Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

NOTCH3 (Notch homolog 3 (Drosophila))

Identity

Other namesCADASIL
CASIL
HGNC (Hugo) NOTCH3
LocusID (NCBI) 4854
Location 19p13.12
Location_base_pair Starts at 15270444 and ends at 15311792 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Gene orientation: telomere-3 NOTCH3 5-centromere.

DNA/RNA

Description The Notch3 gene is encoded by 33 exons spanning 41.35 kb that are located on Chromosome 19p13.12.
Transcription 8.089 Kb mRNA, the coding sequence is from 77 bp-7042 bp.

Protein

Note 2321 amino acids with a predicted molecular mass of 243.66 Kd.
Single-pass type I membrane protein. Contain 1 signal peptide, 36 extracellular EGF repeats, 1 single transmembrane domain, and 2 PEST domains.
Synthesized in the endoplasmic reticulum as an inactive form, which is cleaved by a furin-like convertase in the trans-Golgi complex before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a transmembrane Notch subunit (NTM) and an extracellular Notch subunit (ECN).
Description Notch3 is a cell surface receptor for membrane-bound ligands including Jagged1, Jagged2, Delta-like1, Delta-like3 and Delta-like4. It is activated by ligand-receptor interaction, which triggers two successive proteolytic cleavages that release the active intracellular domain of Notch (NICD). The NICD translocates to the nucleus, where it interacts with CSL (CBF1/RBP-J kappa, Suppressor of Hairless, LAG-1). Binding of NICD to CSL displaces corepressor complexes and recruits coactivators, leading to transcription from promoters containing CSL-binding elements. The Notch3 target genes participate in wide spectrum of biological processes such as differentiation, proliferation and apoptosis.
Expression Expressed in certain types of fetal and adult tissues.
Localisation Mainly located at cell membrane. Following proteolytic events upon ligand binding, its intracellular domain is translocated into the nuclei.
Function Notch3 is a membrane receptor that mediates cell-cell interactions to facilitate cell differentiation, growth and cell death.

Mutations

Germinal Mutation in NOTCH3 is associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL is an adult-onset disorder characterized by recurrent ischemic strokes, dementia, and premature death. It affects predominantly the small cerebral arteries, leads to progressive degeneration of vasculature smooth-muscle cells.
Disease-associated mutations are distributed throughout the epidermal growth factor-like repeats (EGFRs) that compose the extracellular domain of the Notch3 receptor and result in a loss or a gain of a cysteine residue in one of these EGFRs. Mutation hotspots were located at the two exons encoding the first five EGFRs. The findings suggested that aberrant dimerization of NOTCH3, due to abnormal disulfide bridging with NOTCH3 molecule or another protein, may be involved in the pathogenesis of CADASIL.
Somatic Somatic sequence mutations, gene translocation and amplification of chromosomal locus involved Notch3 gene were identified in T-cell lymphoma, non-small-cell lung cancer and ovarian cancer, respectively.

Implicated in

Entity Non-small-cell lung cancer
Cytogenetics t(15;19)(q11;p13)
Hybrid/Mutated Gene A breakpoint was localized to the cosmid R31546. The breakpoint was found about 50 kilobases (kb) upstream of the Notch3 and within the 3' untranslated region of a putative gene, Hunk1, on 19p. Translocation of chromosome 19p was also found in several other chromosomes, including chromosomes 12q, 14q, 17q, 4q, and 6q. Overexpression of Notch3 full-length mRNA is associated with a 19p translocation.
Oncogenesis The translocation is associated with Notch3 over-expression. Transgenic mouse study by constitutive expression of intracellular domain of Notch3 in lung epithelium using surfactant protein C promoter/enhancer resulted in inhibited differentiation of epithelial lung cell, altered lung morphology, and perinatal lethality in the transgenic mice.
  
Entity Ovarian cancer-serous type
Cytogenetics Chromosome 19p13.12 amplification harboring the Notch3 gene is frequently identified in ovarian cancer.
Oncogenesis In vitro study demonstrated that cell lines with Notch3 over-expression are more sensitive to the anti-proliferative effect of Notch3 signaling pathway inhibitors including gamma-secretase inhibitor and Notch3-specific siRNA.
  

External links

Nomenclature
HGNC (Hugo)NOTCH3   7883
Cards
AtlasNOTCH3ID41557ch19p13
Entrez_Gene (NCBI)NOTCH3  4854  notch 3
GeneCards (Weizmann)NOTCH3
Ensembl (Hinxton)ENSG00000074181 [Gene_View]  chr19:15270444-15311792 [Contig_View]  NOTCH3 [Vega]
ICGC DataPortalENSG00000074181
cBioPortalNOTCH3
AceView (NCBI)NOTCH3
Genatlas (Paris)NOTCH3
WikiGenes4854
SOURCE (Princeton)NM_000435
Genomic and cartography
GoldenPath (UCSC)NOTCH3  -  19p13.12   chr19:15270444-15311792 -  19p13.2-p13.1   [Description]    (hg19-Feb_2009)
EnsemblNOTCH3 - 19p13.2-p13.1 [CytoView]
Mapping of homologs : NCBINOTCH3 [Mapview]
OMIM125310   600276   615293   
Gene and transcription
Genbank (Entrez)AB209447 DQ156540 DQ156541 DQ156542 DQ156543
RefSeq transcript (Entrez)NM_000435
RefSeq genomic (Entrez)AC_000151 NC_000019 NC_018930 NG_009819 NT_011295 NW_001838484 NW_004929414
Consensus coding sequences : CCDS (NCBI)NOTCH3
Cluster EST : UnigeneHs.8546 [ NCBI ]
CGAP (NCI)Hs.8546
Alternative Splicing : Fast-db (Paris)GSHG0015579
Alternative Splicing GalleryENSG00000074181
Gene ExpressionNOTCH3 [ NCBI-GEO ]     NOTCH3 [ SEEK ]   NOTCH3 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UM47 (Uniprot)
NextProtQ9UM47  [Medical]
With graphics : InterProQ9UM47
Splice isoforms : SwissVarQ9UM47 (Swissvar)
Domaine pattern : Prosite (Expaxy)ANK_REP_REGION (PS50297)    ANK_REPEAT (PS50088)    ASX_HYDROXYL (PS00010)    EGF_1 (PS00022)    EGF_2 (PS01186)    EGF_3 (PS50026)    EGF_CA (PS01187)    LNR (PS50258)   
Domains : Interpro (EBI)Ankyrin_rpt [organisation]   Ankyrin_rpt-contain_dom [organisation]   DUF3454_notch [organisation]   EG-like_dom [organisation]   EGF-like_Ca-bd_dom [organisation]   EGF-like_CS [organisation]   EGF-type_Asp/Asn_hydroxyl_site [organisation]   EGF_Ca-bd_CS [organisation]   Growth_fac_rcpt_N_dom [organisation]   Notch [organisation]   Notch_3 [organisation]   Notch_dom [organisation]   Notch_NOD_dom [organisation]   Notch_NODP_dom [organisation]  
Related proteins : CluSTrQ9UM47
Domain families : Pfam (Sanger)Ank_2 (PF12796)    DUF3454 (PF11936)    EGF (PF00008)    EGF_CA (PF07645)    hEGF (PF12661)    NOD (PF06816)    NODP (PF07684)    Notch (PF00066)   
Domain families : Pfam (NCBI)pfam12796    pfam11936    pfam00008    pfam07645    pfam12661    pfam06816    pfam07684    pfam00066   
Domain families : Smart (EMBL)ANK (SM00248)  EGF (SM00181)  EGF_CA (SM00179)  NL (SM00004)  
DMDM Disease mutations4854
Blocks (Seattle)Q9UM47
Human Protein AtlasENSG00000074181 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ9UM47
HPRD02607
IPIIPI00029819   IPI00383389   IPI01012918   IPI00979753   
Protein Interaction databases
DIP (DOE-UCLA)Q9UM47
IntAct (EBI)Q9UM47
FunCoupENSG00000074181
BioGRIDNOTCH3
InParanoidQ9UM47
Interologous Interaction database Q9UM47
IntegromeDBNOTCH3
STRING (EMBL)NOTCH3
Ontologies - Pathways
Ontology : AmiGOGolgi membrane  calcium ion binding  protein binding  extracellular region  nucleus  nucleoplasm  nucleolus  cytoplasm  endoplasmic reticulum membrane  cytosol  plasma membrane  regulation of transcription, DNA-templated  transcription initiation from RNA polymerase II promoter  Notch signaling pathway  Notch receptor processing  gene expression  actin cytoskeleton  integral component of membrane  enzyme binding  forebrain development  receptor complex  negative regulation of neuron differentiation  positive regulation of smooth muscle cell proliferation  neuron fate commitment  glomerular capillary formation  
Ontology : EGO-EBIGolgi membrane  calcium ion binding  protein binding  extracellular region  nucleus  nucleoplasm  nucleolus  cytoplasm  endoplasmic reticulum membrane  cytosol  plasma membrane  regulation of transcription, DNA-templated  transcription initiation from RNA polymerase II promoter  Notch signaling pathway  Notch receptor processing  gene expression  actin cytoskeleton  integral component of membrane  enzyme binding  forebrain development  receptor complex  negative regulation of neuron differentiation  positive regulation of smooth muscle cell proliferation  neuron fate commitment  glomerular capillary formation  
Pathways : KEGGDorso-ventral axis formation    Notch signaling pathway    Thyroid hormone signaling pathway    MicroRNAs in cancer   
Protein Interaction DatabaseNOTCH3
Wikipedia pathwaysNOTCH3
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)NOTCH3
snp3D : Map Gene to Disease4854
SNP (GeneSNP Utah)NOTCH3
SNP : HGBaseNOTCH3
Genetic variants : HAPMAPNOTCH3
Exome VariantNOTCH3
1000_GenomesNOTCH3 
ICGC programENSG00000074181 
Somatic Mutations in Cancer : COSMICNOTCH3 
CONAN: Copy Number AnalysisNOTCH3 
Mutations and Diseases : HGMDNOTCH3
Mutations and Diseases : intOGenNOTCH3
Genomic VariantsNOTCH3  NOTCH3 [DGVbeta]
dbVarNOTCH3
ClinVarNOTCH3
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM125310    600276    615293   
MedgenNOTCH3
GENETestsNOTCH3
Disease Genetic AssociationNOTCH3
Huge Navigator NOTCH3 [HugePedia]  NOTCH3 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneNOTCH3
Homology/Alignments : Family Browser (UCSC)NOTCH3
Phylogenetic Trees/Animal Genes : TreeFamNOTCH3
Chemical/Protein Interactions : CTD4854
Chemical/Pharm GKB GenePA31685
Clinical trialNOTCH3
Cancer Resource (Charite)ENSG00000074181
Other databases
Probes
Litterature
PubMed219 Pubmed reference(s) in Entrez
CoreMineNOTCH3
iHOPNOTCH3
OncoSearchNOTCH3

