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General Information
Name
cancer, epithelial, RAS-ATP6V-related
FlyBase ID
FBhh0001052
Disease Ontology Term
Parent Disease
OMIM
Overview

Epithelial cancer has been modeled in flies using the Drosophila Vha44 gene in combination with an activated mutation of the Drosophila Ras85D gene. Dmel\Vha44 is orthologous to two human genes, ATP6V1C1 and ATP6V1C2, which encode cytosolic (V1) subunits of a V-type ATPase proton pump (ATP6V). RNAi targeting constructs and many alleles caused by insertional mutagenesis have been generated for Vha44.

Overexpression of Vha44 in a region of the Drosophila wing disc results in epithelial cell overgrowth and a mild invasive phenotype. Overexpression of Vha44 in combination with an activated mutation of Ras85D results in significantly stronger cell migration phenotypes. The role of apoptosis in this system and dependence on TNF-JNK signaling have been investigated.

The RAS proteins are GDP/GTP-binding proteins that act as intracellular signal transducers and are crucial players in many signaling networks affecting cell cycle progression, growth, migration, cytoskeletal changes, apoptosis, and senescence. The constitutively active Dmel\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). The Ras85DV12 activated mutation produces overproliferation phenotypes, but typically does not result in phenotypes indicative of metastasis (or results in a low frequency of these phenotypes).

[updated Jun. 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, epithelial, RAS-ATP6V-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information
V-type ATPases (ATP6V) couple the energy of ATP hydrolysis to proton transport across intracellular and plasma membranes of eukaryotic cells. (HGNC Gene group: V-type ATPases (ATP6V), https://www.genenames.org/data/genegroup/#!/group/415)
The V-ATPase is a complex enzyme that is composed of several subunits that are assembled into two domains: a transmembrane V0 domain and a cytosolic V1 domain. The V1 domain (ATP6V1) is formed by eight subunits (Breton and Brown, 2013; pubmed:23997191).
Disease synonyms
cancer, epithelial, V-ATPase-related
Ortholog Information
Human gene(s) in FlyBase
    Human gene (HGNC)
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)
    Many to one: 2 human genes to 1 Drosophila gene.
    Human gene (HGNC)
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)
    Many to one: 2 human genes to 1 Drosophila gene.
    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (2)
      Gene Snapshot
      Ras oncogene at 85D (Ras85D) encodes a protein that acts downstream of several cell signals, most notably from Receptor Tyrosine Kinases, to regulate tissue growth and development. When abnormally activated it can direct developmental defects and tissue hyperplasia, mimicking aspects of human disease including Rasopathies and cancer, respectively. [Date last reviewed: 2019-03-14]
      Cellular component (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)
      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.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      In progress.Contributions welcome.
      Gene Groups / Pathways
      Comments on ortholog(s)
      High-scoring ortholog of human ATP6V1C1; moderate-scoring ortholog of human ATP6V1C2 (1 Drosophila to 2 human). Dmel\Vha44 shares 26-30% identity and 34-38% 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 (35 groups)
      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, autoradiography, 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
      gtpase assay, autoradiography
      anti tag coimmunoprecipitation, peptide massfingerprinting
      two hybrid, pull down, western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      two hybrid, pull down, anti tag coimmunoprecipitation, anti tag western blot
      pull down, 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, anti tag western blot
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
      anti tag coimmunoprecipitation, anti tag western blot
      proximity ligation assay, fluorescence microscopy
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      experimental knowledge based
      Alleles Reported to Model Human Disease (Disease Ontology) (14 alleles)
      Models Based on Experimental Evidence ( 4 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 9 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 2 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 0 )
      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
      loss of function allele
      loss of function allele
      P-element activity
      amorphic allele - genetic evidence
      References (3)