Figure 4.

Scheme of a canonical Notch signaling pathway and therapeutic targets. During transport through endoplasmic reticulum and Golgi apparatus, Notch precursor is glycosylated, cleaved into a heterodimer (S1 cleavage) and transported to the cell membrane. Binding with Notch ligand induces second cleavage (S2 cleavage) by a member of ADAM family of proteases, leaving membrane-bound Notch extracellular truncation (NEXT) fragment. NEXT is subsequently cleaved by γ-secretase complex (S3 cleavage) releasing the active form of the Notch receptor, Notch intracellular domain (NICD), which can translocate to the nucleus, where it activates transcription of Notch target genes by forming transcriptional complex with DNA-binding protein CSL (also known as CBF1/in mammals, Suppressor of Hairless in Drosophila, and LAG-1 in C. elegans) and MAML, which further recruits other transcriptional coactivators (Co-A). Classes of inhibitors and antibodies (Abs, ADC) that target Notch pathway components are indicated. References are included in the main text.