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General Information
Name
cancer, epithelial, RAS-Hippo-signaling
FlyBase ID
FBhh0001063
Disease Ontology Term
Parent Disease
OMIM
Overview

This model hyperplastic proliferation uses an activated form of Dmel\Ras85D in combination with a mutation affecting a gene in the Hippo signaling pathway; phenotypes are assayed in imaginal discs. Hippo signaling is compromised using a loss-of-function mutation of either Dmel\ex or Dmel\wts. Each mutation alone, including activated Ras85D, results in mild overproliferation phenotypes; the combination of activated Ras85D and reduced Hippo signaling results in extreme overgrowth phenotypes in discs.

Loss of ex does not fully abolish Hippo pathway activity; animals homozygous for LOF mutations exhibit mild overgrowth phenotypes in discs. Neither of the human genes orthologous to Dmel\ex, FRMD1 and FRMD6, has been introduced into flies.

Amorphic alleles of Dmel\wts are lethal. In wing discs, somatic clones carrying an amorphic mutation of wts exhibit an overgrowth phenotype. Both of the human orthologs of wts, Hsap\LATS1 and Hsap\LATS2, have been introduced into flies. Both human genes exhibit functional complementation (heterologous rescue), rescuing the lethal phenotype of wts knockdown effected by RNAi.

See the human disease model report 'cancer, multiple, Hippo signaling pathway' (FBhh0000764) and the pathway report 'Hippo Signaling Pathway' (FBgg0000917) for a listing of genes encoding core components and regulators of this pathway in flies. Multiple experiments support the model that the Hippo pathway regulates cell invasion by activating JNK signaling.

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). Animals homozygous for loss-of-function alleles of Dmel\Ras85D die during the larval stage. Animals carrying the Ras85DV12 activated allele typically die during the pupal stage, with larvae showing tumorous growths; somatic clones of Ras85DV12 exhibit an overgrowth phenotype in multiple different tissues tested.

[updated Jun. 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, epithelial, RAS-Hippo-signaling
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information
Work in a number of systems supports the role of the Hippo signaling pathway in regulation of organ size and shape through its control of proliferation and apoptosis. A large body of work in multiple systems supports the role of the Hippo signaling pathway as a tumor suppressor. However, other work has implicated the activation of Hippo signaling in tumor progression. [reviewed in FBrf0237433]
The RAS proteins are members of a large superfamily of low-molecular-weight GTP-binding proteins. The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. Three members of the RAS family, HRAS, KRAS and NRAS, are found to be activated by mutation in human tumors. These three members are very closely related, having 85% amino acid sequence identity (Downward, 2003; pubmed:12509763).
External links
Disease synonyms
Ortholog Information
Human gene(s) in FlyBase
    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (3)
      Gene Snapshot
      expanded (ex) encodes a FERM-domain containing protein that localizes to apical cell-cell junctions, where it promotes Hippo signaling by physically interacting with multiple Hippo pathway components. Through its regulation of Hippo signaling, the product of ex functions as an inhibitor of growth. [Date last reviewed: 2019-03-07]
      Gene Groups / Pathways
      Comments on ortholog(s)
      Low- to moderate-scoring ortholog of human FRMD1 and FRMD6 (1 Drosophila to 2 human). Dmel\ex shares 22-24% identity and 37-38% 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
      Gene Snapshot
      warts (wts) encodes a tumor suppressor kinase in the Hippo pathway involved in the control of tissue growth. It also plays a post-mitotic role in R8 photoreceptor cells where it antagonizes the product of melt to control the bistable choice of Rhodospin expression. [Date last reviewed: 2019-03-21]
      Gene Groups / Pathways
      Comments on ortholog(s)
      Moderate-scoring ortholog of human LATS1 and LATS2 (1 Drosophila to 2 human); Dmel\wts shares 38-42% identity and 47-50% 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
      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
      Synthetic Gene(s) Used (0)
      Summary of Physical Interactions (88 groups)
      RNA-RNA
      Interacting group
      Assay
      References
      immunohistochemistry, luminiscence technology, necessary binding region
      protein-protein
      Interacting group
      Assay
      References
      far western blotting, tag visualisation
      anti tag coimmunoprecipitation, anti tag western blot
      pull down, anti tag western blot, anti tag coimmunoprecipitation
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot, pull down, Identification by mass spectrometry
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot
      two hybrid, anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      far western blotting, tag visualisation
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot
      pull down, anti tag western blot, anti bait coimmunoprecipitation
      anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting, pull down, western blot
      anti tag coimmunoprecipitation, anti tag western blot, western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot, Identification by mass spectrometry, anti bait coimmunoprecipitation, western blot, pull down
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, peptide massfingerprinting
      coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      enzymatic study, western blot
      proximity ligation assay, fluorescence microscopy
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot, western blot
      anti tag coimmunoprecipitation, anti tag western blot, enzymatic study, western blot, autoradiography
      enzymatic study, western blot
      coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot, western blot
      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 western blot
      anti tag coimmunoprecipitation, anti tag western blot, proximity ligation assay, fluorescence microscopy
      pull down, anti tag western blot, anti tag coimmunoprecipitation, peptide massfingerprinting, enzymatic study, western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot, enzymatic study, autoradiography, peptide massfingerprinting
      enzymatic study, western blot, anti tag coimmunoprecipitation, anti tag western blot
      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, anti tag western blot, proximity ligation assay, fluorescence microscopy
      anti tag coimmunoprecipitation, peptide massfingerprinting
      pull down, anti tag western blot
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, peptide massfingerprinting
      anti tag coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, anti tag western blot
      enzymatic study, western blot, anti tag coimmunoprecipitation, anti tag western blot, autoradiography, two hybrid, peptide massfingerprinting, pull down
      anti tag coimmunoprecipitation, anti tag western blot
      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
      Alleles Reported to Model Human Disease (Disease Ontology) (18 alleles)
      Models Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 2 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 3 )
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 4 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 9 )
      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
      P-element activity
      loss of function allele
      P-element activity
      loss of function allele
      loss of function allele
      P-element activity
      amorphic allele - genetic evidence
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      References (5)