TNF (Tumor Necrosis Factor) family members play important roles in various physiological and pathological processes, including cell proliferation, differentiation, apoptosis, modulation of immune responses and induction of inflammation. TNFacts through two receptors, TNFR1 and TNFR2 (Tumor Necrosis Factor Receptors). 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). The 75-kDa TNFR2 transduces extracellular signals via receptor-associated cytoplasmic proteins. TNFR2 binds both TNF-Alpha and TNF-Beta. TNF-Beta is produced by activated lymphocytes and can be cytotoxic to many tumor and other cells. In neutrophils, endothelial cells and osteoclasts TNF-Beta can lead to activation while in many other cell types it can lead to increased expression of MHC
and adhesion molecules (Ref.2).
The cytoplasmic tails of TNFR2 do not contain DDs (Death Domains). Instead, it has sequences allowing to associate with a different set of intracellular adaptors called TRAFs (TNF Receptor-Associated Factors). Although six TRAF
proteins (TRAF1-TRAF6) have been identified to date, only five (TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6) actually bind to the cytoplasmic tails of the TNFR2. During the induction of cell survival a number of MAP3K (Mitogen-Activated Protein-3 Kinase) family members associates with TRAF2, which in turn activates JNK (Jun N-terminal Kinases). NIK (NuclearFactor-kappaƒnB Inducing Kinase) acts as the downstream target of TRAF2 in mediating TNF-induced NF-KappaB
(Nuclear Factor-KappaB) activation leading to survival. TNFR2-mediated activation of NF-KappaB
and Activator Protein-1 transcription factors depends on the association of TRAF2 trimers with the receptor, and the subsequent TRAF2-dependent recruitment to the complex of kinases that activate a signaling cascade resulting in NF-KappaB
and Activator Protein-1 activation. The cytokine-induced zinc finger protein A20 inhibits the NF-KappaB
activation. TRAF1 can also associate with TNFR2 through its interaction with TRAF2. TRAF1-TRAF2 heteromers inhibit TNFR2 activities, probably by decreasing TRAF2 binding to the receptor or by interfering with the recruitment or activation of the kinases (Ref.3). Expression of the Caspase inhibitors cIAPs (Cellular Inhibitor of Apoptosis Protein) is NF-KappaB-dependent. CIAPs also interact with TRAF1 and TRAF2, and through this interaction they can also be recruited to the TNFR2 complex. The COOH-terminal TRAF1 fragment potentiates receptor-mediated apoptosis by inhibiting receptor-mediated NF-KappaB activation and possibly by interfering with the recruitment of antiapoptotic complexes to the receptor. NF-KappaB activation can also occur via signaling pathways that are independent of the IKK
(I-KappaB Kinase) complex. T2K (TRAF2-associated Kinase) (also called TBK and NAK) associates with TRAF2 through an intermediary protein; TANK (TRAF family member Associated NF-KappaB Activator). TANK is a serine threonine kinase that is distantly related to IKK-Alpha and IKK-Beta. TANK phosphorylates serine 36 on the I-kappaB-Alpha subunit of I-KappaB, but this partial phosphorylation is not sufficient to trigger degradation of I-KappaB. TNF signaling has been implicated in many other diseases including: multiple sclerosis, Alzheimer¡¦s disease, and TRAPS (TNF-Receptor-Associated Periodic Syndrome) (Ref.4). 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.