The Death Domain Kinase RIP1 is Essential for Tumor Necrosis Factor Alpha Signaling to p38 Mitogen-Activated Protein Kinase

Thomas H. Lee, Qiaojia Huang, Sarah Oikemus, Jennifer Shank, Juan Jose Ventura, Nicole Cusson, Richard R. Vaillancourt, Bing Su, Roger J. Davis, Michelle A. Kelliher

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

The cytokine tumor necrosis factor alpha (TNF-α) stimulates the NF-κB, SAPK/JNK, and p38 mitogen-activated protein (MAP) kinase pathways by recruiting RIP1 and TRAF2 proteins to the tumor necrosis factor receptor 1 (TNFR1). Genetic studies have revealed that RIP1 links the TNFR1 to the IκB kinase (IKK) complex, whereas TRAF2 couples the TNFR1 to the SAPK/JNK cascade. In transfection studies, RIP1 and TRAF2 stimulate p38 MAP kinase activation, and dominant-negative forms of RIP1 and TRAF2 inhibit TNF-α-induced p38 MAP kinase activation. We found TNF-α-induced p38 MAP kinase activation and interleukin-6 (IL-6) production impaired in rip1 -/- murine embryonic fibroblasts (MEF) but unaffected in traf2 -1- MEF. Yet, both rip1-/- and traf2-/- MEF exhibit a normal p38 MAP kinase response to inducers of osmotic shock or IL-1α. Thus, RIP1 is a specific mediator of the p38 MAP kinase response to TNF-α. These studies suggest that TNF-α-induced activation of p38 MAP kinase and SAPK/JNK pathways bifurcate at the level of RIP1 and TRAF2. Moreover, endogenous RIP1 associates with the MAP kinase kinase kinase (MAP3K) MEKK3 in TNF-α-treated cells, and decreased TNF-α-induced p38 MAP kinase activation is observed in Mekk3-/- cells. Taken together, these studies suggest a mechanism whereby RIP1 may mediate the p38 MAP kinase response to TNF-α, by recruiting the MAP3K MEKK3.

Original languageEnglish (US)
Pages (from-to)8377-8385
Number of pages9
JournalMolecular and cellular biology
Volume23
Issue number22
DOIs
StatePublished - Nov 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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