TNFR1 Pathway
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TNFR1 Pathway

The Tumor Necrosis Factor Receptor (TNFR) super family represents a growing family, with over 20 members having been identified so far in mammalian cells. TNF-Alpha (Tumor Necrosis Factor-Alpha), a potent cytokine, elicits a broad spectrum of biologic responses, which are mediated by binding to a cell surface receptor. TNF has been considered as an anti-cancer agent. Members of the TNFR superfamily can send both survival and death signals to cells. TNF family members play important roles in various physiological and pathological processes, including cell proliferation, differentiation, apoptosis and modulation of immune responses and induction of inflammation. TNF acts through two receptors, TNFR1 and TNFR2. TNFR1 is expressed by all human tissues and is the major signaling receptor for TNF-Alpha. TNFR2 is mostly expressed in immune cells and mediates limited biological responses (Ref.1).

TNFR1 (p55) contains a cytoplasmic DD (Death Domain) required for signaling pathways associated with apoptosis and NF-KappaB (Nuclear Factor-KappaB) activation. TNF-induced receptor trimerization aggregates the DD of TNFR1 and recruits the adapter protein TRADD (TNFR-Associated Death Domain). This in turn promotes the recruitment of the DD-containing cytoplasmic proteins FADD (Fas Associated Death Domain), MADD (MAPK Activating Death Domain), RAIDD (RIP-Associated ICH-1/CED-3-homologous protein with a Death Domain) TRAF1/2 (TNF Receptor Associated Factor-1/2) and RIP (Receptor Interacting Protein) to form an active TNFR1 signaling complex containing CIAP (cellular Inhibitor of Apoptosis) (Ref.2). In contrast, SODD (Silencer Of Death Domains), a 60-kDa protein acts as a silencer of TNFR1 signaling and does not interact with MADD, TRADD, FADD, or RIP. It is associated with the DD of TNFR1 and maintains TNFR1 in an inactive, monomeric state. TNF-induced aggregation of TNFR1 promotes the disruption of the SODD-TNFR1 complex. SODD suppresses TNF-induced cell death and NF-KappaB activation demonstrating its role as a negative regulatory protein for these signaling pathways. Binding of TRADD and FADD to TNFR1 leads to the recruitment, oligomerization, and activation of Procaspase, which then activates Caspase8. Activated Caspase8 subsequently initiates a proteolytic cascade that includes other Caspases (Caspase3,6,7) and ultimately induces apoptosis (Ref.3). NF-KappaB stimulation results from IKKs (I-KappaB Kinases) activation. After stimulation, I-KappaB is phosphorylated and targeted to the proteasome for its degradation thereby leading to NF-KappaB release and translocation to the nucleus.

Binding of TNF to the TNFR1 receptor also activates the GCK (Germinal Center Kinase) through the TNF adaptor TRAF2, activating the MAPK (Mitogen Activated Protein Kinase) MEKK1. Both GCK and MEKK1 (Map/ERK Kinase Kinase-1) interact with TRAF2 (TNF Receptor-Associated Factor-2), and GCK is required for MEKK1 activation by TNF, but GCK kinase activity does not appear to be required for MEKK1 activation. Instead, GCK activates MEKK1 by causing MEKK1 oligomerization and autophosphorylation. Once activated, MEKK1 stands at the top of a MAP kinase pathways leading to transcriptional regulation, including JNK1 (Jun NH2-terminal Kinase-1) phosphorylation of c-Jun to stimulate transcriptional activation by Activator Protein-1, a heterodimer of c-Jun and c-Fos or ATF (Activating Transcription Factor) proteins. The activation of the p38 MAP kinase also contributes to AP-1 activation leading to the transcriptional activation of many stress and growth related genes (Ref.4). RIP has been suggested as a component of the p38 pathway in addition to playing a role in NF-KappaB activation. TNF signaling has been implicated in many other diseases including: multiple sclerosis, Alzheimer’s disease, and TRAPS (TNF-Receptor-Associated Periodic Syndrome). A better understanding of TNF and its relatives should eventually result in the development of small molecules that can successfully inhibit and modulate the biological activity of these cytokines and thereby provide new avenues for therapeutic intervention.