Differential Activation of Mitogen-activated Protein Kinases by Nitric Oxide-related Species

doi:10.1074/jbc.271.33.19705

Differential Activation of Mitogen-activated Protein Kinases by Nitric Oxide-related Species*

From the Department of Biochemistry, Cornell University Medical College, New York, New York 10021 and
^§ Howard Hughes Medical Institute, Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

^‡To whom correspondence should be addressed:
Dept. of Biochemistry, Cornell University Medical College, New York, NY 10021.
Tel.: 212-746-6462; Fax: 212-746-8789.

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.

Footnotes

↵* This work was supported by National Institutes of Health Grants HL46403 and AI37637 (to H. M. L.) and CA58396 (to R. J. D.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

NO

nitric oxide

NO_x

nitric oxide-related species

SNP

sodium nitroprusside

SNAP

S-nitroso-N-acetylpenicillamine

ERK

extracellular signal-regulated kinase

JNK

c-Jun NH₂-terminal kinase

MAP

mitogen-activated protein

BSO

L-buthionine-(SR)-sulfoximine

GST

glutathione S-transferase.
- Received March 19, 1996.
- Revision received May 31, 1996.