CSL–Notch intracellular domain transcription complex (CSL-NICD-MAML complex)

The CSL–Notch intracellular domain (NICD) transcription complex is the central nuclear mediator of the canonical Notch signaling pathway, a highly conserved system for cell-to-cell communication (Artavanis-Tsakonas et al., 1999, Science). The complex forms when the Notch receptor is activated by ligands, leading to the proteolytic release of the NICD, which then translocates to the nucleus to bind the DNA-binding protein CSL (also known as RBPJ) (Kovall, 2008, Current Opinion in Structural Biology). This binding event recruits co-activators, specifically the Mastermind-like (MAML) proteins, to convert the CSL protein from a transcriptional repressor into a potent activator of target genes such as HES and HEY (Borggrefe & Oswald, 2009, Cellular and Molecular Life Sciences). This complex is essential for regulating fundamental biological processes, including cell fate determination, stem cell maintenance, and tissue homeostasis. In many cancers, such as T-cell acute lymphoblastic leukemia (T-ALL) and breast cancer, the complex is constitutively active due to mutations, driving uncontrolled cell proliferation (Aster et al., 2017, Annual Review of Pathology). Pharmacological targeting of this complex has shifted from indirect inhibition via gamma-secretase inhibitors to direct disruption of the protein-protein interactions within the ternary complex using small molecules like CB-103 or stapled peptides like SAHM1 (Lehal et al., 2020, Molecular Cancer Therapeutics). However, therapeutic development faces challenges due to the pathway's broad physiological roles, often resulting in dose-limiting gastrointestinal toxicities (Riccio et al., 2008, EMBO Reports).

Other names

RBPJ-NICD-MAML complexNotch transcriptional activator complexCBF1-NICD-Mastermind complexCSL-NICD complex

Direct inhibition of the assembly of the CSL-NICD-MAML ternary complex or indirect inhibition via prevention of NICD release through gamma-secretase inhibition