Notch receptors and their ligands. Drosophila contains one Notch receptor (dNotch) that is bound by two transmembrane DSL-ligands (Delta and Serrate). Mammalians possess four Notch receptors (Notch1–4) and five ligands (Jagged1 and 2, which are homologous to Serrate, and Delta-like (Dll) 1, 3 and 4, which are homologous to Delta). Notch receptors are expressed on the cell surface as heterodimeric proteins. Their extracellular portion contains 29–36 epidermal growth factor (EGF)-like repeats that are associated with ligand binding, followed by three cysteine-rich LIN repeats that prevent ligand-independent signalling, and a heterodimerization domain. The intracellular portion of the receptor harbours two protein interaction domains, the RAM domain (R) and six ankyrin repeats (ANK), two nuclear localizations signals (NLS) and a transactivation domain (TAD, which has not yet been defined for Notch3 and 4), and a PEST (P) sequence. Notch ligands are also expressed as membrane-bound proteins. They all contain an amino-terminal DSL domain (Delta, Serrate and Lag2) followed by EGF-like repeats. Ligands of the Serrate family also harbour a cysteine-rich (CR) domain downstream of the EGF-like repeats. PM, plasma membrane.