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.
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 targetedit
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]
Referencesedit
^ abcGRCh38: Ensembl release 89: ENSG00000074181 - Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000038146 - Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Sugaya K, Fukagawa T, Matsumoto K, Mita K, Takahashi E, Ando A, Inoko H, Ikemura T (September 15, 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): 408–19. doi:10.1006/geno.1994.1517. PMID 7835890.
^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 (2012). "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. doi:10.1016/j.neurobiolaging.2011.10.009. PMC3306507. PMID 22153900.
^Rusanescu G, Mao J (2014). "Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord". J. Cell. Mol. Med. 18 (10): 2103–16. doi:10.1111/jcmm.12362. PMC4244024. PMID 25164209.
^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 (2014). "Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome". Am. J. Med. Genet. A. 167A (2): 271–81. doi:10.1002/ajmg.a.36863. PMC5589071. 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. Vol. 727. pp. 305–319. doi:10.1007/978-1-4614-0899-4_23. ISBN978-1-4614-0898-7. PMC3361718. PMID 22399357.
^"Pfizer Oncology: ADC Development Overview (2016) » ADC Review".
Further readingedit
Lewis J (1996). "Neurogenic genes and vertebrate neurogenesis". Curr. Opin. Neurobiol. 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]". J. Soc. Biol. 196 (1): 109–15. doi:10.1051/jbio/2002196010109. PMID 12134625. S2CID 86151374.
Beleil OM, Mickey MR, Terasaki PI (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 (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): 253–8. doi:10.1006/geno.1994.1613. PMID 7698746.
Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, Mas JL, Cabanis EA, Baudrimont M, Maciazek J (1993). "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12". Nat. Genet. 3 (3): 256–9. doi:10.1038/ng0393-256. PMID 8485581. S2CID 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 (1996). "Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia". Nature. 383 (6602): 707–10. Bibcode:1996Natur.383..707J. doi:10.1038/383707a0. PMID 8878478. S2CID 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 (1997). "Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients". Lancet. 350 (9090): 1511–5. doi:10.1016/S0140-6736(97)08083-5. PMID 9388399. S2CID 38044421.
Gray GE, Mann RS, Mitsiadis E, Henrique D, Carcangiu ML, Banks A, Leiman J, Ward D, Ish-Horowitz D, Artavanis-Tsakonas S (1999). "Human ligands of the Notch receptor". Am. J. Pathol. 154 (3): 785–94. doi:10.1016/S0002-9440(10)65325-4. PMC1866435. PMID 10079256.
Joutel A, Andreux F, Gaulis S, Domenga V, Cecillon M, Battail N, Piga N, Chapon F, Godfrain C, Tournier-Lasserve E (2000). "The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients". J. Clin. Invest. 105 (5): 597–605. doi:10.1172/JCI8047. PMC289174. PMID 10712431.
Joutel A, Dodick DD, Parisi JE, Cecillon M, Tournier-Lasserve E, Bousser MG (2000). "De novo mutation in the Notch3 gene causing CADASIL". Ann. Neurol. 47 (3): 388–91. 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, Lucas C, Leys D, Bousser MG, Tournier-Lasserve E (2000). "Splice site mutation causing a seven amino acid Notch3 in-frame deletion in CADASIL". Neurology. 54 (9): 1874–5. doi:10.1212/wnl.54.9.1874. PMID 10802807. S2CID 19374887.
Shimizu K, Chiba S, Saito T, Kumano K, Hirai H (2000). "Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors". Biochem. Biophys. Res. Commun. 276 (1): 385–9. doi:10.1006/bbrc.2000.3469. PMID 11006133.
Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD (2000). "MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors". Nat. Genet. 26 (4): 484–9. doi:10.1038/82644. PMID 11101851. S2CID 23335042.
Beatus P, Lundkvist J, Oberg C, Pedersen K, Lendahl U (2001). "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. doi:10.1016/S0925-4773(01)00373-2. PMID 11404076. S2CID 9526831.
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 (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". Arch. Neurol. 58 (9): 1418–22. doi:10.1001/archneur.58.9.1418. PMID 11559313.
