NOTCH2 (Notch homolog 2 (Drosophila))

2008-03-01   Anna Bigas , Lluis Espinosa 

Instituto de Investigación Biomédica de Bellvitge, IDIBELL, Barcelona, Spain




Atlas Image


34 exons


7860 bp


Atlas Image
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


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.


    Type I membrane protein. Following proteolytical processing it is translocated to the nucleus.


    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%.



    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 name
    Alagille syndrome (AGS)
    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.
    Notch2 intracellular domain (active Notch2) has neoplastic transformation capacities.
    Entity name
    B-Cell Chronic Lymphoblastic Leukemia (B-CLL).
    Function: upregulation of CD23, which has been correlated with high cell viability and inhibition of apoptosis in B-CLL.
    Entity name
    Embryonal brain tumors, medulloblastoma
    Target gene hes1 expression correlates with shorter patient survival.
    Loss of heterozygosity of Notch2 results in positive survival of Oligodendrioma and glioblastoma.
    Amplification in 15% of 40 analyzed embryonal brain tumors.
    Entity name
    Amplification of 1p12 in melanoma cell lines
    Entity name
    Lung carcinoma
    Amplification in 9 of 12 samples of squamous lung carcinoma.
    Entity name
    Breast carcinoma
    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.


    Pubmed IDLast YearTitleAuthors
    95288021998Notch1 and Notch2 inhibit myeloid differentiation in response to different cytokines.Bigas A et al
    175939752007Loss of NOTCH2 positively predicts survival in subgroups of human glial brain tumors.Boulay JL et al
    93433871997Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and NOTCH2.Capobianco AJ et al
    172297642007Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron.Cheng HT et al
    127940742003Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways.Espinosa L et al
    155201842004Notch1 and notch2 have opposite effects on embryonal brain tumor growth.Fan X et al
    156157702005Involvement of multiple developmental genes on chromosome 1p in lung tumorigenesis.Garnis C et al
    173593022007Notch2 is required for formation of the placental circulatory system, but not for cell-type specification in the developing mouse placenta.Hamada Y et al
    103931201999Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality.Hamada Y et al
    119862312002Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia.Hubmann R et al
    175790382007Synergism between NF-kappa B1/p50 and Notch2 during the development of marginal zone B lymphocytes.Moran ST et al
    176755792007Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth.O'Neill CF et al
    161695482005Notch1 and 2 cooperate in limb ectoderm to receive an early Jagged2 signal regulating interdigital apoptosis.Pan Y et al
    154928452004The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer.Parr C et al
    127537442003Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development.Saito T et al
    115187182001Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis.Saxena MT et al
    113466562001Manic fringe and lunatic fringe modify different sites of the Notch2 extracellular region, resulting in different signaling modulation.Shimizu K et al
    12957451992Notch2: a second mammalian Notch gene.Weinmaster G et al
    146124072003Activated Notch2 potentiates CD8 lineage maturation and promotes the selective development of B1 B cells.Witt CM et al
    176997402007The transcriptional coactivator Maml1 is required for Notch2-mediated marginal zone B-cell development.Wu L et al

    Other Information

    Locus ID:

    NCBI: 4853
    MIM: 600275
    HGNC: 7882
    Ensembl: ENSG00000134250


    dbSNP: 4853
    ClinVar: 4853
    TCGA: ENSG00000134250


    Gene IDTranscript IDUniprot

    Expression (GTEx)



    PathwaySourceExternal ID
    Dorso-ventral axis formationKEGGko04320
    Notch signaling pathwayKEGGko04330
    Notch signaling pathwayKEGGhsa04330
    Dorso-ventral axis formationKEGGhsa04320
    MicroRNAs in cancerKEGGhsa05206
    MicroRNAs in cancerKEGGko05206
    Thyroid hormone signaling pathwayKEGGhsa04919
    Notch signalingKEGGhsa_M00682
    Notch signalingKEGGM00682
    Diseases of glycosylationREACTOMER-HSA-3781865
    Signal TransductionREACTOMER-HSA-162582
    Signaling by NOTCHREACTOMER-HSA-157118
    Pre-NOTCH Expression and ProcessingREACTOMER-HSA-1912422
    Pre-NOTCH Transcription and TranslationREACTOMER-HSA-1912408
    Pre-NOTCH Processing in the Endoplasmic ReticulumREACTOMER-HSA-1912399
    Pre-NOTCH Processing in GolgiREACTOMER-HSA-1912420
    Signaling by NOTCH2REACTOMER-HSA-1980145
    NOTCH2 Activation and Transmission of Signal to the NucleusREACTOMER-HSA-2979096
    NOTCH2 intracellular domain regulates transcriptionREACTOMER-HSA-2197563
    Gene ExpressionREACTOMER-HSA-74160
    Generic Transcription PathwayREACTOMER-HSA-212436
    Notch-HLH transcription pathwayREACTOMER-HSA-350054
    Diseases associated with O-glycosylation of proteinsREACTOMER-HSA-3906995
    Defective LFNG causes SCDO3REACTOMER-HSA-5083630
    Endocrine resistanceKEGGko01522
    Endocrine resistanceKEGGhsa01522
    Breast cancerKEGGko05224
    Breast cancerKEGGhsa05224
    Th1 and Th2 cell differentiationKEGGko04658
    Th1 and Th2 cell differentiationKEGGhsa04658

    Protein levels (Protein atlas)

    Not detected


    Pubmed IDYearTitleCitations
    183729032008Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.829
    190203232008Genotype score in addition to common risk factors for prediction of type 2 diabetes.304
    193300302009A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1).294
    190203242008Clinical risk factors, DNA variants, and the development of type 2 diabetes.262
    192763442009Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway.234
    167735782006NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway.188
    183111472008The Notch pathway in podocytes plays a role in the development of glomerular disease.156
    220063382011Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma.153
    174013722007Structural basis for autoinhibition of Notch.137
    185913882008Assessing the combined impact of 18 common genetic variants of modest effect sizes on type 2 diabetes risk.129


    Anna Bigas ; Lluis Espinosa

    NOTCH2 (Notch homolog 2 (Drosophila))

    Atlas Genet Cytogenet Oncol Haematol. 2008-03-01

    Online version: