In Drosophila, the Ras85DV12 activated mutation produces overproliferation phenotypes, but typically does not result in phenotypes indicative of metastasis; Ras85DV12 expressed in the developing eye results in a mild overgrowth phenotype. To identify genes that cooperate with RAS in tumorigenesis, a screen for mutations that enhance this mild phenotype was undertaken. The fly Rho guanine nucleotide exchange factor RhoGEF2 was one of several genes identified. Dmel\RhoGEF2 is orthologous to three human genes, ARHGEF11, ARHGEF12, ARHGEF1. RhoGEFs comprise a large and diverse family that mediate activation of Rho GTPases in many different developmental contexts. Classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\RhoGEF2.
None of three human genes orthologous to Dmel\RhoGEF2, ARHGEF11, ARHGEF12, or ARHGEF1, has been introduced into flies.
Overexpression of RhoGEF2 with Ras85DV12 in eye-antennal disc clones results in clonal tissue overgrowth through an extended larval stage, cell morphology defects and loss of differentiation. This system has been used to characterize the downstream steps required for RAS-associated tumorigenesis. Similar phenotypes are observed when overexpression of RhoGEF2 is combined with a gain-of-function allele of Dmel\Raf (FBhh0001072), indicating that the combined tumorigenic phenotypes involve the MAPK branch of RAS signalling.
Animals homozygous for loss-of-functions mutations of Dmel\RhoGEF2 die during the embryonic stage. These disease model experiments make use of a transgenic overexpression genotype in somatic clones.
The constitutively active Ras85D mutation, Ras85DV12, is analogous to oncogenic mutations found in human RAS proteins. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G12V in the fly Ras85D gene (corresponds to G12V in the human KRAS and HRAS genes). See also the human disease model report 'cancer, multiple, RAS-related' (FBhh0000474).
[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).
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 genes KRAS, HRAS, and NRAS (many to many; multiple paralogs and orthologs in both species). Dmel\Ras85D shares 78-86% identity and 86-92% similarity with KRAS, HRAS, and NRAS; for these three human genes, Ras85D is the highest-scoring ortholog in Drosophila.
