Biology:Notch 3
 Generic protein structure example |
Neurogenic locus notch homolog protein 3 (Notch 3) is a protein that in humans is encoded by the NOTCH3 gene.[1][2]
Function
This gene encodes the third discovered human homologue of the Drosophila melanogaster type I membrane protein notch. In Drosophila, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined.
Pathology
Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).[2] Mutations in NOTCH3 have also been identified in families with Alzheimer's disease.[3] Adult Notch3 knock-out mice show incomplete neuronal maturation in the spinal cord dorsal horn, resulting in permanently increased nociceptive sensitivity.[4] Mutations in NOTCH3 are associated to lateral meningocele syndrome.[5]
Pharmaceutical target
Notch3 is being investigated as a target for anti-cancer drugs, as it is overexpressed in several types of cancers.[6] Early clinical trials of Pfizer's PF-06650808, an anti-Notch3 antibody linked to a cytotoxic drug, showed efficacy against solid tumors.[7]
References
- ↑ "Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3". Genomics 23 (2): 408–19. September 15, 1994. doi:10.1006/geno.1994.1517. PMID 7835890.
- ↑ 2.0 2.1 "Entrez Gene: NOTCH3 Notch homolog 3 (Drosophila)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4854.
- ↑ "Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease". Neurobiol. Aging 33 (5): 1008.e17–23. 2012. doi:10.1016/j.neurobiolaging.2011.10.009. PMID 22153900.
- ↑ "Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord". J. Cell. Mol. Med. 18 (10): 2103–16. 2014. doi:10.1111/jcmm.12362. PMID 25164209.
- ↑ "Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome". Am. J. Med. Genet. A 167A (2): 271–81. 2014. doi:10.1002/ajmg.a.36863. PMID 25394726.
- ↑ Purow, B (2012). "Notch Inhibition as a Promising New Approach to Cancer Therapy". Notch Signaling in Embryology and Cancer. Advances in Experimental Medicine and Biology. 727. pp. 305–319. doi:10.1007/978-1-4614-0899-4_23. ISBN 978-1-4614-0898-7.
- ↑ "Pfizer Oncology: ADC Development Overview (2016) » ADC Review". http://adcreview.com/pfizer-adc-development-overview-2016/.
Further reading
- "Neurogenic genes and vertebrate neurogenesis". Curr. Opin. Neurobiol. 6 (1): 3–10. 1996. doi:10.1016/S0959-4388(96)80002-X. PMID 8794055.
- "[Molecular basis and physiopathogenic mechanisms of CADASIL: a model of small vessel diseases of the brain]". J. Soc. Biol. 196 (1): 109–15. 2002. doi:10.1051/jbio/2002196010109. PMID 12134625.
- "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy". Clin. Exp. Hypertens. 28 (3–4): 271–7. 2006. doi:10.1080/10641960600549223. PMID 16833034.
- "Comparison of male and female kidney transplant survival rates". Transplantation 13 (5): 493–500. 1972. doi:10.1097/00007890-197205000-00008. PMID 4557798.
- "The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation". Genomics 24 (2): 253–8. 1994. doi:10.1006/geno.1994.1613. PMID 7698746.
- "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12". Nat. Genet. 3 (3): 256–9. 1993. doi:10.1038/ng0393-256. PMID 8485581.
- "Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia". Nature 383 (6602): 707–10. 1996. doi:10.1038/383707a0. PMID 8878478. Bibcode: 1996Natur.383..707J.
- "Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients". Lancet 350 (9090): 1511–5. 1997. doi:10.1016/S0140-6736(97)08083-5. PMID 9388399.
- "Human ligands of the Notch receptor". Am. J. Pathol. 154 (3): 785–94. 1999. doi:10.1016/S0002-9440(10)65325-4. PMID 10079256.
- "The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients". J. Clin. Invest. 105 (5): 597–605. 2000. doi:10.1172/JCI8047. PMID 10712431.
- "De novo mutation in the Notch3 gene causing CADASIL". Ann. Neurol. 47 (3): 388–91. 2000. doi:10.1002/1531-8249(200003)47:3<388::AID-ANA19>3.0.CO;2-Q. PMID 10716263.
- "Splice site mutation causing a seven amino acid Notch3 in-frame deletion in CADASIL". Neurology 54 (9): 1874–5. 2000. doi:10.1212/wnl.54.9.1874. PMID 10802807.
- "Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors". Biochem. Biophys. Res. Commun. 276 (1): 385–9. 2000. doi:10.1006/bbrc.2000.3469. PMID 11006133.
- "MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors". Nat. Genet. 26 (4): 484–9. 2000. doi:10.1038/82644. PMID 11101851.
- "The origin of the ankyrin repeat region in Notch intracellular domains is critical for regulation of HES promoter activity". Mech. Dev. 104 (1–2): 3–20. 2001. doi:10.1016/S0925-4773(01)00373-2. PMID 11404076.
- "Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis". J. Biol. Chem. 276 (43): 40268–73. 2001. doi:10.1074/jbc.M107234200. PMID 11518718.
- "A novel mutation in the Notch3 gene in an Italian family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: genetic and magnetic resonance spectroscopic findings". Arch. Neurol. 58 (9): 1418–22. 2001. doi:10.1001/archneur.58.9.1418. PMID 11559313.
- "NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL". Neurology 57 (9): 1714–7. 2001. doi:10.1212/wnl.57.9.1714. PMID 11706120.
External links
- NOTCH3+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
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