Differential activation of mitogen-activated protein kinases by nitric oxide-related species

Harry M. Lander, Andrew T. Jacovina, Roger J. Davis, James M. Tauras

Research output: Contribution to journalArticle

273 Scopus citations

Abstract

Many studies have identified nitric oxide (NO) and related chemical species (NO(x)) as having critical roles in neurotransmission, vasoregulation, and cellular signaling. Previous work in this laboratory has focused on elucidating the mechanism of NO(x) signaling in cells. We have demonstrated that NO(x)- induced activation of the guanine nucleotide-binding protein p21(ras) leads to nuclear translocation of the transcription factor NFκB. Here, we investigated whether intermediary signaling elements, namely the mitogen-activated protein (MAP) kinases, are involved in mediating NO(x) signaling. We found that NO(x) activates the extracellular signal-regulated kinase (ERK), p38, and c-Jun NH2- terminal kinase (JNK) subgroups of MAP kinases in human Jurkat T cells. JNK was found to be 100-fold more sensitive to NO(x) stimulation than p38 and ERK. In addition, the activation of JNK and p38 by NO(x) was more rapid than ERK activation. Depletion of intracellular glutathione augmented the NO(x)-induced increase in kinase activity. Furthermore, endogenous NO, generated from NO synthase, activated ERK, and NO(x)-induced MAP kinase activation was effectively blocked by the farnesyl transferase inhibitor α-hydroxyfarnesylphosphonic acid. These data support the hypothesis that critical signaling kinases, such as ERK, p38, and JNK, are activated by NO-related species and thus participate in NO signal transduction. These findings establish a role for multiple MAP kinase signaling pathways in the cellular response to NO(x).

Original languageEnglish (US)
Pages (from-to)19705-19709
Number of pages5
JournalJournal of Biological Chemistry
Volume271
Issue number33
DOIs
StatePublished - Sep 5 1996
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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