Notch1

The diverse effects of Notch are also attributed to interactions with other signaling pathways, which are still largely unexplained. The closest interactions have been found between the NOTCH and EGF (Epidermal Growth Factor) signaling pathways, which can be both agonistic and antagonistic in nature.

NOTCH1 (Notch receptor 1) is encoded by the 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.

NOTCH1 is a transmembrane protein that belongs to a type I transmembrane protein family. This proein family 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. After ligand binding, the extracellular part is separated by a metalloprotease and the intracellular part of the receptor migrates into the cell nucleus and acts directly as a gene activator itself.

The transmembrane protein NOTCH1 regulates numerous processes in keratinocytes, such as cell differentiation, cell proliferation and apoptosis. It promotes the differentiation of embryonic keratinocytes and suppresses their uninhibited proliferation.

A lack of NOTCH1 favors the occurrence of squamous cell carcinomas. NOTCH1 expression is reduced in squamous cell carcinomas.

In head and neck squamous cell carcinoma (HNSCC), NOTCH1 is often mutated, leading to its loss of function, which explains the role of NOTCH1 as a tumor suppressor in this type of cancer. In addition, loss of NOTCH1 signaling can promote HNSCC tumorigenesis and clinical aggressiveness. The presence of NOTCH1 mutations may predict response to treatment with an immune checkpoint or phosphatidylinositol 3-kinase inhibitors (Shah PA et al. 2020)

UVA rays have a suppressive effect on NOTCH1 expression.

Furthermore, the NOTCH 1 protein in hematopoiesis is an essential factor for the differentiation of T lymphocytes and a general anti-apoptotic factor for T cells. In immature B cells, however, NOTCH1 tends to have a proapoptotic and antiproliferative effect. Experimental data indicate that the NOTCH1 protein is activated in antigen-stimulated mature B lymphocytes and has an inhibitory effect on both immunoglobulin secretion and the lifespan of the activated B cells.

The NOTCH1 gene exhibits mutations in approx. 50% of all acute T-cell leukemias, which lead to permanent activation.

The intracellular counterpart of NOTCH is Hairless. The names of these signaling components result from the external appearance of the fruit flies. Animals with a mutation in the Hairless gene have no bristles on their surface, while mutations in the Notch receptor result in characteristic notches in the area of the wing edge.

1. Shah PA et al. (2020) NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma. Cells 9:2677.