Canonical Notch signaling complex (Notch complex)

The canonical Notch signaling complex is a highly conserved cell-to-cell communication system essential for determining cell fate and maintaining tissue homeostasis [Siebel & Lendahl, 2017]. It consists of transmembrane receptors (NOTCH1, NOTCH2, NOTCH3, and NOTCH4) and their ligands (DLL1, DLL3, DLL4, JAG1, and JAG2) that, upon interaction, trigger a series of proteolytic cleavages by ADAM proteases and the gamma-secretase complex [UniProt, 2024]. This process releases the Notch intracellular domain (NICD), which translocates to the nucleus to form a transcriptional activator complex with the DNA-binding protein CSL (also known as RBPJ) and the co-activator Mastermind-like (MAML) [Aster et al., 2017]. Dysregulation of this complex is implicated in various pathologies, particularly in oncology where overactivation drives tumor progression, angiogenesis, and the maintenance of cancer stem cells [PubMed, 2023]. Therapeutic strategies targeting this complex include gamma-secretase inhibitors (GSIs) and monoclonal antibodies, though clinical utility is often limited by significant gastrointestinal and skin toxicities [StatPearls, 2023]. Recent clinical successes, such as the approval of Nirogacestat for desmoid tumors, underscore the therapeutic potential of modulating this pathway [FDA, 2023].

Other names

Notch signaling pathwayNICD-CSL-MAML complexRBPJ-MAML-NICD complexNotch transcriptional activator complex

Inhibition of gamma-secretase mediated cleavage of Notch receptors; Monoclonal antibody-mediated blockade of ligand-receptor interaction; Inhibition of the transcriptional activator complex formation.