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General Information
Name
cancer, multiple, RAF-RHOGEF-related
FlyBase ID
FBhh0001072
Disease Ontology Term
Parent Disease
OMIM
Overview

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]

Disease Summary Information
Disease Summary: cancer, multiple, RAF-RHOGEF-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
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)
Genetics
Cellular phenotype and pathology
Molecular information
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).
External links
Disease synonyms
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
Many to one: 3 human to 1 Drosophila. The three human genes are RAF1, BRAF, and ARAF.
Other mammalian ortholog(s) used
    D. melanogaster Gene Information (2)
    Gene Snapshot
    Rho guanine nucleotide exchange factor 2 (RhoGEF2) encodes a protein involved in actin organization and contractility. It contributes to multiple actin-based processes including wound healing, cell shape and cell contraction. [Date last reviewed: 2019-08-01]
    Gene Groups / Pathways
    Comments on ortholog(s)
    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.
    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Gene Snapshot
    Raf oncogene (Raf) encodes a serine-threonine protein kinase that acts downstream of the product of ras. It activates the MEK/ERK pathway to regulate cell proliferation, differentiation and survival downstream of receptor tyrosine kinases such as those encoded by tor, Egfr, and sev. [Date last reviewed: 2019-03-14]
    Cellular component (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)
    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.
    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (100 groups)
    protein-protein
    Interacting group
    Assay
    References
    pull down, autoradiography
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
    pull down, autoradiography
    anti bait coimmunoprecipitation, western blot
    pull down, autoradiography
    anti tag coimmunoprecipitation, Identification by mass spectrometry
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    enzymatic study, autoradiography
    anti tag coimmunoprecipitation, western blot, peptide massfingerprinting, two hybrid
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting, two hybrid
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    two hybrid, anti tag coimmunoprecipitation, anti tag western blot
    two hybrid, pull down, anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    Alleles Reported to Model Human Disease (Disease Ontology) (8 alleles)
    Models Based on Experimental Evidence ( 2 )
    Modifiers Based on Experimental Evidence ( 1 )
    Models Based on Experimental Evidence ( 2 )
    Allele
    Disease
    Evidence
    References
    Modifiers Based on Experimental Evidence ( 3 )
    Models Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Evidence
    References
    Modifiers Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Interaction
    References
    Genetic Tools, Stocks and Reagents
    Sources of Stocks
    Contact lab of origin for a reagent not available from a public stock center.
    Bloomington Stock Center Disease Page
    Selected mammalian transgenes
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila transgenes
    Allele
    Transgene
    Publicly Available Stocks
    RNAi constructs available
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila classical alleles
    Allele
    Allele class
    Mutagen
    Publicly Available Stocks
    amorphic allele - genetic evidence
    nitrosomethyl urea
    loss of function allele
    amorphic allele - genetic evidence
    X ray
    amorphic allele - genetic evidence
    1,2-dichloroethane
    amorphic allele - genetic evidence
    spontaneous
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    loss of function allele
    ethyl methanesulfonate
    hycanthon methanesulfonate
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    X ray
    amorphic allele - genetic evidence
    ethyl methanesulfonate
    loss of function allele
    P-element activity
    loss of function allele
    ethyl methanesulfonate
    loss of function allele
    ethyl methanesulfonate
    References (3)