Human Disease Model Report: cancer, multiple, RAF-RHOGEF-related
Human Disease Model Report: cancer, multiple, RAF-RHOGEF-related
Using an eye phenotype assay that had been successful previously (see FBhh0001071), a gain-of-function mutation of Dmel\Raf has been characterized in combination with overexpression of Dmel\RhoGEF2. Co-expression in somatic clones within the eye-antennal disc results in clonal tissue overgrowth through an extended larval stage; large undifferentiated clonal masses are observed in the basal sections of the posterior region of the eye disc.
Rho family guanine nucleotide exchange factors (RhoGEFs) comprise a large and diverse family that mediate activation of Rho GTPases in many different developmental contexts. Dmel\RhoGEF2 is orthologous to three human genes, ARHGEF11, ARHGEF12, ARHGEF1. Classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\RhoGEF2. Animals homozygous for loss-of-functions mutations of RhoGEF2 die during the embryonic stage. These disease model experiments make use of a transgenic overexpression genotype in somatic clones.
None of three human genes orthologous to Dmel\RhoGEF2, ARHGEF11, ARHGEF12, or ARHGEF1, has been introduced into flies. Multiple constructs of the human Hsap\RAF1 have been introduced into flies, but have not been used in the context of this human disease model; see the human disease model report 'cancer, multiple, RAF1-related' (FBhh0000558).
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. Many genetic and physical interactions of Dmel\Raf have been described; see below and in the Raf gene report.
[updated Jul. 2019 by FlyBase; FBrf0222196]
The aberrant activity of Ras homologous (Rho) family small GTPases (20 human members) has been implicated in cancer and other human diseases. However, rather than direct mutational activation, Rho GTPases are activated most commonly by indirect mechanisms in disease. One prevalent mechanism involves aberrant Rho activation via the deregulated expression and/or activity of Rho family guanine nucleotide exchange factors (RhoGEFs). Many RhoGEFs can activate a single Rho GTPase, reflecting the very specific role of each RhoGEF in controlling distinct signaling mechanisms involved in Rho activation. (Cook et al., 2014; pubmed: 24037532)
RhoGEFs promote formation of the active GTP-bound state of Rho GTPases [Ras homologous (Rho) family small GTPases] (Cook et al., 2014; pubmed:24037532).
The activation of Rho GTPases is mediated by a large and diverse family of proteins, the guanine nucleotide exchange factors (RhoGEFs). GEFs work immediately upstream of Rho proteins to provide a direct link between Rho activation and cell-surface receptors for various cytokines, growth factors, adhesion molecules, and G-protein-coupled receptors (Goicoechea et al., 2014; pubmed:25482524).
Many to one: 3 human to 1 Drosophila. The three human genes are RAF1, BRAF, and ARAF.
Moderate-scoring ortholog of human ARHGEF11, ARHGEF12, and ARHGEF1 (1 Drosophila to 3 human). Dmel\RhoGEF2 shares 21-22% identity and 33-34% similarity with ARHGEF11 and ARHGEF12; ARHGEF1 is a smaller protein with 24% identity and 38% similarity.
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.
