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General Information
Name
cancer, malignant glioma, EGFR-PIK3C-related
FlyBase ID
FBhh0000401
Disease Ontology Term
Parent Disease
OMIM
Overview

Several Drosophila models of malignant glioma use the GAL4/UAS system to drive overexpression of EFGR and a PIK3 catalytic subunit in glial cells and glial precursors. Epidermal growth factor receptor (EGFR) has been implicated in multiple cancers (see FBhh0000398); more than 40% of glioblastomas show amplification and/or mutation of EGFR. Mutations in PTEN, a regulator of the PIK3/AKT pathway (see FBhh0000400), have also been associated with multiple cancers, including susceptibility to glioblastoma. Coactivation of EGFR and PI3K pathways in glial cells gives rise to neoplastic, invasive glial cells that create tumor-like growths in larval brains, mimicking human glioma.

EGFR is a transmembrane receptor kinase that spans the cell membrane and is activated by a number of external ligands, including EGF and transforming growth factor α. Activation of EGFR initiates several signal transduction cascades, leading to DNA synthesis and cell proliferation. There is one orthologous gene in flies, Dmel\Egfr, for which classical amorphic and hypomorphic alleles, constitutively active alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Egfr is orthologous to three additional human genes, ERBB4, ERBB3 and ERBB2. ERBB2 has also been implicated in multiple cancers.

PIK3 (Phosphatidylinositol 3-kinase) activates signaling cascades involved in cell growth, survival, proliferation, motility and morphology. "PIK3C" refers to the catalytic subunit with kinase activity. In humans, there are four genes that encode variants of the PIK3C catalytic subunit, PIK3CD, PIK3CB, PIK3CG, and PIK3CA; PIK3CA has been implicated in multiple cancers. There is one PIK3C catalytic subunit gene in flies, Dmel\Pi3K92E, for which classical loss-of-function alleles, RNAi-targeting constructs, transgenic dominant-negative alleles, and alleles caused by insertional mutagenesis have been generated. A variant of one of the human PIK3C genes, Hsap\PIK3CD, has been introduced into flies; the transgene product is analogous to a truncated protein that is expressed as an alternative splicing isoform in humans. A construct of Hsap\PIK3CB has also been introduced into flies, but has not been characterized.

The human gene Hsap\EGFR has been introduced, using a mutant form that displays constitutive kinase activity, in conjunction with a modified transgenic copy of Dmel\Pi3K92E that results in overexpression of that gene. EGFR overexpression has also been achieved by using a Dmel\Egfr fusion gene that contains a λ dimerization domain; this results in a constitutively active Egfr via forced dimerization. These model systems have been used to screen for genes that interact genetically to suppress or enhance the glial neoplastic phenotype; see the "Alleles Reported to Model Human Disease" section, below.

[updated Oct. 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, malignant glioma, EGFR-PIK3C-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology

Glioblastoma multiforme and other malignant gliomas are characterized by a heterogeneous population of cells that are highly infiltrative, angiogenic and resistant to chemotherapy (Ramirez et al., 2013; pubmed:24287492).

Molecular information

PIK3 (Phosphatidylinositol 3-kinase) activates signaling cascades involved in cell growth, survival, proliferation, motility and morphology. "PIK3C" refers to the catalytic subunit with kinase activity. Multiple genes encode different catalytic subunits and at least two genes encode regulatory subunits. One of the genes encoding a catalytic subunit, PIK3CA (Phosphatidylinositol 3-kinase catalytic subunit alpha), has been implicated in cancer. [from Gene Cards, PIK3CA; 2016.09.30]

External links
Disease synonyms
brain cancer, EGFR-PIK3C-related
cancer, glioblastoma, EGFR-PIK3C-related
cancer, neuronal, EGFR-PIK3C-related
glioblastoma
glioma
Search term: metastatic phenotype(s)
Search term: neoplastic phenotype(s)
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one (4 human to 1 Drosophila); additional human orthologs are ERBB4, ERBB3, and ERBB2.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (3)
    Gene Snapshot
    Epidermal growth factor receptor (Egfr) encodes the transmembrane tyrosine kinase receptor for signaling ligands (encoded by grk, spi, vn, and Krn) in the TGFα family, which utilises the intracellular MAP kinase pathway. The product of Egfr contributes to growth regulation, cell survival and developmental patterning. [Date last reviewed: 2019-06-06]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Orthologous to human genes EGFR, ERBB4, ERBB3, and ERBB2 (1 Drosophila to 4 human). Dmel\Egfr shares 33-37% identity and 46-51% 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 Snapshot
    Pi3K92E (Pi3K92E) encodes the catalytic subunit of a class I phosphatidylinositol 3-kinase that functions downstream of the product of InR and other receptors during several processes, including cell and tissue growth. [Date last reviewed: 2018-09-13]
    Gene Groups / Pathways
    Comments on ortholog(s)

    High-scoring ortholog of human PIK3CD and PIK3CB; moderate-scoring ortholog of PIK3CG and PIK3CA (1 Drosophila to 4 human). Dmel\Pi3K92E shares 31-39% identity and 50-58% simiilarity 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
    Molecular function (GO)
      Cellular component (GO)
        Gene Groups / Pathways
          Comments on ortholog(s)

          Constructs with this fusion gene, plus a lgr; dimerization domain and a UAS promoter, produce a constitutively active Egfr via forced dimerization; expression controlled by use of different GAL4 drivers.

          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 (99 groups)
            RNA-protein
            Interacting group
            Assay
            References
            anti bait coimmunoprecipitation, quantitative reverse transcription pcr, clip-seq
            rna three hybrid
            protein-protein
            Interacting group
            Assay
            References
            solid phase assay, tag visualisation by fluorescence, anti tag coimmunoprecipitation, anti tag western blot
            anti bait coimmunoprecipitation, western blot
            anti bait coimmunoprecipitation, western blot
            anti tag coimmunoprecipitation, peptide massfingerprinting
            anti tag coimmunoprecipitation, western blot, pull down, anti tag western blot
            anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
            anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, peptide massfingerprinting, pull down, two hybrid
            pull down, anti tag western blot, anti tag coimmunoprecipitation, western blot
            anti tag coimmunoprecipitation, peptide massfingerprinting
            anti tag coimmunoprecipitation, anti tag western blot, enzyme linked immunosorbent assay, western blot
            anti tag coimmunoprecipitation, peptide massfingerprinting
            anti tag coimmunoprecipitation, peptide massfingerprinting
            anti tag coimmunoprecipitation, peptide massfingerprinting
            anti tag coimmunoprecipitation, anti tag western blot
            anti tag coimmunoprecipitation, peptide massfingerprinting
            anti tag coimmunoprecipitation, peptide massfingerprinting
            anti tag coimmunoprecipitation, anti tag western blot, western blot, pull down
            anti tag coimmunoprecipitation, anti tag western blot, western blot, pull down
            pull down, western blot, anti bait coimmunoprecipitation, two hybrid, anti tag coimmunoprecipitation, anti tag western blot
            anti bait coimmunoprecipitation, western blot
            surface plasmon resonance, solid phase assay, tag visualisation by fluorescence, x-ray crystallography
            anti tag coimmunoprecipitation, peptide massfingerprinting
            anti tag coimmunoprecipitation, anti tag western blot, two hybrid
            two hybrid, anti tag coimmunoprecipitation, peptide massfingerprinting, anti bait coimmunoprecipitation, western blot
            protein-protein
            Interacting group
            Assay
            References
            protein kinase assay, autoradiography
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry, peptide massfingerprinting
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, peptide massfingerprinting
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, peptide massfingerprinting, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, peptide massfingerprinting, Identification by mass spectrometry, anti bait coimmunoprecipitation, western blot, protein kinase assay, autoradiography, pull down, anti tag western blot
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry, peptide massfingerprinting
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            pull down, autoradiography, anti tag coimmunoprecipitation, anti tag western blot
            pull down, western blot, two hybrid
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, peptide massfingerprinting
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            anti tag coimmunoprecipitation, Identification by mass spectrometry
            Alleles Reported to Model Human Disease (Disease Ontology) (25 alleles)
            Models Based on Experimental Evidence ( 3 )
            Modifiers Based on Experimental Evidence ( 9 )
            Models Based on Experimental Evidence ( 8 )
            Modifiers Based on Experimental Evidence ( 8 )
            Models Based on Experimental Evidence ( 1 )
            Modifiers Based on Experimental Evidence ( 1 )
            Allele
            Disease
            Interaction
            References
            Models Based on Experimental Evidence ( 1 )
            Modifiers Based on Experimental Evidence ( 1 )
            Allele
            Disease
            Interaction
            References
            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
            Selected mammalian 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
            loss of function allele
            ethyl methanesulfonate
            loss of function allele
            ethyl methanesulfonate
            amorphic allele - genetic evidence
            gamma ray
            amorphic allele - genetic evidence
            ethyl methanesulfonate
            amorphic allele - genetic evidence
            ethyl methanesulfonate
            loss of function allele
            ethyl methanesulfonate
            loss of function allele
            ethyl methanesulfonate
            amorphic allele - genetic evidence
            ethyl methanesulfonate
            amorphic allele - genetic evidence
            ethyl methanesulfonate
            amorphic allele - genetic evidence
            ethyl methanesulfonate
            loss of function allele
            ethyl methanesulfonate
            loss of function allele
            ethyl methanesulfonate
            amorphic allele - genetic evidence
            ethyl methanesulfonate
            amorphic allele - genetic evidence
            ethyl methanesulfonate
            amorphic allele - genetic evidence
            ethyl methanesulfonate
            amorphic allele - genetic evidence
            gamma 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
            amorphic allele - genetic evidence
            amorphic allele - genetic evidence
            gamma ray
            ethyl methanesulfonate
            amorphic allele - genetic evidence
            ethyl methanesulfonate
            References (40)