NOTCH1 gene

NOTCH1 (Notch receptor 1) is a protein-coding gene located on chromosome 9q34.3. The NOTCH1 gene is one of four known genes that encode the NOTCH protein family. These are a group of receptors involved in the Notch signaling pathway. The Notch signaling pathway is involved in processes that have to do with essential processes of cell development, such as differentiation, proliferation and survival.

The encoded protein is a transmembrane protein belonging to a type I transmembrane protein family. This proeinfamy shares common structural features, including an extracellular domain consisting of several epidermal growth factor-like (EGF) repeats and an intracellular domain consisting of several different domain types.

The Notch signaling pathway is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through the binding of Notch family receptors to their corresponding ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize and form the mature transmembrane cell surface receptor. This receptor plays a role in the development of numerous cell and tissue types.

Mutations in this gene are associated with:

• aortic valve disease (Pileggi S et al. 2019)
• Adams-Oliver syndrome
• acute lymphoblastic T-cell leukemia
• chronic lymphocytic leukemia
• squamous cell carcinoma of the head and neck

It has been shown that the activation of Notch correlates with mammary tumorigenesis in mice. Furthermore, increased expression of Notch receptors has been observed in a variety of tumor entities, including cervical, colon, head and neck, lung, kidney, pancreatic, leukemia and breast cancer.

The NOTCH1 protein acts as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1), proteins involved in the regulation of cell fate. Upon activation of the ligand by the released intracellular Notch domain (NICD), a transcriptional activator complex with RBPJ/RBPSUH is formed and activates genes of the enhancer of the split locus. This process influences the implementation of differentiation, proliferation and apoptosis programs. It is involved in angiogenesis; negatively regulates the proliferation and migration of endothelial cells as well as angiogenic sprouting. It is also involved in the maturation of CD4(+) and CD8(+) cells in the thymus.

It is involved in follicular differentiation and possibly in the selection of cell fate within the follicle. During cerebellar development, it acts as a receptor for neuronal DNER and is involved in glial differentiation. Suppresses neuronal and myogenic differentiation. May be involved in mesoderm development, somite formation and neurogenesis.

1. Li Z et al. (2024) Single nucleotide polymorphism of Notch1 gene rs3124599 allele is associated with the severity of CVA6-related HFMD in the Chinese Han population. BMC Infect Dis 24):750.
2. Nadeu Fet al. (2016) Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood 127:2122-2130.
3. Pileggi S et al. (2019) Sequencing of NOTCH1 gene in an Italian population with bicuspid aortic valve: Preliminary results from the GISSI OUTLIERS VAR study. Genes 715:143970.