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The Notch pathway is a gene regulatory pathway involved in multiple differentiation processes.
The Notch protein sits like a trigger penetrating the cell membrane, with part of it inside and part outside. Proteins when binding to the exterior part cause the interior part to release other proteins, which typically then make their way to the cell nucleus to alter gene expression.
The Notch signalling pathway is present in all Metazoans. In mammals, there are 4 different Notch receptors, referred to as Notch1 to Notch4. Notch signalling is often repressed in many cancers, and faulty Notch signalling is implicated in many diseases including T-ALL (T-Cell Associated Lymphoblastic Leukemia), CADASIL (Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy), MS (Multiple Sclerosis), Tetralogy of Fallot, Alagille syndrome, and myriad other disease states.
Details of the pathway
Notch is a single pass transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion which associates in a calcium dependent, non-covalent interaction with a smaller piece of the Notch protein composed of a short extracellular region, a single transmembrane pass, and a small intracellular region. When Notch interacts with its ligands, it can send a signal inside the cell to the nucleus to turn on various genes. The Notch ligands are also single pass transmembrane proteins and are members of the DSL family of proteins. In Drosophila melanogaster (the fruit fly) there are two ligands named Delta and Serrate. In mammals, the corresponding names are Delta-like and Jagged. In mammals there are multiple Delta-like and Jagged ligands. Since both Notch and its ligands are transmembrane proteins, the cells expressing the ligands typically need to be adjacent to the Notch expressing cell for signalling to occur. However, there has been at least one report that suggests that some cells can send out processes that allow signalling to occur between cells that are as much as four or five cell diameters apart.
The Notch extracellular domain is composed primarily of small cysteine knot motifs called EGF-like repeats. Notch 1 for example has 36 of these repeats. Each EGF-like repeat is approximately 40 amino acids, and its structure is defined largely by six conserved cysteine residues that form three conserved disulfide bonds. Each EGF-like repeat can be modified by O-linked glycans at specific sites. An O-glucose sugar may be added between the first and second conserved cysteine, and an O-fucose may be added between the second and third conserved cysteine. These sugars are added by an as yet unidentified O-glucosyltransferase, and GDP-fucose Protein O-fucosyltransferase 1 (OFucT1) respectively. The addition of O-fucose by OFucT1 is absolutely necessary for Notch function, and without the enzyme to add O-fucose, all Notch proteins fail to function properly. As yet, the manner in which the glycosylation of Notch affects function is not completely understood.
The O-glucose on Notch can be further elongated to a trisaccharide with the addition of two xylose sugars by xylosyltransferases, and the O-fucose can be elongated to a tetrasaccharide by the ordered addition of an N-acetylglucosamine (GlcNAc) sugar by an N-Acetylglucosaminyltransferase called Fringe, the addition of a galactose by a galactosyltransferase, and the addition of a sialic acid by a sialyltransferase.
To further complicate things, in mammals there are three Fringe GlcNAc-transferases, named Lunatic Fringe, Manic Fringe, and Radical Fringe. These enzymes are responsible for something called a "Fringe Effect" on Notch signalling. If Fringe adds a GlcNAc to the O-fucose sugar, then the subsequent addition of a galactose and sialic acid will occur. In the presence of this tetrasaccharide, Notch signals strongly when it interacts with the Delta ligand, but has markedly inhibited signalling when interacting with the Jagged ligand. The means by which this addition of sugar inhibits signalling through one ligand, and potentiates signalling through another is not clearly understood.
Once the Notch extracellular domain interacts with a ligand, a protease called TACE (Tumor Necrosis Factor Alpha Converting Enzyme) cleaves the Notch protein just outside the membrane. This releases the extracellular portion of Notch, which continues to interact with the ligand. The ligand plus the Notch extracellular domain is then endocytosed (or swallowed) by the ligand expressing cell. There may be signalling effects in the ligand expressing cell after endocytosis, but this part of Notch signalling is only now beginning to be researched. After this first cleavage, an enzyme called γ-secretase (which is implicated in Alzheimer's disease) cleaves the remaining part of the Notch protein just inside the inner leaflet of the cell membrane. This releases the intracellular portion of the Notch protein, which then moves to the nucleus and causes various genes to be expressed. There are many other proteins involved in the intracellular portion of the Notch signalling cascade too numerous, complicated, and incompletely understood to mention here.
Triggering
It is normally only triggered from direct cell to cell contact. In this way groups of cells can organise themselves, such that if one cell expresses a given trait, this may be switched off in neighbour cells by the inter-cellular notch signal. In this way groups of cells influence one another to make large structures.
The Notch cascade consists of Notch and Notch ligands, as well as intracellular proteins transmitting the Notch signal to the cell's nucleus. The Notch/Lin-12/Glp-1 receptor family was found to be involved in the specification of cell fates during development in Drosophila and C. elegans. The Notch signaling pathway begins to inhibit new cell growth when adolescence is reached, and keeps neural networks stable in adulthood.
External links
- Diagram: Notch signaling in Drosophila: http://www.genome.jp/kegg/pathway/dme/dme04330.html
- Drosphila gene family: http://sdb.bio.purdue.edu/fly/aignfam/neuropro.htm
"Notch signaling"