This model hyperplastic proliferation uses an activated form of Dmel\Raf in combination with a loss-of-function mutation of Dmel\ex, a Hippo pathway regulatory component; phenotypes are assayed in imaginal discs. Either mutation alone results in mild overproliferation phenotypes; the combination 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. 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 is classified as a positive regulator of Hippo signaling (FBgg0000912). Multiple experiments support the model that the Hippo pathway regulates cell invasion by activating JNK signaling.
Neither of the human genes orthologous to Dmel\ex, FRMD1 and FRMD6, has been introduced into flies.
A UAS construct of a constitutively activated form of Dmel\Raf, when expressed in wing discs, results in a mild overproliferation phenotype. Animals homozygous for amorphic mutations of Dmel\Raf exhibit lethality in the late larval stage; imaginal discs are undeveloped. Embryos lacking all Dmel\Raf activity (derived from homozygous null germline clones in the mother and not rescued by paternal contribution) die in early embryogenesis.
Multiple constructs of the human Hsap\RAF1 gene have been introduced into flies. Functional conservation between the human and fly genes has been demonstrated in fly several systems; for example, an activated form of the human gene has been shown to recapitulate phenotypes observed for an activated form of, or overexpression of, the fly gene. A UAS construct of a tagged human Hsap\BRAF gene has also been introduced into flies, but has not been characterized in the context of a cancer 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]
RAF1 encodes a serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade; this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). [Gene Cards, RAF1; 2019.06.24]
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 RAF1, BRAF, and ARAF (1 Drosophila to 3 human); Dmel\Raf shares 43-47% identity and 56-60% similarity with the human genes.
