Notch transcriptional activation complex (pan-NOTCH1-4) (NOTCH-CSL-MAML)

The Notch transcriptional activation complex is a nuclear multiprotein assembly essential for the canonical Notch signaling pathway (Artavanis-Tsakonas et al., 1999, Science). It is formed when the Notch intracellular domain (NICD), released from the cell membrane following ligand binding and proteolytic cleavage by gamma-secretase, translocates to the nucleus (Kovall, 2008, Current Opinion in Genetics & Development). Once inside, NICD interacts with the DNA-binding protein CSL (also known as RBPJ) and recruits co-activators from the Mastermind-like (MAML) family to initiate the transcription of target genes such as HES and HEY (Nam et al., 2006, Cell). This complex plays a critical role in regulating cell fate decisions, proliferation, and apoptosis across various tissues (Bray, 2016, Nature Reviews Molecular Cell Biology). Dysregulation of this complex, often through activating mutations in Notch receptors or overexpression of ligands, is a hallmark of several malignancies, including T-cell acute lymphoblastic leukemia (T-ALL) and various solid tumors (Aster et al., 2017, Annual Review of Pathology). Therapeutic strategies targeting this complex include gamma-secretase inhibitors (GSIs) that prevent NICD release and direct protein-protein interaction inhibitors, such as CB-103, that disrupt the assembly of the NICD/CSL/MAML complex (Lehal et al., 2020, Molecular Cancer Therapeutics). However, pan-Notch inhibition is frequently associated with significant dose-limiting toxicities, particularly gastrointestinal issues like goblet cell metaplasia (Riccio et al., 2006, EMBO Reports).

Other names

NICD/CSL/MAML complexNotch ternary complexRBPJ/Notch/MAML complexNotch signaling complexNotch nuclear complex

Inhibition of the Notch signaling pathway by preventing the formation or transcriptional activity of the nuclear Notch intracellular domain (NICD) complex with CSL and MAML (Kovall, 2008, Current Opinion in Genetics & Development).