c-Src is required for oxidative stress-mediated activation of big mitogen-activated protein kinase 1 (BMK1)

Jun Ichi Abe, Masafumi Takahashi, Mari Ishida, Jiing Dwan Lee, Bradford C. Berk

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250 Scopus citations


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 Cc-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.

Original languageEnglish (US)
Pages (from-to)20389-20394
Number of pages6
JournalJournal of Biological Chemistry
Issue number33
StatePublished - Aug 15 1997

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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