Bibliography

Chromosome 19 translocation, overexpression of Notch3, and human lung cancer.
Dang TP, Gazdar AF, Virmani AK, Sepetavec T, Hande KR, Minna JD, Roberts JR, Carbone DP
Journal of the National Cancer Institute. 2000 ; 92 (16) : 1355-1357.
PMID 10944559
 
Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice.
Dang TP, Eichenberger S, Gonzalez A, Olson S, Carbone DP
Oncogene. 2003 ; 22 (13) : 1988-1997.
PMID 12673204
 
Notch3 gene amplification in ovarian cancer.
Park JT, Li M, Nakayama K, Mao TL, Davidson B, Zhang Z, Kurman RJ, Eberhart CG, Shih IeM, Wang TL
Cancer research. 2006 ; 66 (12) : 6312-6318.
PMID 16778208
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

Contributor(s)

Written08-2007Tian-Li Wang
Departments of Gynecology/Obstetrics and Oncology Johns Hopkins Medical Institutions CRBII, Rm: 306 1550 Orleans Street Baltimore, MD 21231, USA

Citation

This paper should be referenced as such :
Wang, TL
NOTCH3 (Notch homolog 3 (Drosophila))
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2):120-121.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/NOTCH3ID41557ch19p13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Tue Sep 23 19:13:54 CEST 2014

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.