TNF-stimulated MAP kinase activation mediated by a Rho family GTPase signaling pathway

  1. Roger J. Davis1,2,8
  1. 1Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;
  2. 2Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;
  3. 3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
  4. 4Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA;
  5. 5Ontario Cancer Institute, Toronto, Ontario M5G 1L7, Canada;
  6. 6Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
  7. 7Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    Abstract

    The biological response to tumor necrosis factor (TNF) involves activation of MAP kinases. Here we report a mechanism of MAP kinase activation by TNF that is mediated by the Rho GTPase family members Rac/Cdc42. This signaling pathway requires Src-dependent activation of the guanosine nucleotide exchange factor Vav, activation of Rac/Cdc42, and the engagement of the Rac/Cdc42 interaction site (CRIB motif) on mixed-lineage protein kinases (MLKs). We show that this pathway is essential for full MAP kinase activation during the response to TNF. Moreover, this MLK pathway contributes to inflammation in vivo.

    Keywords

    Footnotes

    • Received June 13, 2011.
    • Accepted August 26, 2011.

    Freely available online through the Genes & Development Open Access option.

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