The Tumor Necrosis Factor Receptor (TNFR) super family represents a growing family with over 20 members having been identified so far in mammalian cells. TNFα, a potent cytokine, elicits a broad spectrum of biologic responses. 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, modulation of immune responses and induction of inflammation. TNFα acts through two receptors, TNFR1 and TNFR2. TNFR1 is expressed by all human tissues and is the major signaling receptor for TNFα. TNFR2 is mostly expressed in immune cells and mediates limited biological responses.TNFR1 (p55) contains a cytoplasmic death domain required for signaling pathways associated with apoptosis and NF-κB activation. TNF-induced receptor trimerization aggregates the death domain of TNFR1 and recruits the adapter protein TRADD along with other proteins such as FADD, MADD, and RAIDD to form an active TNFR1 signaling complex containing cIAP. Ligand binding to TNFR1 subsequently leads to the activation of caspase-8, which in turn results in a proteolytic cascade that includes other caspases (Casp3,6,7) and ultimately the induction of apoptosis. In contrast, the 60-kDa protein SODD acts as a silencer of TNFR1 signaling. It is associated with the death domain of TNFR1 and maintains this receptor in an inactive, monomeric state. TNFα-induced aggregation of TNFR1 promotes the disruption of the SODD-TNFR1 complex. TNFα-induced TNFR1 activation also results in the activation of the NF-κB pathway.
Binding of TNFα to the TNFR1 receptor activates GCK through the TNF adaptor TRAF2. GCK activates MEKK1 by causing its oligomerization and autophosphorylation. MEKK1 then goes on to initiate the JNK signaling pathway leading to AP1 activation and the transcriptional activation of many stress and growth-related genes. TNFα signaling has been implicated in many diseases including multiple sclerosis, alzheimer's disease, and TNFR-associated periodic syndrome. A better understanding of TNFα and its relatives will aid 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.