Fig. 2

Notch signaling pathways in CRC. Mind bomb-1 (Mib1), an E3 ubiquitin ligase, promotes the endocytosis of Notch ligands. The extracellular domain of Notch ligands (DLL1 or JAG1 shown) consists of an N-terminal MNNL domain, DSL domain, EC and vWF [69]. The Notch receptors are transmembrane proteins containing extracellular or NECD (EC, LNR, S1 and S2), transmembrane domain or TMD and intracellular domains or NICD (ANK, TAD and PEST) [19]. Activation of Notch pathway is initiated by binding of Notch ligands to Notch receptors which leads to their conformational changes. Then, S2 cleavage site is exposed for ADAM to remove the extracellular region. Subsequently, S3 cleavage occurs by γ-secretase which removes the transmembrane region and releases NICD. Then NICD translocates into the nucleus, and binds to the inactive CSL transcription factor which forms a complex [20]. Instead co-activators, such as MAML could bind to CSL, resulting in activating of this transcriptional complex [21]. Finally, expression of target genes, including Hes family, is induced [18]