Notch receptor 3 (Notch3) (Notch3)

Notch receptor 3 (Notch3) is a member of the Notch family of single-pass transmembrane receptors, which are evolutionarily conserved regulators of cell-fate decisions in many tissues during development and in adult homeostasis[2][5]. Notch3 is a type I transmembrane protein with a large extracellular domain containing multiple epidermal growth factor-like (EGF) repeats and a negative regulatory region (NRR), a transmembrane domain, and an intracellular domain (NICD) that mediates downstream signaling[2]. Unlike Notch1 and Notch2, Notch3 lacks a transcription activation domain (TAD) in its NICD[2]. Notch3 is activated primarily by binding to membrane-bound DSL (Delta/Serrate/Lag-2) family ligands such as Jagged1, Jagged2, and Delta1, triggering a series of proteolytic cleavages (S1, S2, S3) that release the NICD, which translocates to the nucleus to regulate target gene expression[2][4]. Notably, Notch3 exhibits higher basal, ligand-independent signaling compared to other Notch receptors, likely due to reduced stability of its autoinhibited NRR conformation[1][5]. Notch3 plays a critical role in the maintenance of vascular smooth muscle cells and is essential for vascular development and function; loss of Notch3 signaling in these cells leads to vascular maturation defects[5][12]. In the central nervous system, Notch3 is preferentially expressed in quiescent neural stem cells and is required for their maintenance, contrasting with the proliferative role of Notch1 in active stem cell populations[5]. Notch3 is also implicated in regulating satellite cells in muscle and luminal stem cells in the mammary gland[5]. Mutations in NOTCH3 are a well-established cause of CADASIL, a hereditary stroke and dementia syndrome[5]. Notch3 is less commonly mutated in T-cell acute lymphoblastic leukemia (T-ALL) compared to Notch1, but it may contribute to tumor biology through both canonical and non-canonical signaling pathways[1][5]. Notch3 is considered a potential therapeutic target in certain cancers and vascular diseases, but challenges remain due to the complexity of Notch signaling and potential for toxicity[5].

Other names

Notch homolog protein 3NOTCH3Neurogenic locus notch homolog protein 3

Inhibition of ligand-receptor interaction, Inhibition of γ-secretase-mediated Notch intracellular domain release, Antagonism of Notch signaling pathway