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Research ArticleCELLULAR AND MOLECULAR

The Platelet-Activating Factor Receptor Activates the Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Induces Proliferation of Epidermal Cells through an Epidermal Growth Factor-Receptor-Dependent Pathway

Silvio A. Marques, Lady C. Dy, Michael D. Southall, Quiaofang Yi, Eva Smietana, Reuben Kapur, Mariangela Marques, Jeffrey B. Travers and Dan F. Spandau
Journal of Pharmacology and Experimental Therapeutics March 2002, 300 (3) 1026-1035; DOI: https://doi.org/10.1124/jpet.300.3.1026
Silvio A. Marques
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Lady C. Dy
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Michael D. Southall
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Quiaofang Yi
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Eva Smietana
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Reuben Kapur
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Mariangela Marques
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Jeffrey B. Travers
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Dan F. Spandau
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Abstract

Platelet-activating factor (PAF) is a lipid mediator that has been implicated in a variety of keratinocyte functions. Keratinocytes express the specific receptor for PAF (PAF-R), a seven-transmembrane G-protein-coupled receptor. Although PAF-R-dependent stimulation of numerous signal transduction pathways has been shown in a variety of cell types, to date there has been no analysis of PAF-R signal transduction in human epidermal cells. There is also contradictory evidence that PAF acts as either a suppressor or activator of keratinocyte proliferation. Using a model system created by retroviral-mediated transduction of the PAF-R into the PAF-R-negative epidermal cell line KB, we now demonstrate that the activation of the epidermal PAF-R results in the activation of both the extracellular signal-regulated kinase (ERK) and p38, but not the jun N-terminal kinase mitogen-activated protein (MAP) kinase pathways. Additionally, we show that the activation of the PAF-R stimulates the replication of epidermal cells. The activation of the ERK signal transduction pathway, as well as the PAF-dependent increase in cell proliferation, was dependent on the transactivation of the epidermal growth factor receptor (EGF-R). PAF-R-induced transactivation of the EGF-R was blocked by pharmacologic inhibitors of matrix metalloproteinases, of heparin-binding epidermal growth factor (HB-EGF), and specific inhibitors of the EGF-R tyrosine kinase. Activation of p38 MAP kinase by the PAF-R was not dependent on EGF-R activation and represents a distinct pathway of PAF-R-mediated signal transduction. In summary, these studies provide a mechanism whereby the PAF-R can exert proliferative effects through the activation of the EGF-R.

Footnotes

  • ↵1 These authors contributed equally to the work.

  • This research was supported in part by grants from the Showalter Memorial Foundation, and National Institute of Health Grants K08AR1993 and R01HL62996. M. M. was supported by Brazilian grants from the Fundcao de Amparo a Pesquisa do Estado de Sao Paulo.

  • Abbreviations:
    PAF
    platelet-activating factor
    PAF-R
    PAF receptor
    CPAF
    1-O-hexadecyl-2-N-methylcarbamoyl-glycerophosphocholine or carbamoyl PAF
    EGF-R
    epidermal growth factor receptor
    HB-EGF
    heparin-binding EGF
    DAPH
    4,5-dianilinophthalimide
    GPCR
    G-protein-coupled receptor
    MMP
    matrix metalloproteinase
    MAP
    mitogen-activated protein
    ERK
    extracellular signal-regulated kinase
    JNK
    jun N-terminal kinase
    PI 3′K
    phosphatidylinositol 3-kinase
    PKC
    protein kinase C
    IL
    interleukin
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    PD98059
    2′-amino-3′-methoxyflavone
    WEB-2086
    morpholine,4-(3-(4-(2-chlorophenyl-9-methyl-6H-thieno(3,2-f)(1,2,4)triazolol(4,3-a)(1,4)diazepin-2-yl)-1-oxopropyl
    LY294002
    2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
    AG 1478
    4-(3-chloroanilino)-6,7-dimethoxyquinazoline
    GM6001
    N-(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide
    CRM 197
    [Glu52]-diphtheria toxin
    • Received September 28, 2001.
    • Accepted November 30, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 300 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 300, Issue 3
1 Mar 2002
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Research ArticleCELLULAR AND MOLECULAR

The Platelet-Activating Factor Receptor Activates the Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Induces Proliferation of Epidermal Cells through an Epidermal Growth Factor-Receptor-Dependent Pathway

Silvio A. Marques, Lady C. Dy, Michael D. Southall, Quiaofang Yi, Eva Smietana, Reuben Kapur, Mariangela Marques, Jeffrey B. Travers and Dan F. Spandau
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 1026-1035; DOI: https://doi.org/10.1124/jpet.300.3.1026

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Research ArticleCELLULAR AND MOLECULAR

The Platelet-Activating Factor Receptor Activates the Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Induces Proliferation of Epidermal Cells through an Epidermal Growth Factor-Receptor-Dependent Pathway

Silvio A. Marques, Lady C. Dy, Michael D. Southall, Quiaofang Yi, Eva Smietana, Reuben Kapur, Mariangela Marques, Jeffrey B. Travers and Dan F. Spandau
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 1026-1035; DOI: https://doi.org/10.1124/jpet.300.3.1026
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