TNF-stimulated MAP kinase activation mediated by a Rho family GTPase signaling pathway
- Shashi Kant1,2,
- Wojciech Swat3,
- Sheng Zhang4,
- Zhong-Yin Zhang4,
- Benjamin G. Neel5,
- Richard A. Flavell6,7 and
- Roger J. Davis1,2,8
- 1Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;
- 2Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;
- 3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
- 4Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA;
- 5Ontario Cancer Institute, Toronto, Ontario M5G 1L7, Canada;
- 6Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
- 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.
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Footnotes
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↵8 Corresponding author.
E-mail roger.davis{at}umassmed.edu.
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.17224711.
- Received June 13, 2011.
- Accepted August 26, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press
Freely available online through the Genes & Development Open Access option.