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, thereby.
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