title: c-Src is required for oxidative stress-mediated activation of big mitogen-activated protein kinase 1.
abstract: Big mitogen-activated kinase 1 (BMK1) or extracellular signal-regulated kinase-5 (ERK5) has recently been identified as a new member of the mitogen-activated protein kinase family. We have shown that BMK1 is activated to a greater extent by H2O2 than growth factors, suggesting that in comparison with other mitogen-activated protein kinase family members, BMK1 is a redox-sensitive kinase. Previous investigations indicate that the tyrosine kinase c-Src mediates signal transduction by reactive oxygen species, including H2O2. Therefore, the role of Src kinase family members (c-Src and Fyn) in activation of the BMK1 by H2O2 in mouse fibroblasts was studied. An essential role for c-Src was suggested by four experiments. First, H2O2 stimulated c-Src activity rapidly in fibroblasts (peak at 5 min), which preceded peak activity of BMK1 (20 min). Second, specific Src family tyrosine kinase inhibitors (herbimycin A and CP-118,556) blocked BMK1 activation by H2O2 in a concentration-dependent manner. Third, BMK1 activation in the response to H2O2 was completely inhibited in cells derived from mice deficient in c-Src, but not Fyn. Finally, BMK1 activity was much greater in v-Src-transformed NIH-3T3 cells than wild type cells. These results demonstrate an essential role for c-Src in H2O2-mediated activation of BMK1 and suggest that redox-sensitive regulation of BMK1 is a new function for c-Src.
authors.affiliation: Department of Medicine, Cardiology Division, University of Washington, Seattle, Washington 98195, USA.
authors.forename: J i
authors.initials: Ji
authors.lastname: Abe
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: M
authors.initials: M
authors.lastname: Ishida
authors.forename: J D
authors.initials: JD
authors.lastname: Lee
authors.forename: B C
authors.initials: BC
authors.lastname: Berk
mesh_terms: D000818:Animals; D016227:Benzoquinones; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D018384:Oxidative Stress; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology*; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives
chemical_list: D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D011518:Proto-Oncogene Proteins; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; D006861:Hydrogen Peroxide; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D016392:Proto-Oncogene Proteins pp60(c-src); D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases