NOTCH1

About NOTCH1

NOTCH1 on chromosome 9q34.3 encodes a transmembrane receptor of the Notch signaling pathway, a highly conserved system of direct cell to cell communication that controls cell fate decisions, proliferation, and differentiation during development and in adult tissues. When a ligand such as Delta like or Jagged on a neighboring cell binds the receptor, sequential cleavages, the last by gamma secretase, release the Notch intracellular domain, which moves to the nucleus and, with the DNA binding protein RBPJ, activates target genes such as HES and HEY. The pathway is named after the notched wings of fruit flies with partial loss of the gene, studied by Thomas Hunt Morgan in the early twentieth century. NOTCH1 was first linked to human cancer through a chromosomal translocation in T cell acute lymphoblastic leukemia, and activating mutations are found in more than half of T ALL cases, driving T cell development programs. Gamma secretase inhibitors have been tested to block this signaling. NOTCH1 mutations also occur in chronic lymphocytic leukemia, where they are associated with a poorer prognosis and Richter transformation. Conversely, inactivating mutations act as tumor suppressors in squamous cell carcinomas of the skin, head and neck, and esophagus. Germline loss of function variants cause Adams Oliver syndrome and bicuspid aortic valve with calcification.