Open Close
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). For additional information and external links relevant to the role of RAS in human cancers see the human disease model report 'cancer, multiple, RAS-related' (FBhh0000474).

[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).

External links
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 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
      Other Genes Used: Viral, Bacterial, Synthetic (0)
        Summary of Physical Interactions (36 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, anti tag western blot
        anti tag coimmunoprecipitation, peptide massfingerprinting
        anti tag coimmunoprecipitation, peptide massfingerprinting
        gtpase assay, autoradiography
        anti tag coimmunoprecipitation, peptide massfingerprinting
        pull down, western blot, two hybrid
        anti tag coimmunoprecipitation, peptide massfingerprinting
        anti tag coimmunoprecipitation, anti tag western blot, two hybrid, pull down
        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) (15 alleles)
        Models Based on Experimental Evidence ( 4 )
        Allele
        Disease
        Evidence
        References
        Modifiers Based on Experimental Evidence ( 11 )
        Allele
        Disease
        Interaction
        References
        model of  cancer
        is ameliorated by Sec6GD11616
        is ameliorated by Sec8KK101531
        is ameliorated by Sec15GD12109
        is ameliorated by Sec151
        is ameliorated by Src64BGD12263
        is exacerbated by Nek2UAS.GFP
        is ameliorated by JraNIG.2275R
        is ameliorated by bskDN.UAS
        is ameliorated by bskHMS00777
        is exacerbated by hepAct.UAS
        is exacerbated by imdUAS.cGa
        is ameliorated by TimpUAS.cPa
        ameliorates  cancer
        model of  prostate cancer
        model of  kidney cancer
        is ameliorated by Pka-C1B3
        is ameliorated by TorΔP
        Models Based on Experimental Evidence ( 2 )
        Allele
        Disease
        Evidence
        References
        Modifiers Based on Experimental Evidence ( 0 )
        Allele
        Disease
        Interaction
        References
        Alleles Representing Disease-Implicated Variants
        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 (4)