FB2026_03 , released September 17, 2026
Human Disease Model Report: cancer, epithelial, NOTCH-LLGL-related
Open Close
General Information
Name
cancer, epithelial, NOTCH-LLGL-related
FlyBase ID
FBhh0001055
Disease Ontology Term
Parent Disease
OMIM
Overview

A model of cancer of epidermal origin has been developed using the Drosophila l(2)gl gene in combination with an activated form of the Drosophila Notch (N) gene. See also the human disease model reports 'cancer, epithelial, LLGL-related' (FBhh0000591), and 'cancer, epithelial, Scribble-complex-related' (FBhh0000586).

l(2)gl encodes a component of the Scribble polarity complex; this complex plays a key role in determining cell polarity and cell proliferation in epithelial cells. In human, there are two genes orthologous to Dmel\l(2)gl, the cytoskeletal proteins LLGL1 and LLGL2. Animals homozygous for loss-of-function mutations of Dmel\l(2)gl typically die during the larval stage and exhibit abnormal overproliferation of tissues, including in the brain, imaginal discs, and hematopoietic organs; cell-polarity defects are observed. Classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\l(2)gl.

The Notch signaling pathway is involved in processes related to cell fate specification, differentiation, proliferation, and survival. In human, there are 4 known genes that encode NOTCH family proteins; there is a single orthologous gene in Drosophila (the founding member of this gene family), Notch or N. In flies, most work relevant to cancer has been done with a constitutively active N transgene; ectopic expression of constitutively active N in somatic clones surrounded by wild-type tissue results in hyperproliferative effects. N is one the most thoroughly studied genes in Drosophila: hundreds of alleles, extensive physical interactions, and an unwieldy number of genetic interactions have been described; see below and in the gene report for N.

In eye discs, RNAi-mediated knockdown of l(2)gl in combination with constitutively active N results in more extreme overproliferation than is observed with either modification alone, resulting in dramatic tissue overgrowth. MMP1 (a reporter for JNK signaling) upregulation and loss of epithelial integrity are observed.

[updated Jun. 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, epithelial, NOTCH-LLGL-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information

LLGL1 and LLGL2 encode cortical cytoskeleton proteins found in a complex involved in maintaining cell polarity and epithelial integrity, the Scribble Cell Polarity Complex. This complex plays a role in the initial phase of the establishment of epithelial cell polarity; it is involved in the regulation of mitotic spindle orientation, proliferation, differentiation, and tissue organization of neuroepithelial cells. [Gene Cards, LLGL1, LLGL2; 2017.08.01]

In human, there are 4 known genes encoding the NOTCH family of proteins, a group of receptors involved in the Notch signaling pathway. NOTCH proteins are characterized by N-terminal EGF-like repeats followed by LNR domains which form a complex with ligands to prevent signaling. The Notch signaling pathway is involved in processes related to cell fate specification, differentiation, proliferation, and survival. [Gene Cards, NOTCH1; 2017.12.06]

External links
Disease synonyms
Ortholog Information
Human gene(s) in FlyBase
Other mammalian ortholog(s) used
    D. melanogaster Gene Information (2)
    Gene Snapshot
    lethal (2) giant larvae (l(2)gl) encodes a tumor suppressor protein that regulates cell polarity and asymmetric cell division. It acts on the basolateral side of epithelial cells, antagonizing the activity of apical complex proteins encoded by baz, par-6 and aPKC. [Date last reviewed: 2019-09-26]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Moderate- to high-scoring ortholog of human LLGL1 and LLGL2 (1 Drosophila to 2 human). Dmel\l(2)gl shares 34-36% identity and 51-54% 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
    Gene Groups / Pathways
    Comments on ortholog(s)

    Moderate- to high-scoring ortholog of human NOTCH1, NOTCH2, NOTCH3 and NOTCH4 (1 Drosophila to 4 human). Dmel\N shares 33-44% identity and 44-57% 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 (73 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, anti tag western blot
      experimental knowledge based, anti bait coimmunoprecipitation, western blot, proximity ligation assay, fluorescence microscopy, anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot
      proximity ligation assay, fluorescence microscopy
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation
      anti bait coimmunoprecipitation, anti tag western blot, western blot, experimental knowledge based, pull down, autoradiography, anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot, proximity ligation assay, fluorescence microscopy, pull down, Identification by mass spectrometry
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      protein-protein
      Interacting group
      Assay
      References
      two hybrid, enzyme linked immunosorbent assay
      anti bait coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot, 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
      two hybrid, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, autoradiography
      proximity ligation assay, fluorescence microscopy
      affinity technology, tag visualisation by alkaline phosphatase activity
      pull down, autoradiography, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation
      anti bait coimmunoprecipitation, cross-linking study, western blot, enzyme linked immunosorbent assay, bead aggregation assay, fluorescence microscopy, inferred by author, affinity technology, atomic force microscopy, tag visualisation, tag visualisation by alkaline phosphatase activity, phenotype-based detection assay, pull down
      pull down, western blot, anti bait coimmunoprecipitation, two hybrid, autoradiography
      two hybrid, nuclear magnetic resonance, cosedimentation in solution, predetermined participant, anti tag coimmunoprecipitation, anti tag western blot, western blot
      anti tag coimmunoprecipitation, western blot, proximity ligation assay, fluorescence microscopy
      two hybrid, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot
      pull down, western blot, anti tag coimmunoprecipitation, two hybrid
      protease assay, western blot, inferred by author
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting, three hybrid, protein three hybrid
      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, anti tag western blot
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot, pull down
      pull down, autoradiography, two hybrid
      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, fluorescence microscopy, inferred by author, bead aggregation assay, tag visualisation by alkaline phosphatase activity, anti bait coimmunoprecipitation, cross-linking study, western blot, anti tag coimmunoprecipitation, confocal microscopy, pull down, tag visualisation
      anti bait coimmunoprecipitation, western blot
      anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot, pull down
      pull down, molecular weight estimation by staining, isothermal titration calorimetry, predetermined participant, autoradiography, nuclear magnetic resonance, western blot
      isothermal titration calorimetry, predetermined participant, electron microscopy, two hybrid, protein three hybrid, pull down, autoradiography, anti tag coimmunoprecipitation, western blot, three hybrid, peptide massfingerprinting, anti bait coimmunoprecipitation, anti tag western blot, molecular sieving, molecular weight estimation by staining, coimmunoprecipitation, cosedimentation, electrophoretic mobility shift assay, electrophoretic mobility supershift assay
      anti tag coimmunoprecipitation, anti tag western blot
      two hybrid, pull down, western blot, anti tag coimmunoprecipitation
      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, Identification by mass spectrometry, anti tag western blot
      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
      Alleles Reported to Model Human Disease (Disease Ontology) (34 alleles)
      Models Based on Experimental Evidence ( 8 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 4 )
      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 ameliorated by cncUAS.cSa
      is exacerbated by Sod2HMS00499
      is exacerbated by cncHMS00650
      is ameliorated by Sod2UAS.cMa
      ameliorates  carcinoma
      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
      loss of function allele
      spontaneous
      amorphic allele - genetic evidence
      spontaneous
      spontaneous
      amorphic allele - molecular evidence
      ends-out gene targeting
      References (6)