Fig. 2.

The canonical Notch signaling pathway. a The structure of Notch receptor and Notch ligands. The Notch receptors are single transmembrane proteins that consist of multiple extracellular epidermal growth factor (EGF)-like repeats (29–36 repeats), cysteine-rich Lin12-Notch repeats (LNR) (three repeats), a heterodimerization (HD) domain, a transmembrane domain (TMD), a RBPjκ association module (RAM) domain, nuclear localization sequences (NLSs), seven ankyrin repeats (ANK) domain, and proline/glutamic acid/serine/threonine-rich motifs (PEST). The Delta/Serrate/LAG-2 (DSL) ligands are characterized by the presence or absence of a cysteine-rich (C-rich) domain, Serrate/Jagged or Delta/Delta-like (Dll), respectively. Classical DSL ligands contain a DSL domain, a Delta and OSM-11-like proteins (DOS) domain and EGF-like repeats. A subtype of DSL ligands lacking DSL and DOS domains, such as mouse Dll3 and 4, may act alone or along with DOS co-ligands such as DLK-1. b The core Notch signaling pathway. Translated precursor of Notch receptor is glycosylated and cleaved by Furin at site 1 (S1). Matured heterodimer receptor is targeted to the cell surface. The interaction between Notch receptors and ligands on neighboring cells results in the conformational change of receptor and the site 2 (S2) is exposed for the cleavage by ADAM metalloproteases. This cleavage creates the membrane-anchored Notch extracellular truncation (NEXT) fragment and γ-secretase complex then cleaves NEXT from site 3 (S3) to site 4 (S4) to release the Notch intracellular domain (NICD). The NICD translocates into the nucleus and binds to DNA-binding protein CBF1/RBPjκ/Su(H)/Lag-1 (CSL). The NICD/CSL complex is recognized by transcriptional co-activator Mastermind (MAM). This ternary complex recruits additional co-activators (Co-A) to activate transcription. In the absence of NICD, CSL protein associates with a variety of co-repressors (Co-R) and histone deacetylases to suppress transcription of target genes