14.1 : Notch Signaling Pathway

Notch proteins are single-pass transmembrane receptors with an extracellular domain that binds the ligand, a transmembrane domain that spans the plasma membrane, and an intracellular domain that acts in signaling.

These receptors act to control cell fate decisions, such as proliferation or apoptosis, in many tissues.

They do this by regulating multiple specific target genes that are critical during animal embryonic development, as well as for adult homeostasis.

Because of their critical functions, the notch signaling pathway is a highly conserved cell signaling system present in most animals.

Notch signaling requires direct cell-to-cell interaction and is controlled by three critical cleavages of the notch protein.

The first proteolytic cleavage of the Notch protein happens in the Golgi apparatus of the responding cell, and this generates a heterodimeric Notch receptor, which is then transported to the cell surface as a Notch receptor.

The second proteolytic cleavage occurs when a Delta-Serrate ligand expressed on a signaling cell interacts with the Epidermal growth factor-like repeats present on the extracellular domain of the Notch receptor.

Once bound, the Delta protein undergoes endocytosis in the signaling cell, stretching the notch protein and making it accessible to a family of metalloproteinases for an extracellular cleavage.

The third and final cleavage is critical, as an intramembrane cleavage mediated by the gamma-secretase complex releases the Notch Intracellular Domain, also known as the NICD, from the membrane.

This NICD then translocates to the nucleus and forms a complex with a sequence-specific DNA binding protein of the CSL family, as well as several other transcriptional co-activators, to switch on the expression of the Notch target genes. 

The primary target genes include the Hes family of transcriptional repressors that have been shown to play an essential role in the development of many organs during embryogenesis.

However, Notch signaling and its diverse outcomes are dependent on many factors.

For example, the relative level of expression of the ligand and the notch receptor on a cell can determine whether it will act as a signaling or a responding cell.

Additionally, a cis- interaction between a ligand and receptor on the same cell can lead to inhibition of the whole pathway.

Similarly, the extent of the cell to cell contact in tissue, such as high amounts of surface contact, versus lower or filopodia only contacts, can also affect the strength and frequency of notch signaling in the responding cell.

Since Notch signaling has a crucial role in animal development, any abnormalities in its functioning can lead to many diseases in humans, including cancers or neurological and developmental disorders.