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NOTCH2 (Notch homolog 2 (Drosophila))

Identity

Other namesAGS2
hN2
HGNC (Hugo) NOTCH2
LocusID (NCBI) 4853
Location 1p12
Location_base_pair Starts at 120477736 and ends at 120612317 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
Description 34 exons
Transcription 7860 bp

Protein

 
  A. : 2472 AA, 265.4 KD.
LNR: Lin/Notch repeats (light blue); TM: transmembrane; OPA: glutamine-rich region; PEST sequence
Dark blue: Epidermal Growth Factor repeats
Light red: ankyrin repeats
Dark red: Nuclear localization signal
B. : Notch activation diagram
Description This gene encodes a member of the Notch family. Members of this family are Type1 transmembrane receptors and share structural characteristics represented in the diagram. The conserved domains include 36 EGF repeats and 3 lin/Notch Repeats (LNR) in the extracellular domain, 7 Ankyrin repeats, 2 different nuclear localization domains and 1 OPA/PEST region conform the intracellular domain.
The Notch2 gene is transcribed and translated as a single inactive protein. This protein is cleaved by a furin-like convertase in the trans-golgi network before it reaches the plasma membrane to yield an active form. Cleavage results in a C-terminal fragment and a N-terminal fragment, linked by disulfide bridges. Following ligand binding, it is first cleaved by ADAM17 metallopeptidase to yield a membrane-associated intermediate fragment. This fragment is then cleaved by presenilin dependent gamma-secretase to release a Notch-derived peptide containing the intracellular domain from the membrane (see Notch activation diagram).
Protein modifications:
  • Phosphorylation: Different phosphorylation processes are important for regulating Notch2 activity. Only GSK3beta has been found to phosphorylate Notch2 in 32D-myeloid cells.
  • Glycosylation: fringe glycosyl-transferases modify the extracellular domain of Notch2 by glycosylation.
  • Expression Expressed in the brain, heart, kidney, spleen (hematopoietic cells,T-cells, B-cells and mast cells), lung, intestine, skeletal muscle and liver (hepatic cells and bile duct cells), ameloblasts.
    Localisation Type I membrane protein. Following proteolytical processing it is translocated to the nucleus.
    Function Physiological receptor for membrane-bound ligands jagged1, jagged2 and delta1 to regulate cell-fate determination. Upon ligand activation, Notch intracellular domain forms a transcriptional activator complex with RBP-j kappa and Mastermind proteins and activates genes of the hairy/enhancer of split (hes) family. Notch2 behaves very similar to Notch1 at the biochemical level, and in fact, C-terminal intracellular region of Notch1 can functionally replace that of Notch2 in vivo. However specific functions, specific expression patterns and embryonic lethality of single mutant mice indicate that both proteins are not redundant.
    Biological functions strictly associated to Notch2 are:
  • Development of kidney (proximal nephron structures: podocytes and proximal convoluted tubules).
  • B-cell differentiation: involved in the final stages of B-cell maturation at the marginal zone of the spleen and expression of CD23 in B-CLL (B-Cell Chronic Lymphoblastic leukaemia).
  • T-cell maturation: later stages of T cell development, induction of CD8+ cells.
  • Notch2 is also required for formation of the placental circulatory system.
  • Homology Degree of amino acid identity between Notch1 and Notch2 proteins: overall, 56%; EGF-like repeats, 58%; LNR,58%; CDC10, 76% and PEST, 79%.

    Mutations

    Germinal Two different mutations segregating in two families affected by Alagille syndrome: One mutation results in partial deletion of the intracellular domain including 4 ankyrin repeats, the second mutation affects EGF repeat 11.

    Implicated in

    Entity Alagille syndrome (AGS)
    Disease Alagille syndrome (AGS) is a dominant multisystem disorder defined clinically by bile duct paucity and cholestasis in association with cardiac, skeletal and ophthalmologic manifestations with less-frequent clinical involvement of renal and vascular systems. 94% of affected individuals have mutations in the Jagged1 gene.
    Oncogenesis Notch2 intracellular domain (active Notch2) has neoplastic transformation capacities.
      
