol: NOTCH1; UniProt P46531; 2,555 amino acids; EGF repeats, Notch domain, ankyrin repeats, PEST region.
- The name is from the notched wing of the Drosophila mutant.