title: Enhanced PKCδ and ERK signaling mediate cell migration of retinal pigment epithelial cells synergistically induced by HGF and EGF.
abstract: Proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR) are characterized by the development of epi-retinal membranes which may exert a tractional force on retina. A lot of inflammatory growth factors may disturb the local ocular cells such as retinal pigment epithelial (RPE) cells, causing them to migrate and proliferate in the vitreous cavity and ultimately forming the PVR membrane. In this study, the signal pathways mediating cell migration of RPE induced by growth factors were investigated. Hepatocyte growth factor (HGF), epidermal growth factor (EGF) or heparin-binding epidermal growth factor (HB-EGF) induced a greater extent of migration of RPE50 and ARPE19 cells, compared with other growth factors. According to inhibitor studies, migration of RPE cells induced by each growth factor was mediated by protein kinase C (PKC) and ERK (MAPK). Moreover, HGF coupled with EGF or HB-EGF had synergistic effects on cell migration and enhanced activation of PKC and ERK, which were attributed to cross activation of growth factor receptors by heterogeneous ligands. Furthermore, using the shRNA technique, PKCδ was found to be the most important PKC isozyme involved. Finally, vitreous fluids from PVR and PDR patients with high concentration of HGF may induce RPE cell migration in PKCδ- and ERK- dependent manner. In conclusion, migration of RPE cells can be synergistically induced by HGF coupled with HB-EGF or EGF, which were mediated by enhanced PKCδ activation and ERK phosphorylation.
authors.affiliation: Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Yu Jung
authors.initials: YJ
authors.lastname: Chen
authors.forename: Rong Kung
authors.initials: RK
authors.lastname: Tsai
authors.forename: Wen Chen
authors.initials: WC
authors.lastname: Wu
authors.forename: Ming Shan
authors.initials: MS
authors.lastname: He
authors.forename: Ying-Hsien
authors.initials: YH
authors.lastname: Kao
authors.forename: Wen Sheng
authors.initials: WS
authors.lastname: Wu
mesh_terms: D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051745:Protein Kinase C-delta / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D018630:Vitreoretinopathy, Proliferative / Q000473:pathology
chemical_list: C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases