MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines

  1. Cathy Tournier1,4,
  2. Chen Dong2,5,
  3. Tod K. Turner3,
  4. Stephen N. Jones3,
  5. Richard A. Flavell2, and
  6. Roger J. Davis1,6
  1. 1Howard Hughes Medical Institute, Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA; 2Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA; 3Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

Abstract

Mitogen-activated protein kinases (MAPK) are activated by phosphorylation on Thr and Tyr by MAPK kinases. Two MAPK kinases (MKK4 and MKK7) can activate the c-Jun NH2-terminal kinase (JNK) group of MAPK in vitro. JNK is phosphorylated preferentially on Tyr by MKK4 and on Thr by MKK7. Targeted gene-disruption studies in mice were performed to examine the role of MKK4 and MKK7 in vivo. Simultaneous disruption of the Mkk4 and Mkk7 genes was required to block JNK activation caused by exposure of cells to environmental stress. In contrast, disruption of the Mkk7 gene alone was sufficient to prevent JNK activation caused by proinflammatory cytokines. These data demonstrate that MKK4 and MKK7 serve different functions in the JNK signal transduction pathway.

Keywords

Footnotes

  • Present addresses: 4School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK; 5Department of Immunology, University of Washington, Seattle, WA 98195, USA.

  • 6 Corresponding author.

  • E-MAIL Roger.Davis{at}Umassmed.Edu; FAX (508) 856-3210.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.888501.

    • Received February 14, 2001.
    • Accepted April 2, 2001.
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