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Molecular Pharmacology

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Research ArticleArticle

Epidermal Growth Factor Treatment Switches δ-Opioid Receptor-Stimulated Extracellular Signal-Regulated Kinases 1 and 2 Signaling from an Epidermal Growth Factor to an Insulin-Like Growth Factor-1 Receptor-Dependent Mechanism

Daniela A. Eisinger and Hermann Ammer
Molecular Pharmacology February 2011, 79 (2) 326-335; DOI: https://doi.org/10.1124/mol.110.064956
Daniela A. Eisinger
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Hermann Ammer
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Abstract

δ-Opioid receptor (DOR)-induced activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) is mediated by the transactivation of epidermal growth factor (EGF) receptors. Here we demonstrate that in stably DOR-expressing human embryonic kidney (HEK) 293 (HEK/DOR) cells, down-regulation of EGF receptors by long-term EGF (0.1 μg for 18 h) treatment, but not by small interfering RNA, results in functional desensitization of EGF (10 ng/ml)-stimulated ERK1/2 signaling. In EGF receptor-desensitized (HEK/DOR−EGFR) cells, however, [d-Ala2,d-Leu5]enkephalin (1 μM) and etorphine (0.1 μM) retained their ability to stimulate ERK1/2 activation. The newly acquired signal transduction mechanism is insensitive to the EGF receptor blockers 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) and N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (CL-387,785), does not involve DOR internalization and activation of the focal adhesion kinase pp125FAK, but requires matrix metalloproteinase-dependent release of soluble growth factors. A supernatant transfer assay in which conditioned growth media of opioid-treated HEK/DOR and HEK/DOR−EGFR “donor” cells are used to stimulate ERK1/2 activity in DOR-lacking HEK293 wild type and HEK293−EGFR “acceptor” cells revealed that long-term EGF treatment produces a switch in the receptor tyrosine kinase (RTK) system transactivated by opioids. Using microfluidic electrophoresis, chemical inhibitors, phosphorylation-specific antibodies, and EGF receptor-deficient Chinese hamster ovary-K1 cells, we identified the release of an insulin-like growth factor-1 (IGF-1)-like peptide and activation of IGF-1 receptors in HEK/DOR−EGFR cells after DOR activation. A similar switch from a neurotrophic tyrosine kinase receptor type 1 to an IGF-1 receptor-dependent ERK1/2 signaling was observed for chronically nerve growth factor-treated neuroblastoma × glioma (NG108-15) cells. These results indicate that transactivation of the dominant RTK system in a given cellular setting may represent a general feature of opioids to maintain mitogenic signaling.

Footnotes

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.064956.

  • ABBREVIATIONS:

    RTK
    receptor tyrosine kinase
    Con A
    concanavalin A
    DADLE
    [d-Ala2,d-Leu5]enkephalin
    CHO
    Chinese hamster ovary
    DOR
    δ-opioid receptor
    EGCG
    epigallocatechin-3-gallate
    EGF
    epidermal growth factor
    ERK1/2
    extracellular signal-regulated protein kinases 1/2
    FAK
    focal adhesion kinase
    GPCR
    G protein-coupled receptor
    HB-EGF
    heparin binding epidermal growth factor
    HEK
    human embryonic kidney
    IGF-1
    insulin-like growth factor type 1
    MMP
    matrix metalloproteinase
    NGF
    nerve growth factor
    wt
    wild type
    TrkA
    neurotrophic tyrosine kinase receptor type 1
    CL-387,785
    N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide
    HA
    hemagglutinin
    FCS
    fetal calf serum
    siRNA
    small interfering RNA
    DMEM
    Dulbecco's modified Eagle's medium
    SOCS-3
    suppressor of cytokine signaling 3
    PDGF
    platelet-derived growth factor
    PBS
    phosphate-buffered saline
    AG538
    α-cyano-(3-methoxy,4-hydroxy,5-iodo)cinnamoyl-(3′,4′-dihydroxyphenyl)ketone
    AG1295
    6,7-dimethyl-2-phenylquinoxaline
    AG1024
    3-bromo-5-t-butyl-4-hydroxy-benzylidenemalo-nitrile
    AG879
    α-cyano-(3,5-di-t-butyl-4-hydroxy)thiocinnamide
    AG1478
    4-(3-chloroanilino)-6,7-dimethoxyquinazoline
    GM6001
    N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide.

  • Received March 22, 2010.
  • Accepted November 15, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (2)
Molecular Pharmacology
Vol. 79, Issue 2
1 Feb 2011
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Research ArticleArticle

Epidermal Growth Factor Treatment Switches δ-Opioid Receptor-Stimulated Extracellular Signal-Regulated Kinases 1 and 2 Signaling from an Epidermal Growth Factor to an Insulin-Like Growth Factor-1 Receptor-Dependent Mechanism

Daniela A. Eisinger and Hermann Ammer
Molecular Pharmacology February 1, 2011, 79 (2) 326-335; DOI: https://doi.org/10.1124/mol.110.064956

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Research ArticleArticle

Epidermal Growth Factor Treatment Switches δ-Opioid Receptor-Stimulated Extracellular Signal-Regulated Kinases 1 and 2 Signaling from an Epidermal Growth Factor to an Insulin-Like Growth Factor-1 Receptor-Dependent Mechanism

Daniela A. Eisinger and Hermann Ammer
Molecular Pharmacology February 1, 2011, 79 (2) 326-335; DOI: https://doi.org/10.1124/mol.110.064956
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