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NOTCH3 (Notch homolog 3 (Drosophila))

Written2007-08Tian-Li Wang
Departments of Gynecology/Obstetrics, Oncology Johns Hopkins Medical Institutions CRBII, Rm: 306 1550 Orleans Street Baltimore, MD 21231, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesCADASIL
Notch (Drosophila) homolog 3
Notch homolog 3 (Drosophila)
Alias_symbol (synonym)CASIL
HGNC (Hugo) NOTCH3
LocusID (NCBI) 4854
Atlas_Id 41557
Location 19p13.12  [Link to chromosome band 19p13]
Location_base_pair Starts at 15270444 and ends at 15311792 bp from pter ( according to hg19-Feb_2009)  [Mapping NOTCH3.png]
Local_order Gene orientation: telomere-3' NOTCH3 5'-centromere.
Fusion genes
(updated 2016)
GSE1 (16q24.1) / NOTCH3 (19p13.12)MIR143 (5q32) / NOTCH3 (19p13.12)NOTCH3 (19p13.12) / C3 (19p13.3)
NOTCH3 (19p13.12) / LOC100130992 (10p12.31)

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

Note
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.
  

Bibliography

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
 
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
 
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
 

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 journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/NOTCH3ID41557ch19p13.html


Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ]
  Congenital myofibromatosis


