NOTCH4

Official Full Name

notch receptor 4

Organism

Homo sapiens

GeneID

4855

Background

This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor may play a role in vascular, renal and hepatic development. Mutations in this gene may be associated with schizophrenia. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

Synonyms

INT3;

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Detailed Information

Notch4 is a member of a family of transmembrane receptor proteins. Its structure includes extracellular epidermal growth factor-like (EGF) sequences and six different ankyrin repeats within 33d cells. Members of the Notch family play an important role in controlling the final stages of cell growth. Notch signaling proteins evolved as the only conserved protein family that regulates interactions between adjacent cells.

Figure 1. The Notch pathway is regulated by short-range cell–cell signaling. (Mahnaz, J., et al. 2018)

Notch4 Signaling Pathway

Notch signaling pathway includes Notch receptor (Notch1 receptor, Notch2 receptor, Notch3 receptor, Notch4 receptor), Notch ligand (Jagged1 ligand, Jagged2 ligand, Deha1 ligand, Delta3 ligand, and Delta4 ligand) and CSL (a DNA binding protein).

Notch signaling is activated by the interaction of extracellular Notch receptors with nearby extracellular Notch ligands. The binding of the receptor to the ligand leads to a change in the conformation of the receptor. After two digestions, a transcriptional activation factor is formed, which activates the downstream target genes HES family and HRT family. This further hinders the expression of cell-specific differentiation effector genes and ultimately affects cell differentiation, proliferation, and apoptosis. In addition, studies have shown that the binding of Notch receptors and ligands in the Notch signaling pathway can promote the expression of HRT1 and HRT2, but when HRT1 and HRT2 accumulate to a certain concentration, they will in turn inhibit the expression of themselves and Notch downstream target genes. That is, there is a negative feedback regulation mechanism in the Notch signal path itself.

Notch4 and Tumor

The study found that immunohistochemical analysis of tissues from patients with primary glioblastoma showed that DLL4 (delta-like ligand 4) and Notch4 are mainly distributed on tumor endothelial cells. The analysis showed that there was a significant correlation between the high expression of DLL4 and Notch4 on tumor endothelial cells and the reduction of microvascular density in primary glioblastoma. It is speculated that the DLL4-Notch4 signaling pathway plays an important role in tumor angiogenesis of primary glioblastoma.

Compared with breast cancer tissues, Notch4 expression is lower in normal breast tissues. The study also showed that Notch 4 expression was not found in normal breast tissue, while the Notch4 positive rate in patients with breast invasive ductal carcinoma was 81.48%, and the Notch4 positive rate in patients with breast invasive lobular carcinoma was 92.86%. Notch4 expression in breast cancer tissues was higher than that in normal breast tissues. In addition, Notch4 is expressed differently in different molecular types of breast cancer. Notch4 expression is different in breast cancer patients, and the prognosis is also different. Those with high Notch4 expression have a poor prognosis. Increased expression of Notch4 is related to resistance to endocrine therapy. Studies have found that with the development of acquired resistance to endocrine therapy, the level of Notch4 is increasing, and the expression of Notch4 is higher in resistant cells after endocrine therapy. Another study found that triple-negative breast cancer cells transfected with the Notch4 plasmid had stronger infiltration and migration ability than the non-transfected group, suggesting that Notch4 overexpressing triple negative breast cancer had a higher degree of malignancy.

References:

Mahnaz, J. , Li, X. , Rosen, J. M. , & H.-F., Z. X. . (2018). Notch signaling as a regulator of the tumor immune response: to target or not to target?. Frontiers in Immunology, 9, 1649-.
Bonyadirad, E., Hammerlindl, H., Menon, D. R., Hafner, C., Herlyn, M., & Schaider, H. (2016). Abstract 1679: notch4 mediates mesenchymal-epithelial-like transition in melanoma. , 76(14 Supplement), 1679-1679.
CHENG Rui, KE Kun, & CAI Xinran. (2015). Expression of notch4 affects vasculogenic mimicry formation in hepatocellular carcinoma. Journal of Clinical Hepatology, 31(2).

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