FB2026_02 , released June 18, 2026
Human Disease Model Report: cancer, multiple, Notch signaling pathway
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General Information
Name
cancer, multiple, Notch signaling pathway
FlyBase ID
FBhh0000766
Disease Ontology Term
Parent Disease
OMIM
Overview

Notch signaling is an evolutionarily conserved intercellular signaling pathway that participates in critical processes throughout development, from embryogenesis to determination of adult stem cells. Activation of the Notch signaling pathway is also observed in a number of cancers. Many of the genes in this pathway were first identified in Drosophila; experiments in flies continue to contribute to understanding of the Notch signaling pathway, including its role in development and progression of cancer.

In human, there are 4 genes that encode NOTCH family transmembrane receptor proteins (NOTCH1-NOTCH4); there are 2 genes similar to the Drosophila Notch ligand Delta (DLL1 and DLL4) and 2 genes similar to the Drosophila Notch ligand Serrate (JAG1 and JAG2).

Much of the work in flies investigating the role of the Notch pathway in development of cancer has involved combining Notch signaling dysregulation with another cancer model (see 'Related Diseases' below). This is typically achieved by using targeted expression of an activated form of Notch (N) or overexpression of one of the Notch ligands, Delta (Dl) or Serrate (Ser). Frequently used are constructs of Notch lacking its extracellular domain; the functional intracellular domain (NICD) is constitutively active. Genes potentially involved in tumorigenesis have also been identified using these systems. For example, overexpression of Dl in the adult eye results in a mild overgrowth phenotype (often called a 'sensitized model"); mutations of interacting genes have been identified that enhance this phenotype and result in much increased, tumorous overgrowth.

The loss of N, Dl or other Notch pathway components in stem cells results in a population of differentiation-defective cells; this system has been used to investigate stem-cell-derived cancers, such as intestinal stem cell tumors and neural stem cell tumors. See human disease model reports 'cancer, intestinal stem cell models' (FBhh0000767) and 'cancer, neural stem cell dedifferentiation' (FBhh0001139).

[updated Feb. 2022 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, multiple, Notch signaling pathway
OMIM report
Human gene(s) implicated
Symptoms and phenotype

The Notch signaling pathway is commonly activated in cancer and its activation plays key roles in cancer development and progression. Inappropriate Notch signalling has been associated with virtually all aspects of cancer, including tumor cell growth, survival, apoptosis, angiogenesis, invasion and metastasis (Dominguez, 2014; pubmed:24780858, FBrf0225143).

Genetics
Cellular phenotype and pathology
Molecular information

Notch signaling is an intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their membrane-bound ligands on the adjacent cells. The NOTCH family of proteins are Type I single-pass transmembrane proteins that share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. [from Gene Cards, NOTCH1; 2018.03.15]

External links
Disease synonyms
Search term: hyperplastic phenotype(s)
Ortholog Information
Human gene(s) in FlyBase
Other mammalian ortholog(s) used
    D. melanogaster Gene Information (3)
    Gene Groups / Pathways
    Comments on ortholog(s)

    Moderate- to high-scoring ortholog of human NOTCH1, NOTCH2, NOTCH3, NOTCH4 (1 Drosophila to 4 human). Dmel\N shares 43-44% identity and 56-57% similarity with NOTCH1 and NOTCH2.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Gene Snapshot
    Delta (Delta) encodes a single pass transmembrane EGF family protein and one of two ligands of the Notch signaling pathway. It regulates cell fate decisions and cell proliferation. Post transcriptional modification (such as by fucosylation, ubiquitination and proteolysis) of the product of Delta is key for its functions. [Date last reviewed: 2019-03-07]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Moderate- to high-scoring ortholog of human DLL1 and DLL4 (1 Drosophila to 2 human); additional less closely related genes in human. Dmel\Dl shares 39% identity and 51-53% similarity with human DLL1 and DLL4.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Gene Groups / Pathways
    Comments on ortholog(s)