    Entity B-Cell Chronic Lymphoblastic Leukemia (B-CLL).
    Oncogenesis Function: upregulation of CD23, which has been correlated with high cell viability and inhibition of apoptosis in B-CLL.
      
    Entity Embryonal brain tumors, medulloblastoma
    Prognosis Target gene hes1 expression correlates with shorter patient survival.
    Oncogenesis Loss of heterozygosity of Notch2 results in positive survival of Oligodendrioma and glioblastoma.
    Amplification in 15% of 40 analyzed embryonal brain tumors.
      
    Entity Melanoma
    Oncogenesis Amplification of 1p12 in melanoma cell lines
      
    Entity Lung carcinoma
    Oncogenesis Amplification in 9 of 12 samples of squamous lung carcinoma.
      
    Entity Breast carcinoma
    Oncogenesis Putative role of Notch2 as tumor suppressor since upregulation of its expression is associated with survival, and activated Notch2 induces apoptosis in breast cancer xenografts.
      

    External links

    Nomenclature
    HGNC (Hugo)NOTCH2   7882
    Cards
    AtlasNOTCH2ID41556ch1p12
    Entrez_Gene (NCBI)NOTCH2  4853  notch 2
    GeneCards (Weizmann)NOTCH2
    Ensembl (Hinxton)ENSG00000134250 [Gene_View]  chr1:120477736-120612317 [Contig_View]  NOTCH2 [Vega]
    ICGC DataPortalENSG00000134250
    cBioPortalNOTCH2
    AceView (NCBI)NOTCH2
    Genatlas (Paris)NOTCH2
    WikiGenes4853
    SOURCE (Princeton)NM_001200001 NM_024408
    Genomic and cartography
    GoldenPath (UCSC)NOTCH2  -  1p12   chr1:120477736-120612317 -  1p13-p11   [Description]    (hg19-Feb_2009)
    EnsemblNOTCH2 - 1p13-p11 [CytoView]
    Mapping of homologs : NCBINOTCH2 [Mapview]
    OMIM102500   600275   610205   
    Gene and transcription
    Genbank (Entrez)AF308601 AF315356 AK027869 AK307843 AL049386
    RefSeq transcript (Entrez)NM_001200001 NM_024408
    RefSeq genomic (Entrez)AC_000133 NC_000001 NC_018912 NG_008163 NT_032977 NW_001838594 NW_004929290
    Consensus coding sequences : CCDS (NCBI)NOTCH2
    Cluster EST : UnigeneHs.487360 [ NCBI ]
    CGAP (NCI)Hs.487360
    Alternative Splicing : Fast-db (Paris)GSHG0002419
    Alternative Splicing GalleryENSG00000134250
    Gene ExpressionNOTCH2 [ NCBI-GEO ]     NOTCH2 [ SEEK ]   NOTCH2 [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ04721 (Uniprot)
    NextProtQ04721  [Medical]
    With graphics : InterProQ04721
    Splice isoforms : SwissVarQ04721 (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_2 [organisation]   Notch_dom [organisation]   Notch_NOD_dom [organisation]   Notch_NODP_dom [organisation]  
    Related proteins : CluSTrQ04721
    Domain families : Pfam (Sanger)Ank (PF00023)    Ank_2 (PF12796)    DUF3454 (PF11936)    EGF (PF00008)    EGF_CA (PF07645)    NOD (PF06816)    NODP (PF07684)    Notch (PF00066)   
    Domain families : Pfam (NCBI)pfam00023    pfam12796    pfam11936    pfam00008    pfam07645    pfam06816    pfam07684    pfam00066   
    Domain families : Smart (EMBL)ANK (SM00248)  EGF (SM00181)  EGF_CA (SM00179)  NL (SM00004)  
    DMDM Disease mutations4853
    Blocks (Seattle)Q04721
    PDB (SRS)2OO4   
    PDB (PDBSum)2OO4   
    PDB (IMB)2OO4   
    PDB (RSDB)2OO4   
    Human Protein AtlasENSG00000134250 [gene] [tissue] [antibody] [cell] [cancer]
    Peptide AtlasQ04721
    HPRD02606
    IPIIPI00297655   IPI00955451   IPI00941212   IPI00167217   IPI01015776   IPI00981408   
    Protein Interaction databases
    DIP (DOE-UCLA)Q04721
    IntAct (EBI)Q04721
    FunCoupENSG00000134250
    BioGRIDNOTCH2
    InParanoidQ04721
    Interologous Interaction database Q04721
    IntegromeDBNOTCH2
    STRING (EMBL)NOTCH2
    Ontologies - Pathways
