Program in Molecular Medicine
Animals; Cells, Cultured; Enzyme Activation; Inflammation; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-vav; *Signal Transduction; Tumor Necrosis Factor-alpha; Tyrosine; cdc42 GTP-Binding Protein
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Developmental Biology | Molecular Biology | Molecular Genetics
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.
MAP kinase, MLK, mixed-lineage protein kinase, TNF
Rights and Permissions
Freely available online through the Genes and Development Open Access option.
DOI of Published Version
Genes Dev. 2011 Oct 1;25(19):2069-78. doi: 10.1101/gad.17224711. Link to article on publisher's site
Genes and development
Kant, Shashi; Swat, Wojciech; Zhang, Sheng; Zhang, Zhong-Yin; Neel, Benjamin G.; Flavell, Richard A.; and Davis, Roger J., "TNF-stimulated MAP kinase activation mediated by a Rho family GTPase signaling pathway" (2011). Davis Lab Publications. 39.