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Differential Regulation of TNF-R1 Signaling: Lipid Raft Dependency of p42^mapk/erk2 Activation, but Not NF-B Activation¹

Joyce E. S. Doan^*, David A. Windmiller^*, and David W. H. Riches^2,*,,

^* Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206; and Department of Immunology and Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262

The TNFR, TNF-R1, is localized to lipid raft and nonraft regions of the plasma membrane. Ligand binding sets in motion signaling cascades that promote the activation of p42^mapk/erk2 and NF-B. However, the role of receptor localization in the activation of downstream signaling events is poorly understood. In this study, we investigated the dynamics of TNF-R1 localization to lipid rafts and the consequences of raft localization on the activation of p42^mapk/erk2 and NF-B in primary cultures of mouse macrophages. Using sucrose density gradient ultracentrifugation and a sensitive ELISA to detect TNF-R1, we show that TNF-R1 is rapidly and transiently recruited to lipid rafts in response to TNF-. Disruption of lipid rafts by cholesterol depletion prevented the TNF--dependent recruitment of TNF-R1 to lipid rafts and inhibited the activation of p42^mapk/erk2, while the activation of NF-B was unaffected. In addition, phosphorylated p42^mapk/erk2, but not receptor interacting protein, I-B kinase-, or I-B was detected in raft-containing fractions following TNF- stimulation. These findings suggest that TNF-R1 is localized to both lipid raft and nonraft regions of the plasma membrane and that each compartment is capable of initiating different signaling responses. We propose that segregation of TNF-R1 to raft and nonraft regions of the plasma membrane contributes to the diversity of signaling responses initiated by TNF-R1.

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