The overall goal of this research program is to understand how the death domain kinase RIP mediates signal transduction by the proinflammatory cytokine, tumor necrosis factor (TNF). The potent biological action of TNF has been studied in detail and known to contribute to sepsis, inflammation and cancer. TNF activates multiple transduction pathways including the NF-kappaB, SAPK/JNK and p38 MAP kinase pathways. RIP is the only known serine/threonine kinase recruited to the tumor necrosis factor receptor (TNFR1) upon receptor activation. Yet the function of the kinase activity of RIP is unknown. The contribution of the kinase activity of RIP to mammalian development and to TNF signal transduction will be investigated. To assess RIP function in TNF signaling, we created RIP-deficient mice. In the absence of RIP, mice exhibit postnatal lethality and apoptosis of the immune, adipocyte and muscle lineages. A specific focus of this proposal is to understand whether the RIP- associated lethality and tissue apoptosis is TNF-mediated. The RIP-deficient phenotype contrasts sharply with that of the TNF alphaminus/minus or TNFR1minus/minus mice, which are for the most part normal. These studies suggest that RIP may have additional biologic roles beyond that of TNF signaling. RIP interacts with other TNFR1-related death receptors (DR3, DR4 and DR5). An additional objective of this proposal is to determine the functional contribution of RIP to signaling by these death receptors and to identify the biological processes regulated by these death receptor pathways in lymphocytes. Our genetic analysis revealed a critical role for RIP in the NF- kappaB response to TNF. Our preliminary studies suggest that RIP may also contribute to the p38 MAP kinase pathway. The molecular mechanisms of RIP mediated NF-kappaB and p38 MAP kinase activation will be investigated.
| Cusson-Hermance, Nicole; Khurana, Smriti; Lee, Thomas H et al. (2005) Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation. J Biol Chem 280:36560-6 |
| Lee, Thomas H; Shank, Jennifer; Cusson, Nicole et al. (2004) The kinase activity of Rip1 is not required for tumor necrosis factor-alpha-induced IkappaB kinase or p38 MAP kinase activation or for the ubiquitination of Rip1 by Traf2. J Biol Chem 279:33185-91 |
| Lee, Thomas H; Huang, Qiaojia; Oikemus, Sarah et al. (2003) The death domain kinase RIP1 is essential for tumor necrosis factor alpha signaling to p38 mitogen-activated protein kinase. Mol Cell Biol 23:8377-85 |
| Cusson, Nicole; Oikemus, Sarah; Kilpatrick, Elizabeth D et al. (2002) The death domain kinase RIP protects thymocytes from tumor necrosis factor receptor type 2-induced cell death. J Exp Med 196:15-26 |
