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General Information
Name
alcohol, response to, EGFR-MAPK/ERK signaling
FlyBase ID
FBhh0000685
OMIM
Overview

This report describes characterization of the fly alcohol response using Drosophila genes within the EGFR and MAPK/ERK signaling pathways. Multiple cell surface receptors have been shown to activate the MAPK/ERK signaling pathway (also called the RAS-RAF-MEK-ERK pathway), including EGFR. Mutations in fly genes Egfr, rl (orthologous to multiple human MAPK genes), spi (an EGFR ligand), rho (an activator of spi), and S (a regulator of cellular trafficking of EGFR ligands) all exhibit changes in ethanol sensitivity.

In a genetic screen for mutants with altered sensitivity to ethanol sedation, alleles of the Drosophila MAP4K mitogen-activated protein kinase hppy exhibited a decrease in ethanol sensitivity (resistance to ethanol-induced sedation); see FBhh0000684. Since MAPKs are known to act via the JNK, p38, and MAPK/ERK signaling pathways, additional mutations in Drosophila genes within these pathways were assessed for ethanol sensitivity. Only genes within the MAPK/ERK pathway and the upstream EGFR signaling pathway exhibited changes in sensitivity: activated or overexpressing mutations result in decreased sensitivity; loss-of-function alleles result in increased sensitivity. See also the human disease model report alcohol, response to, EPS8-related (FBhh0000688).

Administration of EGFR inhibitors [erlotinib (Tarceva) or gefitinib (Iressa)] to adult animals by feeding also results in increased ethanol sensitivity. Thus, in flies, inhibition of the EGFR pathway during adulthood is sufficient to produce enhanced ethanol sensitivity.

[updated Dec. 2018 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: alcohol use disorder, susceptibility to (fly models overview)
Symptoms and phenotype

Alcoholism can be defined as persistence of excessive drinking over a long period of time despite adverse health effects and disruption of social relations (Morozova et al., 2014; pubmed:24395673).

The 2013 Diagnostic and Statistical Manual of Mental Disorders (DSM) combined the two former categorizations of abnormal alcohol use (alcohol abuse and alcohol dependence) into one diagnosis: alcohol use disorder. The severity of an individual's AUD is broken into classifications: mild, moderate, or severe. "Alcoholism" is a non-medical term often used to describe a severe form of alcohol use disorder. (https://www.therecoveryvillage.com/recovery-blog/alcoholism-alcohol-use-disorder-whats-difference/)

Excessive alcohol consumption is associated with increased risk of different types of cancer, higher cardiovascular disease mortality, birth defects, liver diseases, and neuropsychiatric disorders (Morozova et al., 2014; pubmed:24395673).

Alcoholism is a multifactorial, genetically influenced disorder. [from OMIM:103780; 2017.12.19]

Specific Disease Summary: alcohol, response to, EGFR-MAPK/ERK signaling
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information

Epidermal Growth Factor Receptor (EGFR) is a transmembrane receptor tyrosine kinase of the ErbB family. Binding of the protein to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation. Binding of EGFR can activate at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. [from Gene Cards, EGFR; 2016.09.30]

