Open Close
General Information
Name
cancer, epithelial, RAS-SCRIB-related
FlyBase ID
FBhh0000585
Disease Ontology Term
Parent Disease
OMIM
Overview

Models of epithelial cancer initiation and progression have been developed using the Drosophila scrib gene in combination with the Drosophila Ras85D gene. Investigations using these models include assessment of anti-tumor pharmaceutical candidates, identification of induced transcription factors, and characterization of involvement of the JNK and Hippo signaling pathways. See also the human disease model reports 'cancer, multiple, RAS-related' (FBhh0000474), 'cancer, epithelial, SCRIB-related' (FBhh0000587), and 'cancer, epithelial, Scribble-complex-related' (FBhh0000586).

Expression of scrib loss-of-function alleles in combination with the Ras85DV12 activated mutation results in extensive tumors in larvae; metastatic phenotypes, including basement membrane degradation, loss of E-cadherin expression, migration, invasion, and secondary tumor formation, are observed. Metastatic phenotypes are not observed for either type of mutation alone.

The Scribble polarity complex plays a key role in determining cell polarity and cell proliferation in epithelial cells. The eponymous Drosophila scrib gene is a cell polarity regulator and neoplastic tumor suppressor; there are two orthologous genes in human, SCRIB and LRRC1. The mammalian SCRIB gene has also been characterized as a tumor suppressor. Dmel\scrib is well characterized genetically: classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. A tagged wild-type transgene of human Hsap\SCRIB has been introduced into flies; partial heterologous rescue (functional complementation) of homozygous Dmel\scrib loss-of-function phenotypes is observed.

Animals homozygous for loss-of-function mutations of Dmel\scrib typically die during the larval stage; somatic clones that are homozygous for scrib exhibit overgrowth phenotypes. Many physical and genetic interactions for Dmel\scrib have been described; see below and in the gene report for scrib.

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. Originally defined as oncogenes, the RAS GTPase family includes KRAS (OMIM:190070), HRAS (OMIM:190020), and NRAS (OMIM:164790); mutations in these three genes are among the most common events in human cancers. For KRAS, HRAS and NRAS, there is a single high-scoring ortholog in Drosophila, Ras85D, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. There are multiple other paralogous and orthologous genes in both species. Of the three human RAS GTPase genes, a tagged UAS construct of Hsap\HRAS has been introduced into flies, but has not been characterized.

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. Most work relevant to cancer has been done with an activated form of the gene, Ras85DV12. This allele is usually lethal during the pupal stage, with larvae showing tumorous growths; somatic clones of Ras85DV12 exhibit an overgrowth phenotype in multiple different tissues tested. Many physical and genetic interactions for Dmel\Ras85D have been described; see below and in the gene report for Ras85D.

[updated Nov. 2018 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, epithelial, RAS-SCRIB-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information

SCRIB is a cytoplasmic multi-modular scaffold protein targeted to epithelial adherens junctions and neuronal presynaptic compartments. SCRIB and its orthologs in vertebrates and invertebrates participate in cell polarization (summary by Nola et al., 2008; pubmed:18716323). [from OMIM:607733; 2017.08.01]

The SCRIB gene encodes a scaffold protein involved in cell polarization processes; it is involved in tumor suppression pathways (Gene Cards, SCRIB; 2017.08.01).

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
carcinoma, RAS-SCRIB-related
RasV12 scrib- tumors
Search term: neoplastic phenotype(s)
Search term: metastatic phenotype(s)
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to many: multiple paralogs and orthologs in both species.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 2 human to 1 Drosophila; the second human gene is LRRC1.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to many: multiple paralogs and orthologs in both species.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to many: multiple paralogs and orthologs in both species.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (2)
    Gene Snapshot
    scribble (scrib) encodes a scaffolding protein that is part of the conserved machinery regulating apicobasal polarity. It acts with the products of dlg1 and l(2)gl to distinguish the basolateral domain of epithelial cells and neuroblasts, via reciprocally antagonistic interactions with the aPKC/par-6 complex that impacts vesicle trafficking. The product of scrib also organizes synaptic architecture and is implicated in learning and memory. [Date last reviewed: 2019-03-14]
    Molecular function (GO)
    Gene Groups / Pathways
      Comments on ortholog(s)

      Ortholog of human SCRIB and LRRC1 (1 Drosophila to 2 human); Dmel\scrib shares 33% identity and 45% similarity with the human SCRIB gene. The human LRRC1 gene encodes a much smaller protein, corresponding to the amino end of SCRIB and Dmel\scrib; it shares 57% identity and 73% similarity with Dmel\scrib within that extent.

      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 (42 groups)
        protein-protein
        Interacting group
        Assay
        References
        anti tag coimmunoprecipitation, anti tag western blot
        proximity ligation assay, fluorescence microscopy
        anti tag coimmunoprecipitation, western blot, proximity ligation assay, fluorescence microscopy, anti bait coimmunoprecipitation, colocalization, inferred by author
        proximity ligation assay, fluorescence microscopy
        x-ray crystallography, isothermal titration calorimetry, predetermined participant, anti bait coimmunoprecipitation, western blot
        anti tag coimmunoprecipitation, anti tag western blot
        pull down, western blot, anti tag coimmunoprecipitation
        anti tag coimmunoprecipitation, western blot
        anti tag coimmunoprecipitation, western blot
        anti tag coimmunoprecipitation, anti tag western blot
        anti tag coimmunoprecipitation, western blot
        anti tag coimmunoprecipitation, anti tag western blot
        pull down, autoradiography
        anti tag coimmunoprecipitation, western blot
        pull down, autoradiography, two hybrid
        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
        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
        Alleles Reported to Model Human Disease (Disease Ontology) (20 alleles)
        Models Based on Experimental Evidence ( 6 )
        Modifiers Based on Experimental Evidence ( 5 )
        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 Sec8KK101531
        is ameliorated by Sec6GD11616
        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
        model of  carcinoma
        Models Based on Experimental Evidence ( 1 )
        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
        loss of function allele
        ethyl methanesulfonate
        loss of function allele
        ethyl methanesulfonate
        loss of function allele
        ethyl methanesulfonate
        References (71)