Dichgans M, Herzog J, Gasser T (2001). "NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL". Neurology. 57 (9): 1714–7. doi:10.1212/wnl.57.9.1714. PMID 11706120. S2CID 21180235.
notch3, neurogenic, locus, notch, homolog, protein, notch, protein, that, humans, encoded, gene, available, structurespdbortholog, search, pdbe, rcsblist, codes4zlp, 5czx, 5czvidentifiersaliases, cadasil, casil, imf2, lmns, cadasil1, notch, notch, receptor, 3e. Neurogenic locus notch homolog protein 3 Notch 3 is a protein that in humans is encoded by the NOTCH3 gene 5 6 NOTCH3Available structuresPDBOrtholog search PDBe RCSBList of PDB id codes4ZLP 5CZX 5CZVIdentifiersAliasesNOTCH3 CADASIL CASIL IMF2 LMNS CADASIL1 notch 3 notch receptor 3External IDsOMIM 600276 MGI 99460 HomoloGene 376 GeneCards NOTCH3Gene location Human Chr Chromosome 19 human 1 Band19p13 12Start15 159 038 bp 1 End15 200 995 bp 1 Gene location Mouse Chr Chromosome 17 mouse 2 Band17 B1 17 17 37 cMStart32 339 794 bp 2 End32 385 826 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inpopliteal arteryright coronary arteryascending aortaleft coronary arterysaphenous veinstromal cell of endometriumpericardiumskin of abdomenvaginasubcutaneous adipose tissueTop expressed inexternal carotid arterycorneal stromainternal carotid arteryankle jointmolarvas deferensleft lung lobecarotid bodybody of femurlipMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functioncalcium ion binding protein binding enzyme binding cadherin binding identical protein binding signaling receptor activityCellular componentintegral component of membrane endoplasmic reticulum membrane membrane Golgi membrane receptor complex plasma membrane nucleoplasm extracellular region actin cytoskeleton nucleus cytosol cell surfaceBiological processNotch 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 pathwaySources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez485418131EnsemblENSG00000074181ENSMUSG00000038146UniProtQ9UM47Q61982RefSeq mRNA NM 000435NM 008716RefSeq protein NP 000426NP 032742Location UCSC Chr 19 15 16 15 2 MbChr 17 32 34 32 39 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Function 2 Pathology 3 Pharmaceutical target 4 References 5 Further reading 6 External linksFunction editThis 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 edit nbsp 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 editNotch3 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 References edit a b c GRCh38 Ensembl release 89 ENSG00000074181 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000038146 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Sugaya K Fukagawa T Matsumoto K Mita K Takahashi E Ando A Inoko H Ikemura T September 15 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 19 doi 10 1006 geno 1994 1517 PMID 7835890 a b Entrez Gene NOTCH3 Notch homolog 3 Drosophila Guerreiro RJ Lohmann E Kinsella E Bras JM Luu N Gurunlian N Dursun B Bilgic B Santana I Hanagasi H Gurvit H Gibbs JR Oliveira C Emre M Singleton A 2012 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 doi 10 1016 j neurobiolaging 2011 10 009 PMC 3306507 PMID 22153900 Rusanescu G Mao J 2014 Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord J Cell Mol Med 18 10 2103 16 doi 10 1111 jcmm 12362 PMC 4244024 PMID 25164209 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 2014 Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome Am J Med Genet A 167A 2 271 81 doi 10 1002 ajmg a 36863 PMC 5589071 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 Vol 727 pp 305 319 doi 10 1007 978 1 4614 0899 4 23 ISBN 978 1 4614 0898 7 PMC 3361718 PMID 22399357 Pfizer Oncology ADC Development Overview 2016 ADC Review Further reading editLewis J 1996 