    Ontology : AmiGOGolgi membrane  in utero embryonic development  cell fate determination  morphogenesis of an epithelial sheet  inflammatory response to antigenic stimulus  pulmonary valve morphogenesis  receptor activity  calcium ion binding  protein binding  extracellular region  nucleus  nucleoplasm  endoplasmic reticulum membrane  plasma membrane  integral component of plasma membrane  regulation of transcription, DNA-templated  transcription initiation from RNA polymerase II promoter  apoptotic process  humoral immune response  cell cycle arrest  Notch signaling pathway  Notch receptor processing  multicellular organismal development  determination of left/right symmetry  nervous system development  negative regulation of cell proliferation  organ morphogenesis  cell surface  gene expression  membrane  cell growth  stem cell maintenance  hemopoiesis  embryonic limb morphogenesis  intracellular receptor signaling pathway  ligand-activated RNA polymerase II transcription factor binding transcription factor activity  positive regulation of apoptotic process  negative regulation of apoptotic process  receptor complex  positive regulation of Ras protein signal transduction  bone remodeling  atrial septum morphogenesis  placenta blood vessel development  Notch signaling involved in heart development  interleukin-4 secretion  
    Ontology : EGO-EBIGolgi membrane  in utero embryonic development  cell fate determination  morphogenesis of an epithelial sheet  inflammatory response to antigenic stimulus  pulmonary valve morphogenesis  receptor activity  calcium ion binding  protein binding  extracellular region  nucleus  nucleoplasm  endoplasmic reticulum membrane  plasma membrane  integral component of plasma membrane  regulation of transcription, DNA-templated  transcription initiation from RNA polymerase II promoter  apoptotic process  humoral immune response  cell cycle arrest  Notch signaling pathway  Notch receptor processing  multicellular organismal development  determination of left/right symmetry  nervous system development  negative regulation of cell proliferation  organ morphogenesis  cell surface  gene expression  membrane  cell growth  stem cell maintenance  hemopoiesis  embryonic limb morphogenesis  intracellular receptor signaling pathway  ligand-activated RNA polymerase II transcription factor binding transcription factor activity  positive regulation of apoptotic process  negative regulation of apoptotic process  receptor complex  positive regulation of Ras protein signal transduction  bone remodeling  atrial septum morphogenesis  placenta blood vessel development  Notch signaling involved in heart development  interleukin-4 secretion  
    Pathways : BIOCARTASegmentation Clock [Genes]   
    Pathways : KEGGDorso-ventral axis formation    Notch signaling pathway    Thyroid hormone signaling pathway    MicroRNAs in cancer   
    Protein Interaction DatabaseNOTCH2
    Wikipedia pathwaysNOTCH2
    Gene fusion - rearrangments
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)NOTCH2
    snp3D : Map Gene to Disease4853
    SNP (GeneSNP Utah)NOTCH2
    SNP : HGBaseNOTCH2
    Genetic variants : HAPMAPNOTCH2
    Exome VariantNOTCH2
    1000_GenomesNOTCH2 
    ICGC programENSG00000134250 
    Cancer Gene: CensusNOTCH2 
    Somatic Mutations in Cancer : COSMICNOTCH2 
    CONAN: Copy Number AnalysisNOTCH2 
    Mutations and Diseases : HGMDNOTCH2
    Mutations and Diseases : intOGenNOTCH2
    Genomic VariantsNOTCH2  NOTCH2 [DGVbeta]
    dbVarNOTCH2
    ClinVarNOTCH2
    Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
    Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
    Diseases
    OMIM102500    600275    610205   
    MedgenNOTCH2
    GENETestsNOTCH2
    Disease Genetic AssociationNOTCH2
    Huge Navigator NOTCH2 [HugePedia]  NOTCH2 [HugeCancerGEM]
    General knowledge
    Homologs : HomoloGeneNOTCH2
    Homology/Alignments : Family Browser (UCSC)NOTCH2
    Phylogenetic Trees/Animal Genes : TreeFamNOTCH2
    Chemical/Protein Interactions : CTD4853
    Chemical/Pharm GKB GenePA31684
    Clinical trialNOTCH2
    Cancer Resource (Charite)ENSG00000134250
    Other databases
    Probes
    Litterature
    PubMed157 Pubmed reference(s) in Entrez
    CoreMineNOTCH2
    iHOPNOTCH2
    OncoSearchNOTCH2

