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Molecular and Cellular Biology, November 2003, p. 8377-8385, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8377-8385.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Thomas H. Lee,1 Qiaojia Huang,2 Sarah Oikemus,1 Jennifer Shank,1 Juan-Jose Ventura,3 Nicole Cusson,1 Richard R. Vaillancourt,4 Bing Su,2 Roger J. Davis,3 and Michelle A. Kelliher1*

Department of Cancer Biology and Interdisciplinary Graduate Program,1 Program in Molecular Medicine and Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts,3 Department of Immunology, M. D. Anderson Cancer Center, The University of Texas, Houston, Texas,2 Department of Pharmacology and Toxicology, University of Arizona College of Pharmacy, Tucson, Arizona4

Received 13 December 2002/ Returned for modification 10 June 2003/ Accepted 7 August 2003

The cytokine tumor necrosis factor alpha (TNF-{alpha}) stimulates the NF-{kappa}B, 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 I{kappa}B 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-1{alpha}. 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.

* Corresponding author. Mailing address: Department of Cancer Biology, University of Massachusetts Medical School, Lazare Research Building, Worcester, MA 01605. Phone: (508) 856-8620. Fax: (508) 856-1310. E-mail: Michelle.Kelliher{at}umassmed.edu.

Molecular and Cellular Biology, November 2003, p. 8377-8385, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8377-8385.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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