The Notch signaling pathway. Signal-sending Cell: Functional Notch ligands are ubiquitinated by the E3-ubiquitin ligases mindbomb or neuralized. After ligands interact with the Notch receptor, the ligand and the extracellular part of Notch are endocytosed, and ligands may be degraded or recycled. Signal-receiving Cell: The Notch mRNA is translated as a precursor protein, which is cleaved by a furin-like convertase in the Golgi apparatus to produce a functional heterodimeric receptor. During endoplasmic reticulum/Golgi transit, Notch is modified by different glycosyltransferases (Rumi/poglut, pofut, fringes). In cells that express fringe, specific sugar moieties (diamonds) are conjugated to confer higher affinity to Delta-type ligands. After ligand binds to the EGF-like repeats of the Notch extracellular domain, an ADAM metalloprotease cleaves Notch at the S2 site, removing most of the extracellular domain. The membrane-tethered intracellular domain is then cleaved by the Presenilin complex at site S3, either in the plasma membrane or after endocytosis, freeing the Notch intracellular domain (ICN). ICN translocates to the nucleus, displaces the corepressor complex, associates with RBP-J, and recruits coactivators, such as Mastermind. ICN becomes monoubiquitylated (Ub), targeting the receptor for degradation. Several E3 ubiquitin ligases (Deltex, Nedd4, Su(Dx)/Itch, Cbl) can direct Notch receptor trafficking toward lysosomal degradation or toward recycling. Numb can also promote Notch degradation in daughters of an asymmetrically dividing cell.