• TNF and MAP kinase signalling pathways

      Sabio, Guadalupe; Davis, Roger J. (2014-06-01)
      The binding of tumour necrosis factor alpha (TNFalpha) to cell surface receptors engages multiple signal transduction pathways, including three groups of mitogen-activated protein (MAP) kinases: extracellular-signal-regulated kinases (ERKs); the cJun NH2-terminal kinases (JNKs); and the p38 MAP kinases. These MAP kinase signalling pathways induce a secondary response by increasing the expression of several inflammatory cytokines (including TNFalpha) that contribute to the biological activity of TNFalpha. MAP kinases therefore function both upstream and down-stream of signalling by TNFalpha receptors. Here we review mechanisms that mediate these actions of MAP kinases during the response to TNFalpha.
    • TNF-stimulated MAP kinase activation mediated by a Rho family GTPase signaling pathway

      Kant, Shashi; Swat, Wojciech; Zhang, Sheng; Zhang, Zhong-Yin; Neel, Benjamin G.; Flavell, Richard A.; Davis, Roger J. (2011-10-01)
      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.