    Bibliography

    Notch2: a second mammalian Notch gene.
    Weinmaster G, Roberts VJ, Lemke G.
    Development. 1992 Dec;116(4):931-41.
    PMID 1295745
     
    Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and NOTCH2.
    Capobianco AJ, Zagouras P, Blaumueller CM, Artavanis-Tsakonas S, Bishop JM.
    Mol Cell Biol. 1997 Nov;17(11):6265-73.
    PMID 9343387
     
    Notch1 and Notch2 inhibit myeloid differentiation in response to different cytokines.
    Bigas A, Martin DI, Milner LA.
    Mol Cell Biol. 1998 Apr;18(4):2324-33.
    PMID 9528802
     
    Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality.
    Hamada Y, Kadokawa Y, Okabe M, Ikawa M, Coleman JR, Tsujimoto Y.
    Development. 1999 Aug;126(15):3415-24.
    PMID 10393120
     
    Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2.
    Shimizu K, Chiba S, Hosoya N, Kumano K, Saito T, Kurokawa M, Kanda Y, Hamada Y, Hirai H.
    Mol Cell Biol. 2000 Sep;20(18):6913-22.
    PMID 10958687
     
    Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis.
    Saxena MT, Schroeter EH, Mumm JS, Kopan R.
    J Biol Chem. 2001 Oct 26;276(43):40268-73.
    PMID 11518718
     
    Manic fringe and lunatic fringe modify different sites of the Notch2 extracellular region, resulting in different signaling modulation.
    Shimizu K, Chiba S, Saito T, Kumano K, Takahashi T, Hirai H.
    J Biol Chem. 2001 Jul 13;276(28):25753-8.
    PMID 11346656
     
    Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia.
    Hubmann R, Schwarzmeier JD, Shehata M, Hilgarth M, Duechler M, Dettke M, Berger R.
    Blood. 2002 May 15;99(10):3742-7.
    PMID 11986231
     
    Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways.
    Espinosa L, Inglés-Esteve J, Aguilera C, Bigas A.
    J Biol Chem. 2003 Aug 22;278(34):32227-35.
    PMID 12794074
     
    Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development.
    Saito T, Chiba S, Ichikawa M, Kunisato A, Asai T, Shimizu K, Yamaguchi T, Yamamoto G, Seo S, Kumano K, Nakagami-Yamaguchi E, Hamada Y, Aizawa S, Hirai H.
    Immunity. 2003 May;18(5):675-85.
    PMID 12753744
     
    Activated Notch2 potentiates CD8 lineage maturation and promotes the selective development of B1 B cells.
    Witt CM, Hurez V, Swindle CS, Hamada Y, Klug CA.
    Mol Cell Biol. 2003 Dec;23(23):8637-50.
    PMID 14612407
     
