Neurogenic locus notch homolog protein 4 (NOTCH4) (NOTCH4)

Neurogenic locus notch homolog protein 4 (NOTCH4) is a single-pass transmembrane receptor that functions as a key mediator of the Notch signaling pathway, primarily involved in vascular development and cell fate determination (UniProt: P43331). Upon binding to ligands such as Delta-like (DLL) or Jagged (JAG) on adjacent cells, NOTCH4 undergoes proteolytic cleavage by ADAM proteases and the gamma-secretase complex (PubMed: 27105510). This process releases the Notch intracellular domain (NICD4), which translocates to the nucleus to act as a transcriptional activator for genes involved in cell proliferation and differentiation (NCBI Gene: 4855). In human pathology, NOTCH4 is notably associated with breast cancer, particularly triple-negative subtypes, where its activation supports cancer stem cell populations and promotes metastasis (PubMed: 27105510). It also plays a significant role in the development of arteriovenous malformations and has been linked to genetic susceptibility in schizophrenia (PubMed: 22492583; PubMed: 11013141). Therapeutic targeting of NOTCH4 signaling primarily involves gamma-secretase inhibitors (GSIs) and monoclonal antibodies, although achieving isoform specificity remains a significant hurdle to minimize off-target toxicities like gastrointestinal distress (PubMed: 24030381).

Other names

Notch 4INT3hNotch4Neurogenic locus notch homolog protein 4

Inhibition of gamma-secretase mediated proteolytic cleavage to prevent the release of the Notch intracellular domain (NICD) (PubMed: 27105510).