Tumor necrosis factor receptor 1 and 2 (TNF-R1 and TNF-R2), are 55 and 75 kDa members of a family cell surface molecules including nerve growth factor receptor, Fas/Apo-1, CD30, Ox40 and 4-1BB, which are characterized by cysteine rich motifs in the extracellular domain. While TNF-R1 and TNF-R2 share 28% sequence identity in their extracellular domains, their intracellular domains lack sequence homology which suggests that they differ in their internal signal transduction pathways. TNF-R1 initiates the majority of TNF.s activities, which includes triggering apoptosis of certain tumor cells, mediating the inflammatory response and regulating immune function (Chen). Each pathway is characterized by TNF-induced formation of a multi-protein signaling complex at the cell membrane. TNF and TNF-R1 binding initiates a series of intracellular events that result in activation of the transcription factors NF kappa B and c-Jun. TNF and TNF-R1 binding triggers release of the 80 residue inhibitory protein silencer of death domains (SODD) from the C-terminal intracellular domain of TNF-R1. This domain interacts with TNF receptor-associated death domain (TRADD) which in turn recruits receptor-interacting protein (RIP) TNF-R-associated factor 2 (TRAF2) and Fas-associated death domain (FADD). These three proteins recruit enzymes responsible for initiating signaling events. For example, interaction of SODD with TRADD, and subsequent interactions with FADD initiates Caspase-8 mediated apoptosis. TRAF2 links TNF-R1 with stress activated protein kinase (SAPK) and p38 mitogen activated protein kinases via germinal center kinase (GCK) and receptor interacting protein (RIP). The cytoplasmic domain of TNF-R1 can directly interact with Jak kinases.
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- Sasaki, Nobuyuki MD, PhD; Sekiguchi, Miho MD, PhD; Kikuchi, Shin-ichi MD, PhD; Konno, Shin-ichi MD, PhD. (2011). Effects of Asialo-Erythropoietin on Pain-Related Behavior and Expression of Phosphorylated-P38 Map Kinase and Tumor Necrosis Factor-Alpha Induced by Application of Autologous Nucleus Pulposus on Nerve Root in Rat. Spine, Volume 36, Issue 2, p.E86–E94. doi: 10.1097/BRS.0b013e3181f137a8
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