Notch4 intracellular domain (NICD4, N4ICD, NIC4)

The **Notch4 intracellular domain** (NIC4, NICD4) is the active nuclear form cleaved from the membrane-bound Notch4 receptor after ligand-induced proteolysis. Upon release by sequential ADAM metalloprotease (S2) and γ-secretase (S3) cleavage, NIC4 translocates into the nucleus, where it forms a transcriptional coactivator complex with CSL/RBPJ and other cofactors to regulate expression of Notch target genes. Unlike Notch1 and Notch2, Notch4 lacks a canonical transcription activation domain but retains ankyrin repeats and PEST domains for stability regulation[2][3]. The **Notch4 intracellular domain** participates in critical biological processes including cell fate decisions, apoptosis resistance (especially to DNA-damaging agents; nucleolar localization is crucial for this function), modulation of immune and inflammatory responses (notably in macrophages), and vascular development. Its dysregulation is implicated in multiple pathologies, particularly various cancers, inflammatory states, pulmonary fibrosis, and certain psychiatric diseases[1][4][5][6]. NIC4 function depends on precise subnuclear localization, and its non-canonical roles (distinct from other Notch receptors) make it a promising but challenging therapeutic target, with ongoing research into selective inhibitors or modulators of Notch4 signaling.

Other names

Notch4 ICDNotch4 intracellular domain (often abbreviated as NICD4, NIC4, or N4ICD)Notch 4 (refers to the full receptor; context for specificity as intracellular domain)

γ-secretase inhibition: Prevents release of Notch4 intracellular domain, thus blocking its nuclear signaling. ADAM metalloprotease inhibition: Prevents canonical S2 cleavage, thereby inhibiting NICD formation and downstream signaling.