Neurogenic genes and vertebrate neurogenesis Curr Opin Neurobiol 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 J Soc Biol 196 1 109 15 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 Clin Exp Hypertens 28 3 4 271 7 doi 10 1080 10641960600549223 PMID 16833034 S2CID 360190 Beleil OM Mickey MR Terasaki PI 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 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 8 doi 10 1006 geno 1994 1613 PMID 7698746 Tournier Lasserve E Joutel A Melki J Weissenbach J Lathrop GM Chabriat H Mas JL Cabanis EA Baudrimont M Maciazek J 1993 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12 Nat Genet 3 3 256 9 doi 10 1038 ng0393 256 PMID 8485581 S2CID 13031278 Joutel A Corpechot C Ducros A Vahedi K Chabriat H Mouton P Alamowitch S Domenga V Cecillion M Marechal E Maciazek J Vayssiere C Cruaud C Cabanis EA Ruchoux MM Weissenbach J Bach JF Bousser MG Tournier Lasserve E 1996 Notch3 mutations in CADASIL a hereditary adult onset condition causing stroke and dementia Nature 383 6602 707 10 Bibcode 1996Natur 383 707J doi 10 1038 383707a0 PMID 8878478 S2CID 4351873 Joutel A Vahedi K Corpechot C Troesch A Chabriat H Vayssiere C Cruaud C Maciazek J Weissenbach J Bousser MG Bach JF Tournier Lasserve E 1997 Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients Lancet 350 9090 1511 5 doi 10 1016 S0140 6736 97 08083 5 PMID 9388399 S2CID 38044421 Gray GE Mann RS Mitsiadis E Henrique D Carcangiu ML Banks A Leiman J Ward D Ish Horowitz D Artavanis Tsakonas S 1999 Human ligands of the Notch receptor Am J Pathol 154 3 785 94 doi 10 1016 S0002 9440 10 65325 4 PMC 1866435 PMID 10079256 Joutel A Andreux F Gaulis S Domenga V Cecillon M Battail N Piga N Chapon F Godfrain C Tournier Lasserve E 2000 The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients J Clin Invest 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 2000 De novo mutation in the Notch3 gene causing CADASIL Ann Neurol 47 3 388 91 doi 10 1002 1531 8249 200003 47 3 lt 388 AID ANA19 gt 3 0 CO 2 Q PMID 10716263 S2CID 11532027 Joutel A Chabriat H Vahedi K Domenga V Vayssiere C Ruchoux MM Lucas C Leys D Bousser MG Tournier Lasserve E 2000 Splice site mutation causing a seven amino acid Notch3 in frame deletion in CADASIL Neurology 54 9 1874 5 doi 10 1212 wnl 54 9 1874 PMID 10802807 S2CID 19374887 Shimizu K Chiba S Saito T Kumano K Hirai H 2000 Physical interaction of Delta1 Jagged1 and Jagged2 with Notch1 and Notch3 receptors Biochem Biophys Res Commun 276 1 385 9 doi 10 1006 bbrc 2000 3469 PMID 11006133 Wu L Aster JC Blacklow SC Lake R Artavanis Tsakonas S Griffin JD 2000 MAML1 a human homologue of Drosophila mastermind is a transcriptional co activator for NOTCH receptors Nat Genet 26 4 484 9 doi 10 1038 82644 PMID 11101851 S2CID 23335042 Beatus P Lundkvist J Oberg C Pedersen K Lendahl U 2001 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 doi 10 1016 S0925 4773 01 00373 2 PMID 11404076 S2CID 9526831 Saxena MT Schroeter EH Mumm JS Kopan R 2001 Murine notch homologs N1 4 undergo presenilin dependent proteolysis J Biol Chem 276 43 40268 73 doi 10 1074 jbc M107234200 PMID 11518718 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 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 Arch Neurol 58 9 1418 22 doi 10 1001 archneur 58 9 1418 PMID 11559313 Dichgans M Herzog J Gasser T 2001 NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL Neurology 57 9 1714 7 doi 10 1212 wnl 57 9 1714 PMID 11706120 S2CID 21180235 External links editNOTCH3 protein human at the U S National Library of Medicine Medical Subject Headings MeSH Retrieved from https en wikipedia org w index php title NOTCH3 amp oldid 1191182660, wikipedia, wiki, book, books, library,
