FB2024_04 , released June 25, 2024
Human Disease Model Report: cancer, epithelial, RAS-TSPAN-related
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General Information
Name
cancer, epithelial, RAS-TSPAN-related
FlyBase ID
FBhh0001030
Disease Ontology Term
Parent Disease
OMIM
Overview

In Drosophila, the Ras85DV12 activated RAS mutation produces overproliferation phenotypes, but typically does not result in phenotypes indicative of metastasis (see FBhh0000474). In a screen for loss-of-function mutations that, in combination with this activated RAS mutation, induce invasive tumors, the Drosophila tetraspanin gene Tsp29Fb was identified. Tetraspanins mediate signal transduction events, in part by regulating the trafficking and function of other membrane proteins. Other tetraspanin genes in human have been implicated in the development of cancer, including CD9, CD82, CD151 and TSPAN8.

Tsp29Fb is one of 37 or 38 tetraspanin genes in flies; there are 33 tetraspanin genes in human. Dmel\Tsp29Fb and its close paralogs (Dmel\Tsp29Fa, Dmel\Tsp47F, Dmel\Tsp39D) comprise a group most closely related to 3 genes in human: CD63, TSPAN6, and TSPAN7. A UAS construct of the Hsap\CD63 has been introduced into flies, but has not been characterized.

Dmel\Tsp29Fb has not been well characterized; two RNAi-targeting constructs have been generated. In experiments using various different GAL4 drivers for RNAi-mediated knockdown, knockdown of Tsp29Fb itself results in reduced tissue growth. However, in Ras85DV12 expressing tissue, it enhances RAS-driven tumor growth and invasion. It is postulated that Tsp29Fb is necessary for maintaining epithelial cell polarity, acting via EGFR signaling: loss-of-function clones result in phenotypes in the retinal epithelium; Tsp29Fb interacts genetically with scrib, dlg1 and Egfr.

See also human disease model reports 'cancer, multiple, RAS-related' (FBhh0000474) and 'cancer, epithelial, Scribble-complex-related' (FBhh0000586).

[updated Oct. 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, epithelial, RAS-TSPAN-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype

Other tetraspanin genes in human in human have been implicated in the development of cancer: evidence suggests that CD9 and CD82 are suppressors of metastasis, whereas CD151 and TSPAN8 promote metastasis (Charrin et al., 2014; pubmed:25128561).

Genetics

There are 33 tetraspanin genes in human ( https://www.genenames.org/data/genegroup/#!/group/768 ).

Cellular phenotype and pathology
Molecular information

Tetraspanins (TSP) have four transmembrane domains and two extracellular loops containing specific short motifs, including highly conserved cysteine residues. TSPs are thought to function as scaffolds that bring multiple proteins, including other TSPs, membrane-associated proteins, extracellular and cytosolic proteins, into single membrane region (FBgg0000532).

Tetraspanin proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility.

Tetraspanins play a key role in regulating the trafficking and function of other membrane proteins (Charrin et al., 2014; pubmed:25128561).

External links
    Disease synonyms
    Search term: metastatic phenotype(s)
    Ortholog Information
    Human gene(s) in FlyBase
    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (2)
      Molecular function (GO)
        Cellular component (GO)
        Gene Groups / Pathways
        Comments on ortholog(s)

        Low-scoring ortholog of human CD63, TSPAN6, and TSPAN7 (many to many; multiple paralogs and orthologs in both species). Dmel\Tsp29Fb shares 27-30% identity and 49-50% 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
        Other Genes Used: Viral, Bacterial, Synthetic (0)
          Summary of Physical Interactions (29 groups)
          protein-protein
          Interacting group
          Assay
          References
          experimental knowledge based
          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
          two hybrid, anti tag coimmunoprecipitation, autoradiography
          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
          two hybrid, pull down, western blot
          anti tag coimmunoprecipitation, peptide massfingerprinting
          pull down, two hybrid, 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
          anti tag coimmunoprecipitation, Identification by mass spectrometry, pull down, covalent binding, western blot
          Alleles Reported to Model Human Disease (Disease Ontology) (27 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 ( 16 )
          Allele
          Disease
          Evidence
          References
          model of  cancer
          Modifiers Based on Experimental Evidence ( 17 )
          Allele
          Disease
          Interaction
          References
          model of  cancer
          is ameliorated by NetBΔ
          is ameliorated by NetBKK103672
          is ameliorated by InRGL00139
          is ameliorated by InRJF01183
          is ameliorated by InRJF01482
          is ameliorated by unc-5MI04273
          is ameliorated by TimpUAS.cPa
          is ameliorated by bskDN.UAS
          is ameliorated by bskHMS00777
          is exacerbated by hepAct.UAS
          is exacerbated by imdUAS.cGa
          is ameliorated by JraNIG.2275R
          ameliorates  cancer
          model of  kidney cancer
          is ameliorated by Pka-C1B3
          is ameliorated by mTorΔP
          model of  cancer
          is exacerbated by exe1
          is exacerbated by Ptp61FΔ
          is exacerbated by M6W186stop
          is ameliorated by Ptip3804
          is exacerbated by p53UAS.cUa
          is ameliorated by Ilp8MI00727
          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
          Related mammalian, viral, bacterial, or synthetic 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)