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

J Biol Chem. 1996 Aug 16;271(33):19705-9. doi: 10.1074/jbc.271.33.19705.

Abstract

Many studies have identified nitric oxide (NO) and related chemical species (NOx) as having critical roles in neurotransmission, vasoregulation, and cellular signaling. Previous work in this laboratory has focused on elucidating the mechanism of NOx signaling in cells. We have demonstrated that NOx-induced activation of the guanine nucleotide-binding protein p21(ras) leads to nuclear translocation of the transcription factor NFkappaB. Here, we investigated whether intermediary signaling elements, namely the mitogen-activated protein (MAP) kinases, are involved in mediating NOx signaling. We found that NOx 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 NOx stimulation than p38 and ERK. In addition, the activation of JNK and p38 by NOx was more rapid than ERK activation. Depletion of intracellular glutathione augmented the NOx-induced increase in kinase activity. Furthermore, endogenous NO, generated from NO synthase, activated ERK, and NOx-induced MAP kinase activation was effectively blocked by the farnesyl transferase inhibitor alpha-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 NOx.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkyl and Aryl Transferases*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Enzyme Activation
  • Farnesyltranstransferase
  • GTP-Binding Proteins / physiology
  • Humans
  • Hydrogen Peroxide / metabolism
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Nitric Oxide / chemistry*
  • Nitric Oxide / physiology
  • Nitrogen Oxides / pharmacology
  • Nitroprusside / metabolism
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors
  • Signal Transduction
  • T-Lymphocytes / physiology*
  • Transferases / antagonists & inhibitors
  • Tumor Cells, Cultured
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Nitrogen Oxides
  • Nitroprusside
  • Nitric Oxide
  • Hydrogen Peroxide
  • Transferases
  • Alkyl and Aryl Transferases
  • Farnesyltranstransferase
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • GTP-Binding Proteins
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)