| First Author | Doan JE | Year | 2004 |
| Journal | J Immunol | Volume | 172 |
| Issue | 12 | Pages | 7654-60 |
| PubMed ID | 15187147 | Mgi Jnum | J:90827 |
| Mgi Id | MGI:3044843 | Doi | 10.4049/jimmunol.172.12.7654 |
| Citation | Doan JE, et al. (2004) Differential regulation of TNF-R1 signaling: lipid raft dependency of p42mapk/erk2 activation, but not NF-kappaB activation. J Immunol 172(12):7654-60 |
| abstractText | 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-kappaB. 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-kappaB 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-alpha. Disruption of lipid rafts by cholesterol depletion prevented the TNF-alpha-dependent recruitment of TNF-R1 to lipid rafts and inhibited the activation of p42(mapk/erk2), while the activation of NF-kappaB was unaffected. In addition, phosphorylated p42(mapk/erk2), but not receptor interacting protein, I-kappaB kinase-gamma, or I-kappaBalpha was detected in raft-containing fractions following TNF-alpha 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. |
