GSBS Student Publications


The death domain kinase RIP1 is essential for tumor necrosis factor alpha signaling to p38 mitogen-activated protein kinase

UMMS Affiliation

Graduate School of Biomedical Sciences; Department of Cancer Biology and Interdisciplinary Graduate Program; Program in Molecular Medicine and Howard Hughes Medical Institute; Program in Gene Function and Expression



Document Type


Medical Subject Headings

Animals; Antigens, CD; Base Sequence; Cells, Cultured; DNA; Enzyme Activation; GTPase-Activating Proteins; Interleukin-6; MAP Kinase Kinase Kinase 3; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases; Models, Biological; Proteins; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; TNF Receptor-Associated Factor 2; Tumor Necrosis Factor-alpha; p38 Mitogen-Activated Protein Kinases


Life Sciences | Medicine and Health Sciences


The cytokine tumor necrosis factor alpha (TNF-alpha) stimulates the NF-kappaB, 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 IkappaB 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-alpha-induced p38 MAP kinase activation. We found TNF-alpha-induced p38 MAP kinase activation and interleukin-6 (IL-6) production impaired in rip1(-/-) murine embryonic fibroblasts (MEF) but unaffected in traf2(-/-) MEF. Yet, both rip1(-/-) and traf2(-/-) MEF exhibit a normal p38 MAP kinase response to inducers of osmotic shock or IL-1alpha. Thus, RIP1 is a specific mediator of the p38 MAP kinase response to TNF-alpha. These studies suggest that TNF-alpha-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-alpha-treated cells, and decreased TNF-alpha-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-alpha, by recruiting the MAP3K MEKK3.

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Citation: Mol Cell Biol. 2003 Nov;23(22):8377-85.

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Link to article in PubMed

Journal Title

Molecular and cellular biology

PubMed ID