title: Extracellular oxidation by taurine chloramine activates ERK via the epidermal growth factor receptor.
abstract: Taurine is present in high concentrations in neutrophils, and when the cells are stimulated taurine can react with hypochlorous acid (HOCl) to form taurine-chloramine (Tau-Cl). This compound retains oxidant activity and can affect the neutrophil itself or surrounding tissue cells. We have investigated the effects of Tau-Cl on MAPK signaling in human umbilical vein endothelial cells (HUVEC). Tau-Cl caused no loss in intracellular glutathione or inactivation of the thiol-sensitive enzyme glyceraldehyde-3-phosphate dehydrogenase, indicating that it had not entered the cells. However, stimulation of HUVEC with Tau-Cl (20-100 microM) induced the rapid activation of ERK within 10 min. This activation was abolished by inhibition of MEK by U0126, indicating that it was not because of direct oxidation of ERK. No activation of p38 was detected. These results suggest that Tau-Cl reacts with a cell membrane target that results in intracellular ERK activation. Tau-Cl over the same concentration range and time scale stimulated epidermal growth factor (EGF) receptor tyrosine phosphorylation in A431 cells and HUVEC. The EGF receptor inhibitor PD158780 significantly attenuated Tau-Cl-induced phosphorylation of both the EGF receptor and ERK. This implicates the EGF receptor in the upstream activation of ERK. The Src tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolol[3,4-d]pyrimidine had no effect on Tau-Cl-induced EGF receptor or ERK activation. We propose that Tau-Cl acts on an oxidant-sensitive target on the cell surface, this being either the EGF receptor itself or another target that can interact with the EGF receptor, with consequential activation of ERK.
authors.affiliation: Free Radical Research Group, Department of Pathology, Christchurch School of Medicine and Health Sciences, P. O. Box 4345, Christchurch 8001, New Zealand. robyn.midwinter@chmeds.ac.nz
authors.forename: Robyn G
authors.initials: RG
authors.lastname: Midwinter
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Peskin
authors.forename: Margret C M
authors.initials: MC
authors.lastname: Vissers
authors.forename: Christine C
authors.initials: CC
authors.lastname: Winterbourn
mesh_terms: D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002700:Chloramines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009504:Neutrophils / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D013654:Taurine / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology
chemical_list: C107875:6-(methylamino)pyrido(3,4-d)pyrimidine; C412373:AG 1879; D002070:Butadienes; D002700:Chloramines; D004791:Enzyme Inhibitors; D009570:Nitriles; D016877:Oxidants; D011743:Pyrimidines; C113580:U 0126; D013654:Taurine; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione; C030816:chloramine; D010100:Oxygen