Notch intracellular domain–Recombining binding protein for immunoglobulin kappa J region complex (NICD–CSL) (NICD–CSL)

The Notch intracellular domain–Recombining binding protein for immunoglobulin kappa J region complex (NICD–CSL) is the central transcriptional activator of the Notch signaling pathway [Kopan and Ilagan, 2009, Cell]. Upon activation of Notch receptors by ligands, the receptor is cleaved by gamma-secretase, releasing the NICD into the cytoplasm, which then translocates to the nucleus [Bray, 2016, Nat Rev Mol Cell Biol]. In the nucleus, NICD binds to the DNA-binding protein RBPJ (also known as CSL), converting it from a transcriptional repressor into an activator by recruiting co-activators like Mastermind-like (MAML) [Borggrefe and Oswald, 2009, Cell Signal]. This complex regulates genes involved in cell fate decisions, proliferation, and apoptosis, such as the HES and HEY family of transcription factors [UniProt P31266]. Aberrant activity of the NICD–CSL complex is linked to various malignancies, particularly T-cell acute lymphoblastic leukemia (T-ALL), where gain-of-function mutations in NOTCH1 lead to constitutive complex formation [Aster et al., 2017, Annu Rev Pathol]. Therapeutic targeting of this complex, for instance with small molecules like CB-103, aims to disrupt the protein-protein interaction between NICD and RBPJ to inhibit downstream oncogenic signaling while potentially avoiding some toxicities associated with upstream Notch inhibition [Lehal et al., 2020, Leukemia]. This approach is particularly relevant for cancers that are resistant to gamma-secretase inhibitors or have mutations downstream of the cleavage site. Monitoring target gene expression, such as HES1, serves as a biomarker for the efficacy of these inhibitors in clinical settings.

Other names

NICD-RBPJ complexNotch transcriptional activation complexCSL-NICD-MAML complexRBPJ-NICD complexCBF1-NICD complex

Inhibition of the protein-protein interaction between the Notch intracellular domain (NICD) and the DNA-binding protein RBPJ (CSL), preventing the assembly of the Notch transcriptional activation complex and subsequent recruitment of co-activators like MAML.