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]
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).
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]
Many to one (4 human to 1 Drosophila); additional human orthologs are ERBB4, ERBB3, and ERBB2.
Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.
Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.
Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.
Many to one (4 human to one Drosophila); the 4 human genes are PIK3CD, PIK3CB, PIK3CG, and PIK3CA.
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.
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.
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.
