Fig. 1. Notch signaling involves regulated-intramembrane proteolysis. Upon ligand binding, N undergoes two successive proteolytic cleavages (Brown et al., 2000). The first cleavage at the S2 site is ligand induced and generates an activated membrane-bound form of N (blue) that is further processed at the S3 site by the -secretase complex. This leads to the release of the NICD. The association of the NICD with DNA-bound CSL factors disrupts CSL-co-repressor (R) complexes and promotes the assembly of CSL-co-activator (A) complexes, thereby mediating a transcriptional switch. DSL ligands (pink) can be similarly processed, first at extracellular sites (S2) and then at an intramembrane S3 site by the -secretase complex (see text for details). CSL, CBF1, Suppressor of Hairless, Lag-1; Dl, Delta; N, Notch; NECD, Notch extracellular domain; NICD, N intracellular domain; Ser, Serrate.