TNFR2 Signaling

Tumor Necrosis Factor (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. TNF family members act 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. The 75-kDa TNFR2 binds both TNFα and TNFβ (LTA). TNFβ is produced by activated lymphocytes and can be cytotoxic to many tumor and other cells. In neutrophils, endothelial cells and osteoclasts, TNFβ can lead to activation while in many other cell types it can lead to increased expression of MHC and adhesion molecules.The cytoplasmic tail of TNFR2 does not contain a death domain. Instead, it has sequences allowing it to associate with a different set of intracellular adaptors called TNF Receptor-Associated Factors (TRAFs). Although six TRAF proteins have been identified to date, only five members (TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6) actually bind to the cytoplasmic tail of TNFR2. During the induction of cell survival a number of MAP3K family members associate with TRAF2, which in turn activates JNK. NIK acts as the downstream target of TRAF2 in mediating TNF-induced NF-κB activation leading to survival. The cytokine-induced zinc finger protein A20 inhibits the NF-κB activation. Expression of the caspase inhibitors cIAPs is NF-κB dependent. CIAPs interact with TRAF1 and TRAF2, and through this interaction they are recruited to the TNFR2 complex. NF-κB activation also occurs via signaling pathways that are independent of the IKK complex. T2K (also called TBK and NAK) associates with TRAF2 through an intermediary protein TANK, a serine threonine kinase that is distantly related to IKK-α and IKK-β. TNF signaling has been implicated in many diseases including multiple sclerosis, alzheimer's disease, and TNFR-associated periodic syndrome. A better understanding of TNF and its relatives should 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.