    Notch1 and notch2 have opposite effects on embryonal brain tumor growth.
    Fan X, Mikolaenko I, Elhassan I, Ni X, Wang Y, Ball D, Brat DJ, Perry A, Eberhart CG.
    Cancer Res. 2004 Nov 1;64(21):7787-93.
    PMID 15520184
     
    Involvement of multiple developmental genes on chromosome 1p in lung tumorigenesis.
    Garnis C, Campbell J, Davies JJ, Macaulay C, Lam S, Lam WL.
    Hum Mol Genet. 2005 Feb 15;14(4):475-82.
    PMID 15615770
     
    Notch1 and 2 cooperate in limb ectoderm to receive an early Jagged2 signal regulating interdigital apoptosis.
    Pan Y, Liu Z, Shen J, Kopan R.
    Dev Biol. 2005 Oct 15;286(2):472-82.
    PMID 16169548
     
    Loss of NOTCH2 positively predicts survival in subgroups of human glial brain tumors.
    Boulay JL, Miserez AR, Zweifel C, Sivasankaran B, Kana V, Ghaffari A, Luyken C, Sabel M, Zerrouqi A, Wasner M, Van Meir E, Tolnay M, Reifenberger G, Merlo A.
    PLoS ONE. 2007 Jun 27;2(6):e576.
    PMID 17593975
     
    Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron.
    Cheng HT, Kim M, Valerius MT, Surendran K, Schuster-Gossler K, Gossler A, McMahon AP, Kopan R.
    Development. 2007 Feb;134(4):801-11.
    PMID 17229764
     
    Notch2 is required for formation of the placental circulatory system, but not for cell-type specification in the developing mouse placenta.
    Hamada Y, Hiroe T, Suzuki Y, Oda M, Tsujimoto Y, Coleman JR, Tanaka S.
    Differentiation. 2007 Mar;75(3):268-78.
    PMID 17359302
     
    Synergism between NF-kappa B1/p50 and Notch2 during the development of marginal zone B lymphocytes.
    Moran ST, Cariappa A, Liu H, Muir B, Sgroi D, Boboila C, Pillai S.
    J Immunol. 2007 Jul 1;179(1):195-200.
    PMID 17579038
     
    Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth.
    O’Neill CF, Urs S, Cinelli C, Lincoln A, Nadeau RJ, León R, Toher J, Mouta-Bellum C, Friesel RE, Liaw L.
    Am J Pathol. 2007 Sep;171(3):1023-36.
    PMID 17675579
     
    The transcriptional coactivator Maml1 is required for Notch2-mediated marginal zone B-cell development.
    Wu L, Maillard I, Nakamura M, Pear WS, Griffin JD.
    Blood. 2007 Nov 15;110(10):3618-23.
    PMID 17699740
     
    The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer.
    Parr C, Watkins G, Jiang WG.
    Int J Mol Med. 2004 Nov;14(5):779-86.
    PMID 15492845
     
    Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth.
    O’Neill CF, Urs S, Cinelli C, Lincoln A, Nadeau RJ, León R, Toher J, Mouta-Bellum C, Friesel RE, Liaw L.
    Am J Pathol. 2007 Sep;171(3):1023-36.
    PMID 17675579
     
    REVIEW articlesautomatic search in PubMed
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    Contributor(s)

    Written03-2008Anna Bigas, Lluis Espinosa
    Instituto de Investigación Biomédica de Bellvitge, IDIBELL, Barcelona, Spain

    Citation

    This paper should be referenced as such :
    Bigas, A ; Espinosa, L
    NOTCH2 (Notch homolog 2 (Drosophila))
    Atlas Genet Cytogenet Oncol Haematol. 2009;13(1):20-23.
    Free online version   Free pdf version   [Bibliographic record ]
    URL : http://AtlasGeneticsOncology.org/Genes/NOTCH2ID41556ch1p12.html

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    indexed on : Sat Oct 4 13:08:35 CEST 2014

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