    Moderate-scoring ortholog of human JAG1 and JAG2 (1 Drosophila to 2 human). Dmel\Ser shares 33-35% identity and 46% similarity with the human genes.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (69 groups)
      protein-protein
      Interacting group
      Assay
      References
      two hybrid, enzyme linked immunosorbent assay
      anti bait coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot, anti tag western blot
      anti bait coimmunoprecipitation, western blot
      proximity ligation assay, fluorescence microscopy
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      pull down, western blot
      experimental knowledge based
      pull down, western blot, anti tag coimmunoprecipitation
      anti tag coimmunoprecipitation, autoradiography, western blot, two hybrid, anti bait coimmunoprecipitation
      proximity ligation assay, fluorescence microscopy
      affinity technology, tag visualisation by alkaline phosphatase activity
      anti bait coimmunoprecipitation, western blot, pull down, anti tag coimmunoprecipitation, autoradiography
      phenotype-based detection assay, anti bait coimmunoprecipitation, western blot, bead aggregation assay, fluorescence microscopy, inferred by author, enzyme linked immunosorbent assay, cross-linking study, affinity technology, atomic force microscopy, pull down, tag visualisation by alkaline phosphatase activity, tag visualisation
      pull down, western blot, anti bait coimmunoprecipitation, two hybrid, autoradiography
      two hybrid, cosedimentation in solution, predetermined participant, anti tag coimmunoprecipitation, western blot, anti tag western blot, nuclear magnetic resonance
      anti tag coimmunoprecipitation, western blot, proximity ligation assay, fluorescence microscopy
      anti bait coimmunoprecipitation, anti tag western blot, anti tag coimmunoprecipitation, western blot, two hybrid
      pull down, western blot, two hybrid, anti tag coimmunoprecipitation
      protease assay, western blot, inferred by author
      anti tag coimmunoprecipitation, anti tag western blot
      protein three hybrid, three hybrid, anti tag coimmunoprecipitation, peptide massfingerprinting
      two hybrid, anti bait coimmunoprecipitation, western blot
      pull down, western blot
      pull down, western blot
      pull down, western blot
      coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot, pull down
      two hybrid, pull down, autoradiography
      anti tag coimmunoprecipitation, western blot, anti tag western blot
      anti tag coimmunoprecipitation, western blot
      experimental knowledge based
      experimental knowledge based
      anti tag coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot
      affinity technology, tag visualisation by alkaline phosphatase activity, pull down, fluorescence microscopy, inferred by author, tag visualisation, bead aggregation assay, anti bait coimmunoprecipitation, cross-linking study, western blot, anti tag coimmunoprecipitation, confocal microscopy
      anti bait coimmunoprecipitation, western blot
      anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot, pull down
      nuclear magnetic resonance, pull down, molecular weight estimation by staining, isothermal titration calorimetry, predetermined participant, autoradiography, western blot
      anti bait coimmunoprecipitation, western blot, pull down, autoradiography, anti tag coimmunoprecipitation, isothermal titration calorimetry, predetermined participant, two hybrid, coimmunoprecipitation, protein three hybrid, anti tag western blot, electrophoretic mobility shift assay, electrophoretic mobility supershift assay, peptide massfingerprinting, three hybrid, cosedimentation, molecular sieving, molecular weight estimation by staining, electron microscopy
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, western blot, pull down, two hybrid
      anti bait coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, cross-linking study, western blot
      inferred by author, confocal microscopy, bead aggregation assay
      proximity ligation assay, fluorescence microscopy
      anti bait coimmunoprecipitation, western blot, anti tag western blot, Identification by mass spectrometry
      RNA-protein
      Interacting group
      Assay
      References
      nucleic acid uv cross-linking assay, autoradiography, anti bait coimmunoprecipitation, quantitative reverse transcription pcr
      pull down, quantitative reverse transcription pcr
      RNA-RNA
      Interacting group
      Assay
      References
      immunohistochemistry, luminiscence technology
      protein-protein
      Interacting group
      Assay
      References
      bead aggregation assay, fluorescence microscopy, inferred by author, atomic force microscopy
      protease assay, western blot, inferred by author
      anti tag coimmunoprecipitation, anti tag western blot, enzymatic study
      phenotype-based detection assay, anti bait coimmunoprecipitation, western blot, bead aggregation assay, fluorescence microscopy, inferred by author, enzyme linked immunosorbent assay, cross-linking study, affinity technology, atomic force microscopy, pull down, tag visualisation by alkaline phosphatase activity, tag visualisation
      pull down, western blot, enzymatic study, anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, coimmunoprecipitation, affinity technology, fluorescence microscopy
      RNA-RNA
      Interacting group
      Assay
      References
      luminiscence technology, necessary binding region, immunohistochemistry, fluorescence technology
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      affinity technology, tag visualisation by alkaline phosphatase activity, pull down, fluorescence microscopy, inferred by author, tag visualisation, bead aggregation assay, anti bait coimmunoprecipitation, cross-linking study, western blot, anti tag coimmunoprecipitation, confocal microscopy
      anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot
      Alleles Reported to Model Human Disease (Disease Ontology) (38 alleles)
      Models Based on Experimental Evidence ( 13 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 22 )
      Allele
      Disease
      Interaction
      References
      is exacerbated by CatHMS00990
      is ameliorated by CatUAS.cUa
      is exacerbated by Sod2HMS00499
      is ameliorated by Sod2UAS.cMa
      is exacerbated by cncHMS00650
      is ameliorated by cncUAS.cSa
      ameliorates  carcinoma
      Models Based on Experimental Evidence ( 2 )
      Modifiers Based on Experimental Evidence ( 9 )
      Allele
      Disease
      Interaction
      References
      ameliorates  brain cancer
      DOES NOT ameliorate  cancer
      ameliorates  cancer
      Models Based on Experimental Evidence ( 2 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 2 )
      Alleles Representing Disease-Implicated Variants
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Related mammalian, viral, bacterial, or synthetic transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      amorphic allele - genetic evidence
      Delta2-3 transposase
      loss of function allele
      spontaneous
      loss of function allele
      spontaneous
      amorphic allele - genetic evidence
      X ray
      loss of function allele
      X ray
      loss of function allele
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      gamma ray
      loss of function allele
      X ray
      loss of function allele
      X ray
      loss of function allele
      X ray
      loss of function allele
      X ray
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      X ray
      loss of function allele
      X ray
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      loss of function allele
      X ray
      loss of function allele
      X ray
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      X ray
      loss of function allele
      X ray
      loss of function allele
      loss of function allele
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      X ray
      amorphic allele - genetic evidence
      loss of function allele
      spontaneous
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      X ray
      loss of function allele
      X ray
      loss of function allele
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      P-element activity
      Delta2-3 transposase
      amorphic allele - molecular evidence
      CRISPR/Cas9
      amorphic allele - genetic evidence
      X ray
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      loss of function allele
      spontaneous
      loss of function allele
      X ray
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      loss of function allele
      spontaneous
      amorphic allele - genetic evidence
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      X ray
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      X ray
      amorphic allele - genetic evidence
      X ray
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      spontaneous
      loss of function allele
      Delta2-3 transposase
      loss of function allele
      minos activity
      amorphic allele - genetic evidence
      loss of function allele
      X ray
      amorphic allele - genetic evidence
      X ray
      loss of function allele
      X ray
      References (54)