This model of hyperplastic proliferation uses an activated form of Dmel\Egfr in combination with a mutation affecting a gene in the Hippo signaling pathway; phenotypes are assayed in imaginal discs. Hippo signaling is compromised using a loss-of-function mutation of either Dmel\ex or Dmel\ft. Each mutation alone, including activated Egfr, results in mild overproliferation phenotypes; the combination of activated Egfr and reduced Hippo signaling results in extreme overgrowth phenotypes in discs.
Loss of ex does not fully abolish Hippo pathway activity; animals homozygous for LOF mutations exhibit mild overgrowth phenotypes in discs. Neither of the human genes orthologous to Dmel\ex, FRMD1 and FRMD6, has been introduced into flies.
Loss-of-function alleles of ft are lethal. In wing discs, somatic clones carrying loss-of-function alleles of ft exhibit overgrowth phenotypes. Dmel\ft also plays a role in planar cell polarity pathways. The human Hsap\FAT4 gene has been introduced into flies; it rescues cell polarity phenotypes of ft loss-of-function mutations, but not overproliferation phenotypes.
See the human disease model report 'cancer, multiple, Hippo signaling pathway' (FBhh0000764) and the pathway report 'Hippo Signaling Pathway' (FBgg0000917) for a listing of genes encoding core components and regulators of this pathway in flies. Dmel\ex or Dmel\ft are classified as positive regulators of Hippo signaling (FBgg0000912). Multiple experiments support the model that the Hippo pathway regulates cell invasion by activating JNK signaling.
Amorphic mutations of Dmel\Egfr act as recessive embryonic lethals; they also act as cell lethals in somatic clones. Hypermorphic (gain-of-function) alleles exhibit dominant visible phenotypes. Egfr overexpression in imaginal disc epithelial cells leads to mild overproliferation phenotypes. Transgenic Egfr alleles that are constitutively active have been used in this disease model.
[updated Jun. 2019 by FlyBase; FBrf0222196]
Work in a number of systems supports the role of the Hippo signaling pathway in regulation of organ size and shape through its control of proliferation and apoptosis. A large body of work in multiple systems supports the role of the Hippo signaling pathway as a tumor suppressor. However, other work has implicated the activation of Hippo signaling in tumor progression. [reviewed in FBrf0237433]
Epidermal Growth Factor Receptor (EGFR) is a transmembrane receptor tyrosine kinase of the ErbB family. Binding of the protein to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation. Binding of DGFR can activate at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. [from Gene Cards, EGFR; 2016.09.30]
One to one: 1 human gene to 1 Drosophila gene.
Many to one: 4 human genes to 1 Drosophila gene.
Many to one: 2 human genes to 1 Drosophila gene.
Many to one: 2 human genes to 1 Drosophila gene.
Low- to moderate-scoring ortholog of human FRMD1 and FRMD6 (1 Drosophila to 2 human). Dmel\ex shares 22-24% identity and 37-38% similarity with the human genes.
High-scoring ortholog of human FAT4 (1 Drosophila to 1 human). Dmel\ft shares 36% identity and 53% similarity with the human gene.
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.
