NOTCH3

NOTCH3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4ZLP, 5CZX, 5CZV
Identifiers
Aliases	NOTCH3, CADASIL, CASIL, IMF2, LMNS, CADASIL1, notch 3, notch receptor 3
External IDs	OMIM: 600276; MGI: 99460; HomoloGene: 376; GeneCards: NOTCH3; OMA:NOTCH3 - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19p13.12 Start 15,159,038 bp[1] End 15,200,995 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17 B1|17 17.37 cM Start 32,339,794 bp[2] End 32,385,826 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in popliteal artery tibial arteries right coronary artery ventricular zone Descending thoracic aorta ascending aorta left coronary artery saphenous vein skin of leg stromal cell of endometrium Top expressed in external carotid artery corneal stroma internal carotid artery ankle joint molar vas deferens Gonadal ridge left lung lobe lactiferous gland carotid body More reference expression data BioGPS More reference expression data
Gene ontology Molecular function calcium ion binding protein binding enzyme binding cadherin binding identical protein binding signaling receptor activity Cellular component integral component of membrane endoplasmic reticulum membrane membrane Golgi membrane receptor complex plasma membrane nucleoplasm extracellular region actin cytoskeleton nucleus cytosol cell surface Biological process Notch signaling pathway cell differentiation regulation of transcription, DNA-templated negative regulation of neuron differentiation negative regulation of cell differentiation glomerular capillary formation negative regulation of transcription by RNA polymerase II transcription, DNA-templated multicellular organism development artery morphogenesis forebrain development neuron fate commitment transcription initiation from RNA polymerase II promoter positive regulation of transcription by RNA polymerase II positive regulation of smooth muscle cell proliferation regulation of developmental process positive regulation of transcription of Notch receptor target Notch receptor processing, ligand-dependent negative regulation of Notch signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4854 18131 Ensembl ENSG00000074181 ENSMUSG00000038146 UniProt Q9UM47 Q61982 RefSeq (mRNA) NM_000435 NM_008716 RefSeq (protein) NP_000426 NP_032742 Location (UCSC) Chr 19: 15.16 – 15.2 Mb Chr 17: 32.34 – 32.39 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Neurogenic locus notch homolog protein 3 (Notch 3) is a protein that in humans is encoded by the NOTCH3 gene.^[5][6]

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

Micrograph showing CADASIL with a Notch 3 immunostain

Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).^[6] Mutations in NOTCH3 have also been identified in families with Alzheimer's disease.^[7] Adult Notch3 knock-out mice show incomplete neuronal maturation in the spinal cord dorsal horn, resulting in permanently increased nociceptive sensitivity.^[8] Mutations in NOTCH3 are associated to lateral meningocele syndrome.^[9]

Pharmaceutical target

Notch3 is being investigated as a target for anti-cancer drugs, as it is overexpressed in several types of cancers.^[10] Early clinical trials of Pfizer's PF-06650808, an anti-Notch3 antibody linked to a cytotoxic drug, showed efficacy against solid tumors.^[11]

Mammalian evolution

An extensive cross-species investigation of the NOTCH3 gene has revealed unexpected natural diversity in a protein that is otherwise highly conserved among mammals. The analysis uncovered multiple cysteine-altering variants in jaguar^[12] a rare splice isoform in humans shared with a small number of other species, and a regulatory-region deletion in Brandt’s bat.^[13]

References

1. GRCh38: Ensembl release 89: ENSG00000074181 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000038146 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Sugaya K, Fukagawa T, Matsumoto K, Mita K, Takahashi E, Ando A, et al. (September 1994). "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): 408–419. doi:10.1006/geno.1994.1517. PMID 7835890.
6. "Entrez Gene: NOTCH3 Notch homolog 3 (Drosophila)".
7. Guerreiro RJ, Lohmann E, Kinsella E, Brás JM, Luu N, Gurunlian N, et al. (May 2012). "Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease". Neurobiology of Aging. 33 (5): 1008.e17–1008.e23. doi:10.1016/j.neurobiolaging.2011.10.009. PMC 3306507. PMID 22153900.
8. Rusanescu G, Mao J (October 2014). "Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord". Journal of Cellular and Molecular Medicine. 18 (10): 2103–2116. doi:10.1111/jcmm.12362. PMC 4244024. PMID 25164209.
9. Gripp KW, Robbins KM, Sobreira NL, Witmer PD, Bird LM, Avela K, et al. (February 2015). "Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome". American Journal of Medical Genetics. Part A. 167A (2): 271–281. doi:10.1002/ajmg.a.36863. PMC 5589071. PMID 25394726.
10. 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. Vol. 727. pp. 305–319. doi:10.1007/978-1-4614-0899-4_23. ISBN 978-1-4614-0898-7. PMC 3361718. PMID 22399357.
11. "Pfizer Oncology: ADC Development Overview (2016) » ADC Review".
12. Figueiró HV, Li G, Trindade FJ, Assis J, Pais F, Fernandes G, et al. (July 2017). "Genome-wide signatures of complex introgression and adaptive evolution in the big cats". Science Advances. 3 (7) e1700299. Bibcode:2017SciA....3E0299F. doi:10.1126/sciadv.1700299. PMC 5517113. PMID 28776029.
13. Seim I, Fang X, Xiong Z, Lobanov AV, Huang Z, Ma S, et al. (2013). "Genome analysis reveals insights into physiology and longevity of the Brandt's bat Myotis brandtii". Nature Communications. 4 2212. Bibcode:2013NatCo...4.2212S. doi:10.1038/ncomms3212. PMC 3753542. PMID 23962925.