External links

Nomenclature
HGNC (Hugo)NOTCH3   7883
Cards
AtlasNOTCH3ID41557ch19p13
Entrez_Gene (NCBI)NOTCH3  4854  notch 3
AliasesCADASIL; CADASIL1; CASIL; IMF2; 
LMNS
GeneCards (Weizmann)NOTCH3
Ensembl hg19 (Hinxton)ENSG00000074181 [Gene_View]  chr19:15270444-15311792 [Contig_View]  NOTCH3 [Vega]
Ensembl hg38 (Hinxton)ENSG00000074181 [Gene_View]  chr19:15270444-15311792 [Contig_View]  NOTCH3 [Vega]
ICGC DataPortalENSG00000074181
TCGA cBioPortalNOTCH3
AceView (NCBI)NOTCH3
Genatlas (Paris)NOTCH3
WikiGenes4854
SOURCE (Princeton)NOTCH3
Genetics Home Reference (NIH)NOTCH3
Genomic and cartography
GoldenPath hg19 (UCSC)NOTCH3  -     chr19:15270444-15311792 -  19p13.12   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)NOTCH3  -     19p13.12   [Description]    (hg38-Dec_2013)
EnsemblNOTCH3 - 19p13.12 [CytoView hg19]  NOTCH3 - 19p13.12 [CytoView hg38]
Mapping of homologs : NCBINOTCH3 [Mapview hg19]  NOTCH3 [Mapview hg38]
OMIM125310   130720   600276   615293   
Gene and transcription
Genbank (Entrez)AB209447 DQ156540 DQ156541 DQ156542 DQ156543
RefSeq transcript (Entrez)NM_000435
RefSeq genomic (Entrez)NC_000019 NC_018930 NG_009819 NT_011295 NW_004929414
Consensus coding sequences : CCDS (NCBI)NOTCH3
Cluster EST : UnigeneHs.8546 [ NCBI ]
CGAP (NCI)Hs.8546
Alternative Splicing GalleryENSG00000074181
Gene ExpressionNOTCH3 [ NCBI-GEO ]   NOTCH3 [ EBI - ARRAY_EXPRESS ]   NOTCH3 [ SEEK ]   NOTCH3 [ MEM ]
Gene Expression Viewer (FireBrowse)NOTCH3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4854
GTEX Portal (Tissue expression)NOTCH3
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UM47   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9UM47  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9UM47
Splice isoforms : SwissVarQ9UM47
PhosPhoSitePlusQ9UM47
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    Ankyrin_rpt-contain_dom    DUF3454_notch    EGF-like_Ca-bd_dom    EGF-like_CS    EGF-like_dom    EGF-type_Asp/Asn_hydroxyl_site    EGF_Ca-bd_CS    Growth_fac_rcpt_    Notch_3    Notch_dom    Notch_NOD_dom    Notch_NODP_dom   
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)  
Conserved Domain (NCBI)NOTCH3
DMDM Disease mutations4854
Blocks (Seattle)NOTCH3
PDB (SRS)4ZLP   
PDB (PDBSum)4ZLP   
PDB (IMB)4ZLP   
PDB (RSDB)4ZLP   
Structural Biology KnowledgeBase4ZLP   
SCOP (Structural Classification of Proteins)4ZLP   
CATH (Classification of proteins structures)4ZLP   
SuperfamilyQ9UM47
Human Protein AtlasENSG00000074181
Peptide AtlasQ9UM47
HPRD02607
IPIIPI00029819   IPI00383389   IPI01012918   IPI00979753   
Protein Interaction databases
DIP (DOE-UCLA)Q9UM47
IntAct (EBI)Q9UM47
FunCoupENSG00000074181
BioGRIDNOTCH3
STRING (EMBL)NOTCH3
ZODIACNOTCH3
Ontologies - Pathways
QuickGOQ9UM47
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  Golgi membrane  calcium ion binding  protein binding  extracellular region  nucleoplasm  nucleoplasm  cytoplasm  endoplasmic reticulum membrane  cytosol  plasma membrane  transcription initiation from RNA polymerase II promoter  Notch signaling pathway  Notch receptor processing  actin cytoskeleton  integral component of membrane  enzyme binding  forebrain development  receptor complex  negative regulation of neuron differentiation  positive regulation of transcription from RNA polymerase II promoter  positive regulation of smooth muscle cell proliferation  neuron fate commitment  artery morphogenesis  glomerular capillary formation  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  Golgi membrane  calcium ion binding  protein binding  extracellular region  nucleoplasm  nucleoplasm  cytoplasm  endoplasmic reticulum membrane  cytosol  plasma membrane  transcription initiation from RNA polymerase II promoter  Notch signaling pathway  Notch receptor processing  actin cytoskeleton  integral component of membrane  enzyme binding  forebrain development  receptor complex  negative regulation of neuron differentiation  positive regulation of transcription from RNA polymerase II promoter  positive regulation of smooth muscle cell proliferation  neuron fate commitment  artery morphogenesis  glomerular capillary formation  
Pathways : KEGGDorso-ventral axis formation    Notch signaling pathway    Thyroid hormone signaling pathway    MicroRNAs in cancer   
REACTOMEQ9UM47 [protein]
REACTOME PathwaysR-HSA-350054 Notch-HLH transcription pathway [pathway]
REACTOME PathwaysR-HSA-1912420 Pre-NOTCH Processing in Golgi [pathway]
REACTOME PathwaysR-HSA-1912408 Pre-NOTCH Transcription and Translation [pathway]
REACTOME PathwaysR-HSA-1912399 Pre-NOTCH Processing in the Endoplasmic Reticulum [pathway]
REACTOME PathwaysR-HSA-1980148 Signaling by NOTCH3 [pathway]
NDEx NetworkNOTCH3
Atlas of Cancer Signalling NetworkNOTCH3
Wikipedia pathwaysNOTCH3
Orthology - Evolution
OrthoDB4854
GeneTree (enSembl)ENSG00000074181
Phylogenetic Trees/Animal Genes : TreeFamNOTCH3
HOVERGENQ9UM47
HOGENOMQ9UM47
Homologs : HomoloGeneNOTCH3
Homology/Alignments : Family Browser (UCSC)NOTCH3
Gene fusions - Rearrangements
Fusion : MitelmanGSE1/NOTCH3 [16q24.1/19p13.12]  [t(16;19)(q24;p13)]  
Fusion : MitelmanMIR143/NOTCH3 [5q32/19p13.12]  [t(5;19)(q32;p13)]  
Fusion : MitelmanNOTCH3/C3 [19p13.12/19p13.3]  [t(19;19)(p13;p13)]  
Fusion: TCGAKIAA0182 NOTCH3 19p13.12 LUAD
Fusion: TCGANOTCH3 19p13.12 C3 19p13.3 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerNOTCH3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)NOTCH3
dbVarNOTCH3
ClinVarNOTCH3
1000_GenomesNOTCH3 
Exome Variant ServerNOTCH3
ExAC (Exome Aggregation Consortium)NOTCH3 (select the gene name)
Genetic variants : HAPMAP4854
Genomic Variants (DGV)NOTCH3 [DGVbeta]
DECIPHER (Syndromes)19:15270444-15311792  ENSG00000074181
CONAN: Copy Number AnalysisNOTCH3 
Mutations
ICGC Data PortalNOTCH3 
TCGA Data PortalNOTCH3 
Broad Tumor PortalNOTCH3
OASIS PortalNOTCH3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICNOTCH3  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDNOTCH3
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)SpainMDB
BioMutasearch NOTCH3
DgiDB (Drug Gene Interaction Database)NOTCH3
DoCM (Curated mutations)NOTCH3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)NOTCH3 (select a term)
intoGenNOTCH3
NCG5 (London)NOTCH3
Cancer3DNOTCH3(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM125310    130720    600276    615293   
Orphanet1001    2537    3545   
MedgenNOTCH3
Genetic Testing Registry NOTCH3
NextProtQ9UM47 [Medical]
TSGene4854
GENETestsNOTCH3
Huge Navigator NOTCH3 [HugePedia]
snp3D : Map Gene to Disease4854
BioCentury BCIQNOTCH3
ClinGenNOTCH3
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4854
Chemical/Pharm GKB GenePA31685
Clinical trialNOTCH3
Miscellaneous
canSAR (ICR)NOTCH3 (select the gene name)
Probes
Litterature
PubMed274 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineNOTCH3
EVEXNOTCH3
GoPubMedNOTCH3
iHOPNOTCH3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Nov 18 20:05:36 CET 2016

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