1096 members of the HES (Hairy/Enhancer of Split) family of basic helix-loophelix transcriptional regulators (not illustrated). Notch proteins (and ligands) contain extracellular EGF (epidermal growth factor)-like repeats. The repeats 11-12 of Notch (pink) interact with the DSL domain of ligands (pink). The EGF repeats in Delta-like ligands are continuous whereas in the Serrate-like ligands they are interspersed with short linker sequences. Notch can be modified in the Golgi by a glycosyltransferase called Fringe (Blair, 2000) on specific fucose-modified EGF repeats. Fringe is expressed only in a subset of cells; Notch is hyperactivated when Fringe-expressing and-nonexpressing territories abut, forming a boundary (Irvine and Rauskolb, 2001; Wu and Rao, 1999). Notch is secreted to the cell surface in a Furin-convertase-dependent step (Logeat et al., 1998). The LNR (Lin/Notch Repeat; red) domain maintains the association between the polypeptides resulting from the Furin cleavage (at site 1 or S1). The intracellular domain contains the RAM23 domain (RAM), which enhances interaction with CSL protein. The Notch intracellular domain (NICD) contains nuclear localization signals (NLS), a CDC10/ankyrin repeat domain (ANK), which mediates interactions with CSL and other proteins, and a domain rich in proline, glutamate, serine and threonine residues (PEST). Also shown are neuralized (an E3 ubiquitin ligase), presenilin (an intramembrane cleaving protease; I-CliP)(Huppert and Kopan, 2001) and Nicastrin, a protein that interacts with presenilin and is required for plasma membrane localization and stabilization of presenilin (Kopan and Goate, 2002). Presenilin and Nicastrin are part of γsecretase, an activity contributing to Alzheimer’s disease (Kopan and Goate, 2000). A metalloprotease at the cell surface is also required for Notch signaling (Mumm and Kopan, 2000). In the nucleus, CSL binds SMRT (silencing mediator of retinoid and thyroid hormone receptor) and SKIP (ski-related protein). These proteins facilitate nuclear localization of CSL (Zhou and Hayward, 2001) and, together with histone deacetylase (HDAC), repress transcription from target genes (Mumm and Kopan, 2000). In Drosophila, CSL interacts with Hairless and C-terminalbinding protein (CtBP) to mediate repression (see panel 5)(Morel et al., 2001). This is the basal state of cells in which Notch is inactive or absent.