The RAF genes encode serine/threonine-protein kinases that act as links between the membrane-associated RAS GTPases and the MAPK/ERK cascade. The RAS-RAF-MEK-ERK pathway impacts proliferation, differentiation, apoptosis, and oncogenic transformation; as might be expected, many of the genes in the pathway are implicated in the development of cancer (see also FBhh0000474). This report describes a fly model that uses an activated form of the human RAF1 gene expressed in specific stem cells; in human, this gene is implicated in multiple diseases (see OMIM:164760; FBhh0000131, FBhh0000132, FBhh0000156). There are two additional RAF genes in human, ARAF and BRAF. In Drosophila, there is a single orthologous gene, Dmel\Raf, for which classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
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.
A model of stem cell tumors utilizes the GAL4-UAS system to express an activated form of Hsap\RAF1 (amino truncation, resulting in constitutive kinase activity) in intestinal stem cells (ISCs). This model system has allowed efficient screening of chemotherapeutic agents and multi-drug combinations. See also the human disease model report 'cancer, intestinal stem cell models' (FBhh0000767).
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. A UAS construct of a constitutively activated form of Dmel\Raf (RafUAS.F179), driven by a glia-specific GAL4, has been to investigate glioma. Many genetic and physical interactions of Dmel\Raf have been described; see below and in the Raf gene report.
[updated Apr. 2019 by FlyBase; FBrf0222196]
RAF1 encodes a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane-associated GTPases, to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual-specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. [NCBI Gene, human RAF1; 2017.06.19]
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). [from UniProt, P04049; 2017.06.19]
Many to one: 3 human to 1 Drosophila. The three human genes are RAF1, BRAF, and ARAF.