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. 2019 May 3;20(8):1068–1082. doi: 10.1080/15384047.2019.1599660

Figure 1.

Figure 1.

Schematic representation of Notch canonical and non-canonical pathway. Initiation of Notch signaling occurs on ligand binding to the receptor. There are five typical Notch ligands Delta like, 1, 3, and 4 and Jagged 1 and 2 with a Delta-Serrate-Lag 2 (DSL) domain, while atypical ligands include DNER, F3/Contactin and NB-3 without a DSL domain and four Notch receptors Notch 1–4.58 Proteolytic cleavage by disintegrin and metalloproteases family proteases (MMP), and gamma-secretase releases active Notch intracellular domain (NICD).59 The biological process is mediated by Notch via canonical and noncanonical pathways. In the canonical Notch pathway, NICD translocates to the nucleus and binds to the transcription factor CSL. Mastermind co-activators activate the CSL-NICD complex leading to suppression of differentiation and maintenance of stemness by activating transcriptional targets HES1 and HEY1. HES1 increases the stemness-related genes in CRC cells and CSC surface markers CD133, ALDH1, and ABCG2. In noncanonical pathway, atypical ligand interacts with receptor promoting differentiation by formation of CSL-NICD-Deltex complex.56,57,60.