Notch signaling pathway

Synonym(s)

Notch

Definition
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One of the most important and widespread signalling pathways in animals and also in humans, which is crucial in the development of all organs and tissues in animal and human embryos. For this reason, the principle sequence of this signalling pathway is the same in all living organisms and has thus been handed down (conserved) with great consistency in the history of evolution. For example, the signals exchanged via Notch receptors between two neighbouring cells of the same type enable them to develop into completely different tissues.

General information
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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 is a transmembrane protein that is encoded by the gene of the same name located on chromosome 9q34.3. The protein eliminates a single transmembrane domain with a large extracellular domain. 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 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.

Notch1 regulates numerous processes in keratinocytes, such as cell differentiation, cell proliferation and apoptosis. Notch1 induces p21, Notch promotes the differentiation of embryonic keratinocytes and suppresses uninhibited proliferation. A deficiency of Notch 1 favors the occurrence of squamous cell carcinomas. Notch 1 is expressed at a reduced level in squamous cell carcinomas. UVA rays have a negative influence on Notch 1 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 Notch1 is activated in antigen-stimulated mature B lymphocytes and has an inhibitory effect on both immunoglobulin secretion and the lifespan of activated B cells. The NOTCH1 gene exhibits mutations in approx. 50% of all acute T-cell leukemias, which lead to permanent activation.