Pictorial representation of a Notch protein and its signalling pathways. (a) The extracellular domain of Notch contains between 29 and 36 tandemly repeated epidermal growth factor (EGF)-like repeats, some of which are required for the interaction of Notch with its ligands, along with three Lin-12/Notch repeats. The most prominent motifs in the intracellular domain are six cdc10/ankyrin repeats and a PEST domain close to the C-terminus of the protein. The intracellular domain also contains two functionally defined domains: the juxtamembrane RAM23 domain that mediates the interaction of the intracellular domain of Notch with CBF1, Suppressor of Hairless, Lag-1 (CSL) proteins; and a transcriptional activation domain that is C-terminal to the cdc10/ankyrin repeats. (b) The interaction of Delta, Serrate, Lag-2 (DSL) ligands (black) with EGF-like repeats 11 and 12 of Notch (dark blue and yellow) leads to two proteolytic cleavages, one extracellularly and one within the membrane, which release the intracellular domain of Notch (NICD). This fragment of Notch then migrates to the nucleus (dotted line) where it interacts with CSL proteins (orange) via its RAM23 domain to form a transcriptional activator. (c) Recent experiments have suggested that Notch can signal through a second distinct signalling pathway that requires the cytoplasmic protein Deltex (light blue). Deltex has been shown to interact directly with the cdc10/ankyrin repeats of Notch, and signalling through this pathway has been proposed to both inhibit Jun N-terminal kinase (JNK) signalling and to sequester the transcriptional coactivator CREB binding protein (CBP)/p300. It is not currently known whether signalling through this pathway is an intrinsic property of Notch proteins or whether it is activated by a ligand (green). It has been shown, however, that Wnt signalling can regulate this pathway and that this regulation requires both EGF-like repeats 17–19 and 24–26, and the region C-terminal to the cdc10/ankyrin repeats.