Neurogenic locus notch homolog protein 3 (NOTCH3) (NOTCH3)

Neurogenic locus notch homolog protein 3 (NOTCH3) is a single-pass transmembrane receptor that plays a critical role in cell-fate determination and vascular homeostasis (UniProt: P31689). Upon binding to ligands such as Jagged or Delta-like, the receptor undergoes sequential proteolytic cleavages by ADAM proteases and the gamma-secretase complex, ultimately releasing the Notch intracellular domain (NICD), which translocates to the nucleus to act as a transcriptional regulator (PubMed: 30104714). In healthy tissues, NOTCH3 is predominantly expressed in vascular smooth muscle cells and is essential for the structural integrity of small arteries (NCBI Gene: 4854). Dysregulation of NOTCH3 signaling is a hallmark of several pathologies, most notably CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a hereditary stroke disorder caused by specific mutations in the receptor's extracellular domain (PubMed: 25118608). Additionally, NOTCH3 is frequently overexpressed in various malignancies, including ovarian, lung, and breast cancers, where it promotes tumor cell survival, epithelial-mesenchymal transition, and chemoresistance (PubMed: 30104714). Therapeutic strategies targeting NOTCH3 include monoclonal antibodies designed to block ligand-receptor interactions and gamma-secretase inhibitors that prevent the activation of the signaling cascade (PubMed: 28701370). Antibody-drug conjugates (ADCs) are also being explored to deliver cytotoxic payloads specifically to NOTCH3-expressing tumor cells (PubMed: 25118608).

Other names

Notch 3CADASILCASILIMF2LMNSCADASIL1

Monoclonal antibody antagonism, gamma-secretase inhibition, and antibody-drug conjugation