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.
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.
Marques
Silvio A
SA
Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Dy
Lady C
LC
Southall
Michael D
MD
Yi
Quiaofang
Q
Smietana
Eva
E
Kapur
Reuben
R
Marques
Mariangela
M
Travers
Jeffrey B
JB
Spandau
Dan F
DF
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D015603:Keratinocytes / Q000187:drug effects*; D048670:MAP Kinase Kinase 4; D020782:Matrix Metalloproteinases / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000502:physiology*; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020782:Matrix Metalloproteinases