Fig. 3. Structure and functional organization of Notch signalling. Notch and its ligands (members of the DSL family) are transmembrane proteins. (A) In the absence of ligand, the full-length Notch protein is present at the cell surface as a heterodimer of the extracellular (ECN) and the transmembrane-intracellular domains. (B) (a) Binding of a Notch ligand (Serrate/Jagged/Delta) to specific EGF-like repeats (blue) triggers (b) a proteolytic cleavage, S2, in the extracellular juxtamembrane region (grey) of Notch by members of the ADAM tumour necrosis factor converting enzyme (TACE) proteases. This event primes (c) a second ligand-independent cleavage, S3, within the transmembrane domain (purple) of Notch, which is catalysed by the Presenilin--secretase complex. As a result of S3 cleavage, (d) the intracellular domain of Notch (NICD) enters the nucleus, where it (e) interacts with CSL, displaces co-repressors and through Mastermind (MAML) recruits co-activators to (f) promote the transcription of target genes. For further details, see text and published literature (Bray, 2006; Ehebauer et al., 2006; Kopan, 2002; Le Borgne, 2006). ADAM, a disintegrin and metalloprotease; CBP, CREB binding protein (also known as Crebbp); CSL, CBF/Suppressor of Hairless/LAG-1; DSL, Delta/Serrate/LAG-2; ECN, Extracellular Notch; Pol II, RNA polymerase II; TACE, TNF-converting enzyme.