Targeting Notch signaling pathway to overcome drug resistance for cancer therapy - PubMed (original) (raw)

Figure-1. A, Structure of Notch receptors (1-4) and ligands (Jagged-1, 2, Dll-1, 3, 4)

Both receptors and ligands contain multiple conserved domains. Notch is a single-pass transmembrane receptor. The extracellular domain contains EGF-like repeats and a cysteine-rich region. The intracellular domain contains the RAM domain, NLS, ANK, TAD and PEST domain. Notch ligands have multiple EGF-like repeats in their extracellular domain and a CR in Jagged which are absent in Delta. B, Schematic of Notch signaling. Notch signaling is activated after ligand binding to an adjacent Notch receptor between two neighboring cells. Upon activation, Notch receptors undergo a series of proteolytic cleavages by the metalloprotease, TACE, and γ-secretase complex. The cleavage releases the NICD into the cytoplasm, which can subsequently translocate into the nucleus. In the absence of NICD, transcription of Notch target genes is inhibited by a repressor complex mediated by the CSL. When NICD is in the nucleus, it forms an active transcriptional complex due to displacing the histone deacetylase-corepressor complex and recruiting the protein MAML1 and histone acetyltransferases to the CSL complex, leading to convert it from a transcriptional repressor into a transcription activator complex, leading to activation of Notch target genes. Diagram of putative therapeutic target in the Notch pathway. Notch signaling could be inhibited theoretically at many different levels. It is possible to (1) interfere with Notch-ligand interactions, (2) inhibit receptor activation, (3) promote Notch ubiquitination and degradation, (4) inhibit its translocation to the nuclear compartment and (5) inhibit NICD nuclear complex formation. ANK: Ankyrin repeat, CR: Cysteine rich region, DSL: Delta-serrate-lag2, EGF: Epidermal growth factor, LNR: Lin12/Notch repeats, NLS: Nuclear localization signals, PEST: Proline, glutamine, serine,threonine, RAM: RBP-J association molecule domain, TAD: Transcriptional activator domain, TM: Transmembrane domain. CSL: C protein binding factor 1/Suppressor of Hairless/Lag-1, NICD: Notch intracellular domain, TACE: tumor necrosis factor-α-converting enzyme, MAML1: mastermind-like 1.