Core components of the canonical Notch signaling pathway. Ligands of the Jagged (JAG1 and JAG2) and Delta-like (DLL1, DLL3, DLL4) families (upper cell, shown in green) interact with Notch family receptors (NOTCH1 through to NOTCH4) on an adjacent cell (lower cell, shown in yellow). The Notch receptor exists at the cell surface as a proteolytically cleaved heterodimer consisting of a large ectodomain and a membrane-tethered intracellular domain. The receptor-ligand interaction induces two additional proteolytic cleavages that free the Notch intracellular domain (NICD) from the cell membrane. The NICD translocates to the nucleus (blue), where it forms a complex with the RBPJ protein, displacing a histone deacetylase (HDAc)-co-repressor (CoR) complex from the RBPJ protein. Components of an activation complex, such as MAML1 and histone acetyltransferases (HAc), are recruited to the NICD-RBPJ complex, leading to the transcriptional activation of Notch target genes.