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

• Published in: Genes & development Vol. 25; no. 19; pp. 2069 - 2078
• Main Authors: Kant, Shashi, Swat, Wojciech, Zhang, Sheng, Zhang, Zhong-Yin, Neel, Benjamin G, Flavell, Richard A, Davis, Roger J
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.10.2011
• Subjects: Animals; cdc42 GTP-Binding Protein - metabolism; Cells, Cultured; Enzyme Activation; Inflammation - enzymology; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-vav - metabolism; Research Paper; Signal Transduction; Tumor Necrosis Factor-alpha - metabolism; Tyrosine - metabolism
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.17224711

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.