Notch receptors (NOTCH)

The Notch signaling pathway is a highly conserved cell-to-cell communication mechanism that plays a fundamental role in determining cell fate and maintaining tissue homeostasis (1.1.1, 1.2.1). In mammals, the pathway is mediated by four transmembrane receptors (NOTCH1, NOTCH2, NOTCH3, and NOTCH4) that interact with ligands such as Delta-like and Jagged on adjacent cells (1.2.3, 1.3.1). Upon ligand binding, the receptor undergoes sequential proteolytic cleavages, the last of which is performed by the gamma-secretase complex, releasing the Notch intracellular domain (NICD) (1.2.5, 1.4.2). The NICD then translocates to the nucleus to regulate the transcription of target genes like HES and HEY (1.1.2, 1.3.4). Dysregulation of Notch signaling is implicated in various diseases, including T-cell acute lymphoblastic leukemia (T-ALL), where activating mutations are common, and solid tumors like breast and colorectal cancer (1.1.4, 1.3.1). Therapeutic strategies include gamma-secretase inhibitors (GSIs) and monoclonal antibodies, though clinical use is often limited by off-target toxicities, particularly in the gastrointestinal tract (1.3.4, 1.4.1).

Other names

Notch signaling pathwayNeurogenic locus notch homolog proteinNOTCH1NOTCH2NOTCH3NOTCH4

Inhibition of gamma-secretase-mediated cleavage to prevent release of the Notch intracellular domain (NICD), or monoclonal antibody-mediated blockade of receptor-ligand interactions.