Notch transcription complex (NTC)

The Notch transcription complex (NTC) is the functional nuclear unit of the Notch signaling pathway, a highly conserved mechanism for cell-to-cell communication that governs cell fate decisions (PMID: 19153652). The complex is a ternary assembly consisting of the Notch intracellular domain (NICD), the DNA-binding protein RBPJ (also known as CSL), and a member of the Mastermind-like (MAML) family of co-activators. In the absence of a signal, RBPJ associates with co-repressors to inhibit target gene expression; however, upon ligand binding and subsequent proteolytic cleavage of the Notch receptor, the NICD translocates to the nucleus to displace these repressors and recruit MAML, thereby initiating the transcription of downstream targets such as HES1 and MYC (PMID: 27959635). Aberrant activation of the NTC, often driven by mutations in the Notch receptor or regulatory proteins like FBXW7, is a hallmark of several malignancies, most notably T-cell acute lymphoblastic leukemia (T-ALL) and adenoid cystic carcinoma. While early therapeutic strategies focused on gamma-secretase inhibitors (GSIs) to prevent NICD release, direct pharmacological targeting of the NTC using small molecule protein-protein interaction (PPI) inhibitors like CB-103 offers a more specific approach to blocking Notch-driven oncogenesis while potentially mitigating some of the pan-Notch toxicities associated with upstream inhibition (PMID: 31616059).

Other names

NICD/RBPJ/MAML complexNotch ternary complexCSL-NICD-MAML complexNotch signaling complexRBPJ-NICD-MAML1 complex

Small molecule inhibition of the assembly of the Notch transcription complex by disrupting the protein-protein interactions between the Notch intracellular domain (NICD), the DNA-binding protein RBPJ (CSL), and the co-activator Mastermind-like (MAML) protein (PMID: 31616059).