Recombination signal binding protein for immunoglobulin kappa J region-Notch intracellular domain complex (RBPJ-NICD complex)

The CSL-NICD complex (more formally known as the RBPJ-NICD complex) is the primary nuclear effector of the Notch signaling pathway. Upon activation of Notch receptors by ligands, the Notch intracellular domain (NICD) is proteolytically released and translocates to the nucleus where it binds to the DNA-binding protein CSL (CBF1/RBPJ/Su(H)/Lag-1). This interaction converts CSL from a transcriptional repressor into an activator by recruiting co-activators such as Mastermind-like (MAML), leading to the expression of genes involved in cell fate, proliferation, and survival (PubMed: 25037574, UniProt: P23508). Dysregulation of this complex is a frequent driver in various malignancies, particularly T-cell acute lymphoblastic leukemia (T-ALL) and several solid tumors where Notch signaling is constitutively active (PubMed: 15333840). Therapeutic strategies targeting this complex include direct small molecule inhibitors that disrupt the assembly of the RBPJ-NICD-MAML ternary complex, offering a more specific alternative to broad-spectrum gamma-secretase inhibitors (Nature Communications: 10.1038/s41467-019-11534-4).

Other names

CSL-NICD complexCBF1-NICD-MAML complexNotch transcriptional activation complexRBP-J kappa-NICD complexCSL-NICD-MAML1 ternary complex

Small molecule inhibition of the protein-protein interaction between RBPJ and NICD, or displacement of the Mastermind-like (MAML) co-activator to prevent the assembly of the transcriptionally active ternary complex and subsequent expression of Notch target genes like HES and HEY.