NOTCH3 explained

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]

Further reading

• Lewis J . Neurogenic genes and vertebrate neurogenesis . Curr. Opin. Neurobiol. . 6 . 1 . 3–10 . 1996 . 8794055 . 10.1016/S0959-4388(96)80002-X . 2921624 .
• Joutel A, Tournier-Lasserve E . [Molecular basis and physiopathogenic mechanisms of CADASIL: a model of small vessel diseases of the brain] . J. Soc. Biol. . 196 . 1 . 109–15 . 2002 . 12134625 . 10.1051/jbio/2002196010109. 86151374 .
• Guidetti D, Casali B, Mazzei RL, Dotti MT . Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy . Clin. Exp. Hypertens. . 28 . 3–4 . 271–7 . 2006 . 16833034 . 10.1080/10641960600549223 . 360190 .
• Beleil OM, Mickey MR, Terasaki PI . Comparison of male and female kidney transplant survival rates . Transplantation . 13 . 5 . 493–500 . 1972 . 4557798 . 10.1097/00007890-197205000-00008 . 32855236 . free .
• Larsson C, Lardelli M, White I, Lendahl U . 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 . 7698746 . 10.1006/geno.1994.1613 .
• Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, Mas JL, Cabanis EA, Baudrimont M, Maciazek J . Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12 . Nat. Genet. . 3 . 3 . 256–9 . 1993 . 8485581 . 10.1038/ng0393-256 . 13031278 .
• Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cécillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E . Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia . Nature . 383 . 6602 . 707–10 . 1996 . 8878478 . 10.1038/383707a0 . 1996Natur.383..707J . 4351873 .
• Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssière C, Cruaud C, Maciazek J, Weissenbach J, Bousser MG, Bach JF, Tournier-Lasserve E . Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients . Lancet . 350 . 9090 . 1511–5 . 1997 . 9388399 . 10.1016/S0140-6736(97)08083-5 . 38044421 .
• Gray GE, Mann RS, Mitsiadis E, Henrique D, Carcangiu ML, Banks A, Leiman J, Ward D, Ish-Horowitz D, Artavanis-Tsakonas S . Human ligands of the Notch receptor . Am. J. Pathol. . 154 . 3 . 785–94 . 1999 . 10079256 . 1866435 . 10.1016/S0002-9440(10)65325-4 .
• Joutel A, Andreux F, Gaulis S, Domenga V, Cecillon M, Battail N, Piga N, Chapon F, Godfrain C, Tournier-Lasserve E . The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients . J. Clin. Invest. . 105 . 5 . 597–605 . 2000 . 10712431 . 289174 . 10.1172/JCI8047 .
• Joutel A, Dodick DD, Parisi JE, Cecillon M, Tournier-Lasserve E, Bousser MG . De novo mutation in the Notch3 gene causing CADASIL . Ann. Neurol. . 47 . 3 . 388–91 . 2000 . 10716263 . 10.1002/1531-8249(200003)47:3<388::AID-ANA19>3.0.CO;2-Q . 11532027 .
• Joutel A, Chabriat H, Vahedi K, Domenga V, Vayssière C, Ruchoux MM, Lucas C, Leys D, Bousser MG, Tournier-Lasserve E . Splice site mutation causing a seven amino acid Notch3 in-frame deletion in CADASIL . Neurology . 54 . 9 . 1874–5 . 2000 . 10802807 . 10.1212/wnl.54.9.1874 . 19374887 .
• Shimizu K, Chiba S, Saito T, Kumano K, Hirai H . Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors . Biochem. Biophys. Res. Commun. . 276 . 1 . 385–9 . 2000 . 11006133 . 10.1006/bbrc.2000.3469 .
• Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD . MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors . Nat. Genet. . 26 . 4 . 484–9 . 2000 . 11101851 . 10.1038/82644 . 23335042 .
• Beatus P, Lundkvist J, Oberg C, Pedersen K, Lendahl U . 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 . 11404076 . 10.1016/S0925-4773(01)00373-2 . 9526831 . free .
• Saxena MT, Schroeter EH, Mumm JS, Kopan R . Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis . J. Biol. Chem. . 276 . 43 . 40268–73 . 2001 . 11518718 . 10.1074/jbc.M107234200 . free .
• Oliveri RL, Muglia M, De Stefano N, Mazzei R, Labate A, Conforti FL, Patitucci A, Gabriele AL, Tagarelli G, Magariello A, Zappia M, Gambardella A, Federico A, Quattrone A . 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 . 11559313 . 10.1001/archneur.58.9.1418 . free .
• Dichgans M, Herzog J, Gasser T . NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL . Neurology . 57 . 9 . 1714–7 . 2001 . 11706120 . 10.1212/wnl.57.9.1714 . 21180235 .

Notes and References

1. Sugaya K, Fukagawa T, Matsumoto K, Mita K, Takahashi E, Ando A, Inoko H, Ikemura T . 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 . 7835890 . 10.1006/geno.1994.1517 .
2. Web site: Entrez Gene: NOTCH3 Notch homolog 3 (Drosophila).
3. Guerreiro RJ, Lohmann E, Kinsella E, Brás JM, Luu N, Gurunlian N, Dursun B, Bilgic B, Santana I, Hanagasi H, Gurvit H, Gibbs JR, Oliveira C, Emre M, Singleton A . 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 . 22153900 . 3306507 . 10.1016/j.neurobiolaging.2011.10.009 .
4. Rusanescu G, Mao J . Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord . J. Cell. Mol. Med. . 18 . 10 . 2103–16 . 2014 . 25164209 . 4244024 . 10.1111/jcmm.12362 .
5. Gripp KW, Robbins KM, Sobreira NL, Witmer PD, Bird LM, Avela K, Makitie O, Alves D, Hogue JS, Zackai EH, Doheny KF, Stabley DL, Sol-Church K . Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome . Am. J. Med. Genet. A . 2014 . 25394726 . 10.1002/ajmg.a.36863 . 167A . 2 . 271–81. 5589071 .
6. Book: 3361718. 2012. Purow. B. Notch Signaling in Embryology and Cancer. 727. 305–319. 10.1007/978-1-4614-0899-4_23. Notch Inhibition as a Promising New Approach to Cancer Therapy. Advances in Experimental Medicine and Biology. 978-1-4614-0898-7. 22399357.
7. Web site: Pfizer Oncology: ADC Development Overview (2016) » ADC Review.