NOTCH1

NOTCH1 is a protein-coding gene in humans that encodes Notch receptor 1, a transmembrane receptor essential for Notch signaling. The NOTCH1 gene is located on chromosome 9q34.3 and is expressed in many tissues during development and in adult life.

Notch1 has an extracellular domain rich in epidermal growth factor-like repeats, a negative regulatory region, a single-pass transmembrane segment, and an intracellular domain containing RAM, ankyrin repeats, and transcriptional activation sequences.

Activation and signaling: Notch ligands such as Delta-like 1, 3, and 4 and Jagged1/2 on adjacent cells bind the receptor. This triggers proteolytic cleavages by ADAM-family proteases and gamma-secretase, releasing the Notch intracellular domain (NICD). NICD translocates to the nucleus, associates with RBPJ (CSL) and Mastermind-like cofactors, and converts target genes such as HES and HEY into transcriptional activation. The pathway is tightly regulated by ligand presentation, receptor conformation, and feedback mechanisms.

Biological roles: Notch1 influences cell fate decisions during embryogenesis and maintains stem and progenitor cell populations in several tissues, including the vasculature and thymus. It regulates angiogenesis, neurogenesis, and hematopoiesis, and its activity is context-dependent.

Clinical significance: In cancer, NOTCH1 mutations can be activating in T-cell acute lymphoblastic leukemia (T-ALL), driving uncontrolled proliferation. In other epithelial cancers, including some squamous cell carcinomas, NOTCH1 can act as a tumor suppressor, with loss-of-function mutations observed. In cardiovascular development, NOTCH1 haploinsufficiency is associated with bicuspid aortic valve and aortic valve disease.

Therapeutics and research: Gamma-secretase inhibitors and Notch-targeted antibodies have been explored to treat NOTCH1-driven tumors, but clinical use is limited by on-target toxicities, particularly gastrointestinal. Research continues into selective inhibitors and biomarker-guided approaches.