The Notch extracellular domain mediates interactions with DSL family ligands, allowing it to participate in juxtacrine signaling.

[3] The most frequently observed phenotype in Notch mutant flies is the appearance of a concave serration at the most distal end of the wings, for which the gene is named, accompanied by the absence of marginal bristles.

[7] Notch-8 mutant males exhibited a lack of the inner germ layers, the endoderm and mesoderm, that resulted in failure to undergo later morphogenesis embryonic lethality.

Genetic screens conducted in Drosophila led to the identification of several proteins that play a central role in Notch signaling, including Enhancer of split,[8] Master mind, Delta,[9] Suppressor of Hairless (CSL),[10] and Serrate.

[21][22][23] The release of the NICD was found to be as a result of proteolytic cleavage of the transmembrane protein through the actions of the γ-secretase complex catalytic subunit Presenilin.

Together the LNR and HD compose the negative regulatory region adjacent to the cell membrane and help prevent signaling in the absence of ligand binding.

Once in the nucleus, several ankyrin repeats and the RAM domain interactions between the NICD and CSL proteins to form a transcriptional activation complex.

[30] Notch family members play a role in a variety of developmental processes by controlling cell fate decisions.

In Drosophila, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development.

In humans, Notch is first cleaved in the NRR domain by furin while being processed in the trans-Golgi network before being presented on the cell surface as a heterodimer.

[40][41] Drosophila Notch does not require this cleavage for signaling to occur,[42] and there is some evidence that suggests that LIN-12 and GLP-1 are cleaved at this site in C. elegans.

[46][47] After proteolytic cleavage, the released NECD is endocytosed into the signal transmitting cell, leaving behind only a small extracellular portion of Notch.