The Notch signaling pathway is a highly conserved system found in many multicellular organisms. Mammals are known to express four different gap receptors, termed Notch1, Notch2, Notch3 and Notch4. Notch signaling is critical in a variety of developmental processes, including neurogenesis, myogenesis, angiogenesis, regulation of hematopoiesis and epithelial to mesenchymal transition, and tissue homeostasis. A gap receptor is a transmembrane protein composed of a large extracellular domain that reversibly binds to the extracellular domain of Notch in a calcium-dependent manner. Abnormal Notch signaling leads to important signaling events that promote cancer development and autoimmune diseases.
The Notch signaling pathway is important for cell-cell communication, which involves genetic regulation mechanisms that control embryonic and multiple cell differentiation processes during adulthood. The Notch signal also works in the following process:
Notch signaling is dysregulated in many cancers, and false Notch signaling is involved in many diseases, including T-ALL (T-cell acute lymphoblastic leukemia), CADASIL (cerebral autosomal dominant arterial disease with subcortical infarction and leukoencephalopathy), MS (multiple sclerosis), tetralogy of Fallot, Alagille syndrome and countless other disease states.
Because most ligands are also transmembrane proteins, receptors are typically triggered only by direct cell-to-cell contact. In this way, the population of cells can be organized by themselves such that if a cell expresses a given trait, it can be shut down in adjacent cells by an intercellular Notch signal. In this way, the cell populations influence each other to form a large structure.
The Notch cascade consists of Notch and Notch ligands, as well as intracellular proteins that transmit Notch signaling to the nucleus. The Notch/Lin-12/Glp-1 receptor family was found to be involved in the regulation of cell fate during the development of Drosophila and Caenorhabditis elegans. When puberty is reached, the Notch signaling pathway begins to inhibit new cell growth and stabilize the adult neural network.
Figure 1. Notch protein pathway.
Notch ligands (Figure 2) are type I transmembrane proteins. Drosophila Notch ligands have two homologues Delta and Serrate, the nematode Notch ligand is LAG2. Hence the Notch ligand is also known as DSL protein. A number of Notch ligands are also found in vertebrate, the Delta homology is called Delta-like molecules, and the Serrate homology is called Jagged. Currently, human Notch ligands are found to have DLL 1, 3, 4 and Jagged 1, 2. Ligand Extracellular DSL domains are highly conserved in evolution and are essential for ligand-receptor binding to activate Notch signaling. Intracellular domain of Notch ligands is short, only contains 70 amino acid residues, the function has not yet been clarified. Recent studies have found that the intracellular domain of Delta 1 can induce cell growth inhibition. It is speculated that the intracellular segment of the ligand may be similar with the receptor intracellular domain to have the function of signal transduction, but the specific mechanism needs further study.
Figure 2. Structures of human Notch ligands: JAG1, JAG2, DLL1, DLL3, DLL4, DLK1, and DLK2.
Notch Signal Pathway and Diseases
Notch signaling pathway has a very conservative mechanism in signal transduction, the abnormality of this regulatory mechanism often leads to congenital genetic diseases. It has been confirmed that the mutations of related genes in the Notch signaling pathway are associated with genetic diseases such as CADASIL, Aligile's syndrome and hypogastric hypoplasia. CADASIL is an autosomal dominant cerebral artery disease with subdural necrosis and leukoencephalopathy. The pathogenesis was mainly due to deletion or insertion of cysteine residues in the extracellular domain of Notch 3 gene expressed on vascular smooth muscle cells. Aligile's syndrome is an autosomal dominant genetic disease that can lead to the developmental defects of many organs such as heart, liver and kidney. The main cause of Aligile's syndrome is that the Jagged 1 gene mutation and cannot produce normal translation products. Delta 3 gene mutations can cause autosomal recessive diseases. In addition, the study found that Notch signaling disorders associated with certain cardiovascular diseases. Animal model experiments show that it may affect the cardiovascular system from four aspects, including vascular remodeling, vascular stability, choice of arteriovenous and heart development. Recent studies have found that the cleavage of amyloid precursor protein and Notch receptor are all dependent on γ-secretase / presenilin. Therefore, it is speculated that Notch signaling pathway may have some connection with the occurrence and development of Alzheimer's disease, and AD related research confirmed the change of Notch signal.
Figure 3. A micrograph showing punctate immunostaining (brown) with a Notch 3 antibody, as is characteristic in CADASIL.
Notch signaling pathway plays an important role in cell differentiation, proliferation and development of the body. It is also expected that the signal transduction abnormality will lead to the tumor. This relationship was first confirmed in human acute T-lymphoblastic leukemia due to chromosomal translocations in which the hNotch 1 gene is fused to the T-cell receptor β gene and a constitutively activated hNotch 1 mutant results in an over-activation of Notch signaling. Subsequent studies found that in prostate cancer, breast cancer, cervical cancer and other tumor cells, as well as their derived cell lines, there are abnormal expression of Notch receptors and ligands. In addition to mutations in Notch receptors and ligands that can cause tumors, mutations in cofactor MAML that mediate association of NICD with CSL in the signaling pathway can also lead to tumorigenesis. In addition, Notch signaling can interact with other signaling pathways to induce tumors. For example, Notch 1 mutants accelerate lymphoma formation and progression by synergizing with Myc. However, it was found that Notch also plays a role of tumor suppressor, which also reflects the cell microenvironment closely related to the specific function of Notch signaling.
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