Further reading

• Lewis J (February 1996). "Neurogenic genes and vertebrate neurogenesis". Current Opinion in Neurobiology. 6 (1): 3–10. doi:10.1016/S0959-4388(96)80002-X. PMID 8794055. S2CID 2921624.
• Joutel A, Tournier-Lasserve E (2002). "[Molecular basis and physiopathogenic mechanisms of CADASIL: a model of small vessel diseases of the brain]". Journal de la Societe de Biologie. 196 (1): 109–115. doi:10.1051/jbio/2002196010109. PMID 12134625. S2CID 86151374.
• Guidetti D, Casali B, Mazzei RL, Dotti MT (2006). "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy". Clinical and Experimental Hypertension. 28 (3–4): 271–277. doi:10.1080/10641960600549223. PMID 16833034. S2CID 360190.
• Beleil OM, Mickey MR, Terasaki PI (May 1972). "Comparison of male and female kidney transplant survival rates". Transplantation. 13 (5): 493–500. doi:10.1097/00007890-197205000-00008. PMID 4557798. S2CID 32855236.
• Larsson C, Lardelli M, White I, Lendahl U (November 1994). "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): 253–258. doi:10.1006/geno.1994.1613. PMID 7698746.
• Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, et al. (March 1993). "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12". Nature Genetics. 3 (3): 256–259. doi:10.1038/ng0393-256. PMID 8485581. S2CID 13031278.
• Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, et al. (October 1996). "Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia". Nature. 383 (6602): 707–710. Bibcode:1996Natur.383..707J. doi:10.1038/383707a0. PMID 8878478. S2CID 4351873.
• Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssière C, et al. (November 1997). "Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients". Lancet. 350 (9090): 1511–1515. doi:10.1016/S0140-6736(97)08083-5. PMID 9388399. S2CID 38044421.
• Gray GE, Mann RS, Mitsiadis E, Henrique D, Carcangiu ML, Banks A, et al. (March 1999). "Human ligands of the Notch receptor". The American Journal of Pathology. 154 (3): 785–794. doi:10.1016/S0002-9440(10)65325-4. PMC 1866435. PMID 10079256.
• Joutel A, Andreux F, Gaulis S, Domenga V, Cecillon M, Battail N, et al. (March 2000). "The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients". The Journal of Clinical Investigation. 105 (5): 597–605. doi:10.1172/JCI8047. PMC 289174. PMID 10712431.
• Joutel A, Dodick DD, Parisi JE, Cecillon M, Tournier-Lasserve E, Bousser MG (March 2000). "De novo mutation in the Notch3 gene causing CADASIL". Annals of Neurology. 47 (3): 388–391. doi:10.1002/1531-8249(200003)47:3<388::AID-ANA19>3.0.CO;2-Q. PMID 10716263. S2CID 11532027.
• Joutel A, Chabriat H, Vahedi K, Domenga V, Vayssière C, Ruchoux MM, et al. (May 2000). "Splice site mutation causing a seven amino acid Notch3 in-frame deletion in CADASIL". Neurology. 54 (9): 1874–1875. doi:10.1212/wnl.54.9.1874. PMID 10802807. S2CID 19374887.
• Shimizu K, Chiba S, Saito T, Kumano K, Hirai H (September 2000). "Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors". Biochemical and Biophysical Research Communications. 276 (1): 385–389. Bibcode:2000BBRC..276..385S. doi:10.1006/bbrc.2000.3469. PMID 11006133.
• Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD (December 2000). "MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors". Nature Genetics. 26 (4): 484–489. doi:10.1038/82644. PMID 11101851. S2CID 23335042.
• Beatus P, Lundkvist J, Oberg C, Pedersen K, Lendahl U (June 2001). "The origin of the ankyrin repeat region in Notch intracellular domains is critical for regulation of HES promoter activity". Mechanisms of Development. 104 (1–2): 3–20. doi:10.1016/S0925-4773(01)00373-2. PMID 11404076. S2CID 9526831.
• Saxena MT, Schroeter EH, Mumm JS, Kopan R (October 2001). "Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis". The Journal of Biological Chemistry. 276 (43): 40268–40273. doi:10.1074/jbc.M107234200. PMID 11518718.
• Oliveri RL, Muglia M, De Stefano N, Mazzei R, Labate A, Conforti FL, et al. (September 2001). "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". Archives of Neurology. 58 (9): 1418–1422. doi:10.1001/archneur.58.9.1418. hdl:11365/23788. PMID 11559313.
• Dichgans M, Herzog J, Gasser T (November 2001). "NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL". Neurology. 57 (9): 1714–1717. doi:10.1212/wnl.57.9.1714. PMID 11706120. S2CID 21180235.

External links

• NOTCH3+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)