Vol. 300, Issue 3, 1026-1035, March 2002

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. Marques¹ , Lady C. Dy¹ , Michael D. Southall , Quiaofang Yi , Eva Smietana, Reuben Kapur, Mariangela Marques, Jeffrey B. Travers and Dan F. Spandau

Departments of Dermatology (S.A.M., L.C.D., M.D.S., Q.Y., E.S., M.M., J.B.T., D.F.S.), Pediatrics and the H. B.Wells Center for Pediatric Research (M.D.S., Q.Y., R.K., J.B.T.), Pharmacology and Toxicology (J.B.T.), and Biochemistry and Molecular Biology (D.F.S.), Indiana University School of Medicine, Indianapolis, Indiana

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.