Figure 2.

The life cycle of Notch. Schematic model of the synthesis, secretory and endocytic transport, activation and turnover of Notch. Locations in the cell where proteolytic cleavages can occur are indicated (1–3) and may be relevant to detachment of the Notch3 extracellular domain (ECD). (1) Notch is cleaved by furin while in transit in the Golgi to form a processed heterodimer. (2) At the cell surface, ligand interaction promotes exposure of the S2 cleavage site, which is a substrate for Adam10-dependent cleavage. The released ECD is endocytosed, along with bound ligand, into the signal-sending cell. (3) In Drosophila, Notch endocytosis is by both clathrin-dependent and -independent routes [20] respectively promoted by ubiquitin ligase regulators deltex (Dx) and suppressor of deltex (Su(dx)). Dx promotes ligand-independent activation of Notch following removal of ECD by an Adam10-independent mechanism and presenilin-dependent release of intracellular domain (ICD) through S3 cleavage. Su(dx) promotes Notch transfer to intraluminal vesicles of the endosome and degradation of the full-length receptor on lysosome fusion.