Series of molecular signals
Notch-mediated juxtacrine signal between adjacent cells
Notch signaling steps
The Notch signaling pathway is a highly conserved cell signaling system present in most animals .[ 1] Mammals possess four different notch receptors , referred to as NOTCH1 , NOTCH2 , NOTCH3 , and NOTCH4 .[ 2] The notch receptor 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.[ 3]
Notch signaling promotes proliferative signaling during neurogenesis , and its activity is inhibited by Numb to promote neural differentiation. It plays a major role in the regulation of embryonic development.
Notch signaling is dysregulated in many cancers, and faulty notch signaling is implicated in many diseases, including T-cell acute lymphoblastic leukemia (T-ALL ),[ 4] cerebral autosomal-dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), multiple sclerosis, Tetralogy of Fallot , and Alagille syndrome . Inhibition of notch signaling inhibits the proliferation of T-cell acute lymphoblastic leukemia in both cultured cells and a mouse model.[ 5] [ 6]
^ Artavanis-Tsakonas S, Rand MD, Lake RJ (April 1999). "Notch signaling: cell fate control and signal integration in development". Science . 284 (5415): 770–776. Bibcode :1999Sci...284..770A . doi :10.1126/science.284.5415.770 . PMID 10221902 .
^ Kumar R, Juillerat-Jeanneret L, Golshayan D (September 2016). "Notch Antagonists: Potential Modulators of Cancer and Inflammatory Diseases" . Journal of Medicinal Chemistry . 59 (17): 7719–7737. doi :10.1021/acs.jmedchem.5b01516 . PMID 27045975 . S2CID 43654713 .
^ Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, et al. (February 2000). "A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE" . Molecular Cell . 5 (2): 207–216. doi :10.1016/S1097-2765(00)80417-7 . PMID 10882063 .
^ Sharma VM, Draheim KM, Kelliher MA (April 2007). "The Notch1/c-Myc pathway in T cell leukemia" . Cell Cycle . 6 (8): 927–930. doi :10.4161/cc.6.8.4134 . PMID 17404512 .
^ Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, et al. (November 2009). "Direct inhibition of the NOTCH transcription factor complex" . Nature . 462 (7270): 182–188. Bibcode :2009Natur.462..182M . doi :10.1038/nature08543 . PMC 2951323 . PMID 19907488 .
^ Arora PS, Ansari AZ (November 2009). "Chemical biology: A Notch above other inhibitors" . Nature . 462 (7270): 171–173. Bibcode :2009Natur.462..171A . doi :10.1038/462171a . PMID 19907487 . S2CID 205050842 .