The Notch3 gene is encoded by 33 exons spanning 41.35 kb that are located on Chromosome 19p13.12.

8.089 Kb mRNA, the coding sequence is from 77 bp-7042 bp.

2321 amino acids with a predicted molecular mass of 243.66 Kd.
Single-pass type I membrane protein. Contain 1 signal peptide, 36 extracellular EGF repeats, 1 single transmembrane domain, and 2 PEST domains.
Synthesized in the endoplasmic reticulum as an inactive form, which is cleaved by a furin-like convertase in the trans-Golgi complex before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a transmembrane Notch subunit (NTM) and an extracellular Notch subunit (ECN).

Notch3 is a cell surface receptor for membrane-bound ligands including Jagged1, Jagged2, Delta-like1, Delta-like3 and Delta-like4. It is activated by ligand-receptor interaction, which triggers two successive proteolytic cleavages that release the active intracellular domain of Notch (NICD). The NICD translocates to the nucleus, where it interacts with CSL (CBF1/RBP-J kappa, Suppressor of Hairless, LAG-1). Binding of NICD to CSL displaces corepressor complexes and recruits coactivators, leading to transcription from promoters containing CSL-binding elements. The Notch3 target genes participate in wide spectrum of biological processes such as differentiation, proliferation and apoptosis.

Expressed in certain types of fetal and adult tissues.

Mainly located at cell membrane. Following proteolytic events upon ligand binding, its intracellular domain is translocated into the nuclei.

Notch3 is a membrane receptor that mediates cell-cell interactions to facilitate cell differentiation, growth and cell death.

Mutation in NOTCH3 is associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL is an adult-onset disorder characterized by recurrent ischemic strokes, dementia, and premature death. It affects predominantly the small cerebral arteries, leads to progressive degeneration of vasculature smooth-muscle cells.
Disease-associated mutations are distributed throughout the epidermal growth factor-like repeats (EGFRs) that compose the extracellular domain of the Notch3 receptor and result in a loss or a gain of a cysteine residue in one of these EGFRs. Mutation hotspots were located at the two exons encoding the first five EGFRs. The findings suggested that aberrant dimerization of NOTCH3, due to abnormal disulfide bridging with NOTCH3 molecule or another protein, may be involved in the pathogenesis of CADASIL.

Somatic sequence mutations, gene translocation and amplification of chromosomal locus involved Notch3 gene were identified in T-cell lymphoma, non-small-cell lung cancer and ovarian cancer, respectively.