Mammal Notch receptors, ligands, and canonical activation pathway. (A) Notch ligands and receptors. There are 5 Notch ligands in mammals: Jagged1, Jagged2, Delta-like1 (Dll1), Delta-like3 (Dll3), and Delta-like4 (Dll4). All ligands have an extracellular domain called DSL (Delta, Serrate, and Lag-2) involved in receptor binding associated with EGF-like repeats. There are 4 Notch receptors in mammals: Notch1 to Notch4. The extracellular domain of the 4 receptors has 3 negative regulatory LIN repeats but varies in the number of EGF-like repeats. The cytoplasmic portion of the receptor contains a RAM domain, nuclear localization signal (NLS), ankyrin (ANK) repeats, and a PEST domain regulating protein stability. Notch1 and Notch 2 have TADs; however, they are absent in Notch3 and Notch4. (B) Cognate interaction between Notch receptors and Notch ligands (Jagged/Delta) triggers 2 consecutive proteolytic cleavages by the ADAM10 metalloprotease and the γ-secretase complex. This generates ICN, the signaling portion of the receptor, which enters the nucleus and displaces corepressors (SMRT and CtBP1) and recruits the coactivator MAML1 and the acetyltransferase p300. ICN activating complex is short-lived, and ICN gets phosphorylated on its PEST domain and subsequently ubiquitinated by Fbw7 and targeted for degradation by the proteasome. ADP, adenosine diphosphate; ATP, adenosine triphosphate.