Biology:Notch 3
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
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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.
- ↑ Jump up to: 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)