External links
Disease synonyms
AUD susceptibility, EGFR/ERK signaling pathway
Search term: alcohol use disorder
alcohol, response to, EGFR/ERK signaling pathway
Ortholog Information
Human gene(s) in FlyBase
    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (5)
      Gene Snapshot
      Epidermal growth factor receptor (Egfr) encodes the transmembrane tyrosine kinase receptor for signaling ligands (encoded by grk, spi, vn, and Krn) in the TGFα family, which utilises the intracellular MAP kinase pathway. The product of Egfr contributes to growth regulation, cell survival and developmental patterning. [Date last reviewed: 2019-06-06]
      Gene Groups / Pathways
      Comments on ortholog(s)
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      rolled (rl) encodes the mitogen activated protein (MAP) kinase, core component of the RAS/MAPK pathway. It is inactivated by the phosphatases encoded by PTP-ER and Mkp3. It phosphorylates a diverse set of downstream cytoplasmic and nuclear effectors, which impact cell fate decisions in a wide array of tissues. [Date last reviewed: 2019-03-14]
      Gene Groups / Pathways
      Comments on ortholog(s)
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      spitz (spi) encodes the cardinal Egfr ligand that is produced as a transmembrane precursor and processed by the products of S and rho. Its roles include growth regulation, cell survival and developmental patterning. [Date last reviewed: 2019-03-14]
      Gene Groups / Pathways
      Comments on ortholog(s)
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      rhomboid (rho) encodes an intra-membrane serine protease that processes the membrane precursors of Egfr ligands. Its roles include growth regulation, cell survival and developmental patterning. [Date last reviewed: 2019-03-14]
      Molecular function (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Gene Snapshot
      Star (S) encodes a type II transmembrane protein that facilitates trafficking of transmembrane Egfr ligands from the endoplasmic reticulum to the late secretory compartment. It is involved in growth regulation, cell survival and developmental patterning. [Date last reviewed: 2019-03-14]
      Molecular function (GO)
        Gene Groups / Pathways
        Comments on ortholog(s)
        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 (73 groups)
          RNA-protein
          Interacting group
          Assay
          References
          anti bait coimmunoprecipitation, quantitative reverse transcription pcr, clip-seq
          rna three hybrid
          protein-protein
          Interacting group
          Assay
          References
          anti tag coimmunoprecipitation, anti tag western blot, solid phase assay, tag visualisation by fluorescence
          anti bait coimmunoprecipitation, western blot
          anti bait coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, peptide massfingerprinting
          pull down, western blot, anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
          anti bait coimmunoprecipitation, western blot, pull down, two hybrid, anti tag coimmunoprecipitation, peptide massfingerprinting
          anti tag coimmunoprecipitation, western blot, pull down, anti tag western blot
          anti tag coimmunoprecipitation, peptide massfingerprinting
          anti tag coimmunoprecipitation, western blot, anti tag western blot, enzyme linked immunosorbent assay
          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
          anti tag coimmunoprecipitation, western blot, anti tag western blot, pull down
          pull down, anti tag western blot, anti tag coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, anti tag western blot, pull down, western blot, two hybrid, anti bait coimmunoprecipitation
          anti bait coimmunoprecipitation, western blot
          surface plasmon resonance, solid phase assay, tag visualisation by fluorescence, x-ray crystallography
          anti tag coimmunoprecipitation, peptide massfingerprinting
          anti tag coimmunoprecipitation, anti tag western blot, two hybrid
          two hybrid, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, peptide massfingerprinting
          protein-protein
          Interacting group
          Assay
          References
          pull down, autoradiography, enzymatic study
          anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
          anti tag coimmunoprecipitation, peptide massfingerprinting
          cross-linking study, Identification by mass spectrometry, comigration in non denaturing gel electrophoresis, western blot, anti tag coimmunoprecipitation, anti tag western blot, pull down, autoradiography, two hybrid
          pull down, autoradiography, anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, western blot, proximity ligation assay, fluorescence microscopy
          anti tag coimmunoprecipitation, peptide massfingerprinting
          anti tag coimmunoprecipitation, peptide massfingerprinting
          anti tag coimmunoprecipitation, peptide massfingerprinting
          enzymatic study, autoradiography
          enzymatic study, autoradiography
          anti tag coimmunoprecipitation, anti tag western blot, western blot
          anti tag coimmunoprecipitation, anti tag western blot, pull down, autoradiography
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, peptide massfingerprinting
          anti bait coimmunoprecipitation, western blot
          enzymatic study, autoradiography
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, peptide massfingerprinting
          anti tag coimmunoprecipitation, peptide massfingerprinting
          pull down, autoradiography, anti tag coimmunoprecipitation, western blot
          RNA-protein
          Interacting group
          Assay
          References
          rna three hybrid
          RNA-RNA
          Interacting group
          Assay
          References
          luminiscence technology, necessary binding region, quantitative reverse transcription pcr, fluorescence technology
          quantitative reverse transcription pcr
          protein-protein
          Interacting group
          Assay
          References
          surface plasmon resonance
          surface plasmon resonance, solid phase assay, tag visualisation by fluorescence, x-ray crystallography
          enzymatic study, autoradiography
          inferred by author, enzymatic study, anti tag western blot, anti tag coimmunoprecipitation, peptide massfingerprinting
          inferred by author, enzymatic study, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot, western blot
          inferred by author, enzymatic study, anti tag western blot
          protein-protein
          Interacting group
          Assay
          References
          pull down, autoradiography
          enzymatic study, western blot, inferred by author, anti tag western blot
          inferred by author, enzymatic study, anti tag western blot
          enzymatic study, autoradiography
          anti tag coimmunoprecipitation, anti tag western blot
          RNA-protein
          Interacting group
          Assay
          References
          pull down, quantitative reverse transcription pcr
          protein-protein
          Interacting group
          Assay
          References
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot, western blot
          Alleles Reported to Model Human Disease (Disease Ontology) (30 alleles)
          Models Based on Experimental Evidence ( 2 )
          Modifiers Based on Experimental Evidence ( 8 )
          Models Based on Experimental Evidence ( 5 )
          Modifiers Based on Experimental Evidence ( 5 )
          Models Based on Experimental Evidence ( 1 )
          Allele
          Disease
          Evidence
          References
          Modifiers Based on Experimental Evidence ( 5 )
          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 ( 0 )
          Allele
          Disease
          Evidence
          References
          Modifiers Based on Experimental Evidence ( 3 )
          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
          ethyl methanesulfonate
          loss of function allele
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          gamma ray
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          loss of function allele
          ethyl methanesulfonate
          loss of function allele
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          loss of function allele
          ethyl methanesulfonate
          loss of function allele
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          gamma ray
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          amorphic allele - genetic evidence
          gamma ray
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          loss of function allele
          P-element activity
          loss of function allele
          Delta2-3 transposase
          loss of function allele
          Delta2-3 transposase
          loss of function allele
          spontaneous
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          Delta2-3 transposase
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          loss of function allele
          P-element activity
          loss of function allele
          P-element activity
          P-element activity
          loss of function allele
          ethyl methanesulfonate
          loss of function allele
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          loss of function allele
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          loss of function allele
          loss of function allele
          spontaneous
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          X ray
          amorphic allele - genetic evidence
          X ray
          loss of function allele
          ethyl methanesulfonate
          References (10)