Core components of the canonical Notch signaling pathway in Drosophila. The two Notch ligands encoded by the Serrate (Ser) and Delta (Dl) genes (upper cell) interact with an adjacent cell expressing the Notch receptor. The Notch receptor is proteolytically cleaved by a Furin protease in the Golgi and 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 additional proteolytic cleavages by ADAM-family metalloproteases and the gamma-secretase complex in the membrane-tethered intracellular domain. The final cleavage, catalyzed by gamma-secretase, frees the Notch intracellular domain (NICD) from the cell membrane. NICD translocates to the nucleus, where it forms a complex with the Supressor of Hairless (Su(H)) protein, displacing a histone deacetylase (HDAc)/corepressor (CoR) complex from the Su(H) protein. Components of an activation complex such as the Mastermind (MAM) protein and histone acetyltransferases (HAc) are recruited to the NICD/Su(H) complex, leading to the transcriptional activation of Notch target genes.