24.1
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.
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985 that the gene was shown to encode a transmembrane surface receptor, the core signaling component of the pathway.
The Notch Signaling Mechanism
The notch receptor present on the target cell surface undergoes two proteolytic cleavages after its direct interaction with the Delta/Serrate ligand expressed on the surface of the signaling cell. These proteolytic cleavages - sequentially mediated by ADAM metalloproteinases and the γ-Secretase complex - release the cytosolic part of the receptor, called the Notch intracellular domain (NICD), from the membrane into the cell. This NICD is the active signaling molecule, which then translocates to the nucleus where it directly participates in the regulation of the expression of Notch target genes.
Regulation of Signaling
The notch signaling is a complex signaling circuitry regulated at various levels:
- The ligand specificity of the notch receptors is regulated by the O-glycosylation of the Notch protein prior to membrane translocation.
- The expression of the ligand/receptor ratio on the cells determines its role as a signaling cell or a responding cell.
- The signaling is only activated by the trans-interaction between the ligand and the receptor expressed on two different cells. The cis-interaction between the ligand and the receptor expressed on the same cell is inhibitory.
- The extent of the cell to cell contact in tissues can also affect the strength and frequency of notch signaling.
Notch Signaling Functions and Associated Diseases
Recent studies on vertebrates and invertebrates indicate that besides driving multiple aspects of metazoan development, the notch signaling pathway also controls stem cell fate and maintenance in adult tissues. However, the pathway is gene dosage-sensitive, and the appropriate level of signaling is vital for normal differentiation and tissue homeostasis. Any dysregulation in the pathway, either by direct mutations or altered signaling output, may lead to disease states. These include vascular dementia, and developmental disorders like Adams-Oliver syndrome, or Alagille syndrome.
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.
From Chapter 24:
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