title: Involvement of reactive oxygen species in stimuli-induced shedding of heparin-binding epidermal growth factor-like growth factor.
abstract: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a critical growth factor for a number of physiological and pathological processes, such as wound healing, atherosclerosis and cancer proliferation. HB-EGF is synthesized as a membrane form (proHB-EGF), and is shedded at the cell surface to yield soluble HB-EGF, resulting in making it active. In this study, the involvement of reactive oxygen species (ROS) in stimuli-induced shedding of HB-EGF was investigated using monkey kidney Vero cells overexpressing HB-EGF (Vero-H cells). 12-O-tetradecanoylphorbol-13-acetate (TPA), lysophosphatidic acid (LPA) as a ligand for seventransmembrane G protein coupled receptors (GPCR) and sorbitol as stress induced shedding of HB-EGF mediated protein kinase C (PKC)-δ, mitogen-activated protein kinase (MAPK) and p38MAPK, respectively. These stimuli-induced sheddings of HB-EGF were inhibited by N-acetyl-L-cysteine (NAC), suggesting the involvement of ROS. As specific inhibitors of these protein kinases inhibited the shedding of HB-EGF, these signaling pathways seem to be independent, respectively. In contrast, γ-ray irradiation did not induce shedding although it did increase intracellular ROS levels. Taken together, these results suggest that the synergistic generation of ROS and the activation of protein kinase are required to promote stimuli-induced shedding of HB-EGF.
authors.affiliation: Radioisotope Research Center, University of Occupational and Environmental Health, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Umata
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002522:Chlorocebus aethiops; D004167:Diphtheria Toxin / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology* / Q000528:radiation effects; D008024:Ligands; D008246:Lysophospholipids / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis; D011493:Protein Kinase C / Q000032:analysis; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects; D013012:Sorbitol / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014709:Vero Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000032:analysis
chemical_list: D004167:Diphtheria Toxin; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008246:Lysophospholipids; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D013012:Sorbitol; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate; C032881:lysophosphatidic acid; D000111:Acetylcysteine