Notch signaling pathway

Notch-mediated juxtacrine signal between adjacent cells

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.

[pmid10221902-1] 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.

[ReferenceB-2] 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.

[pmid10882063-3] 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.

[pmid17404512-4] 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.

[5] 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.

[6] 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.

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