The tumor necrosis factor (TNF) was originally identified as a protein that kills tumor cells. Research during the past two decades has shown the existence of a superfamily of TNF proteins consisting of 19 members that signal through 29 receptors. The members of the TNF super family exhibit 15-25% amino acid sequence homology with each other and bind to distinct receptors, which are homologous in their extracellular domain. The cytokines belonging to TNF family includes TNFa, TNFb, BLys/BAFF, OPGL/TRANCE/RANKL, APRIL, TRAIL, FasL, etc.Members of the TNF receptor superfamily play pivotal roles in numerous biological events in metazoan organisms. Ligand-mediated trimerization by corresponding homo- or hetero-trimeric ligands, the TNF family proteins, causes recruitment of several intracellular adaptors, which activate multiple signal transduction pathways. Based upon their cytoplasmic sequences and signaling properties, these TNF receptors can be classified into three major groups (Ref.1). The first group, including Fas/ CD95/ Apo1/ APT1, TNFR1/CD120a/p55-R/TNFAR/TNFR60, DR3/ TRAMP/ WSL1/ LARD /WSLLR/DDR3/TR3/Apo3, DR4/TRAILR1/Apo2, DR5/TRAILR2/KILLER/TRICK2A/TRICKB, and DR6/TR7, contains a DD (Death Domain) in the cytoplasmic tail. Fas, DR4 and DR5 interact with the FADD (Fas-Associated Death Domain) while TNFR1 and DR3 interact with the adaptor TRADD (TNFR-Associated Death Domain). These molecules, in turn cause activation of the Caspase cascade and induction of apoptosis (Ref.2).

The second group includes TNFR2/p75/CD120b/TNFR80/TNFBR, CD40/p50/Bp50, CD30/Ki-1/D1S166E, CD27/Tp55/S152, TNFR2-RP/TNFCR/TNFRIII, LT-BetaR, OX40/ CD134/ACT35/TXGP1L, 4-1BB/CD137/ILA, BAFFR, BCMA/BCM, TACI/CAML interactor, RANK/TRANCE-R, p75NGFR, HVEM (Herpes Virus Entry Mediator)/HveA/ATAR/TR2/ LIGHTR, GITR/AITR/ TNFRSF18, TROY/TAJ, EDAR, XEDAR/EDA-A2R, RELT and Fn14/TWEAKR. These receptors contain one or more TIM (TRAF Interacting Motifs) in their cytoplasmic tails. Activation of TIM containing TNF receptors lead to recruitment of TRAF family members, and activation of multiple signal transduction pathways such as NF-KappaB (Nuclear Factor-KappaB), JNK (Jun N-terminal Kinase), p38, ERK (Extracellular Signal Regulated Kinase) and PI3K (Phosphoinisitide-3 Kinase) (Ref.3). The third group of TNF receptor family members, including DcR1/TRID/TRAIL-R3, DcR2/ TRUNDD/TRAIL-R4, DcR3 and OPG, does not contain functional intracellular signaling domains or motifs. Although this group of receptors cannot provide intracellular signaling, they can effectively compete with the other two signaling groups of receptors for their corresponding ligands. These DcR (Decoy Receptors) therefore function by impeding the activation of signal transduction pathways by other TNF receptors (Ref.4).

A key component of signaling by members of the tumor necrosis factor receptor (TNF-R) family is interaction with the cytoplasmic adapter proteins known as TRAFs (TNF receptor associate factors). TRAFs are a major group of intracellular adaptors that bind directly or indirectly to many members of the TNF receptor superfamily. Six mammalian TRAFs, TRAF1, TRAF2, TRAF3, TRAF4, TRAF5 and TRAF6, have been identified. TRAFs can induce the activation of several kinase cascades that ultimately lead to the activation of signal transduction pathways such as NF-KappaB, JNK, ERK, p38 and PI3K, which can regulate cellular processes ranging from cell proliferation and differentiation to apoptosis. Other proteins, which are involved in TNF signaling, are DRAKs (Death Receptor Kinase 1 and 2), SODD (Silencer of Death domain), ARTs, etc.

All the cytokines of the TNF superfamily mediate their effects through the activation of the transcription factor NF-kappaB, c-Jun N-terminal kinase, apoptosis, and proliferation. Thus, agents that can either suppress the production of these cytokines or block their action have therapeutic value for a wide variety of diseases. Indeed, a number of biologic TNF blocking therapies are being used now to inhibit the inflammation associated with Crohn’s disease and rheumatoid arthritis Thus, the continued examination of TNFR signal transduction will provide the tools for receptor or tissue specific interventions, allowing more targeted treatments that have fewer side effects.

Fas, CD95, APO1,  APT1, FasL, Fas Ligand, TNFR1, Tumor Necrosis Factor Receptor-1, CD120a, p55R, TNFAR, TNFR60, DR3, Death Receptor-3, TRAMP, WSL1, LARD, Lymphocyte-Associated Receptor of Death, WSLLR, DDR3, TR3, Apo3, DR4, Death Receptor-4, TRAILR1, TNF-Related Apoptosis-Inducing Ligand Receptor-1, Apo2, DR5, Death Receptor-5, TRAILR2, KILLER, TRICK2A, TRICKB,  DR6, Death Receptor-6, TR7, DD, Death Domain, TNFR2, Tumor Necrosis Factor Receptor-2, p75, CD120b, TNFR80, TNFBR, CD40, p50, Bp50, CD30, Ki-1, D1S166E, CD27, Tp55, S152, LT-BetaR, TNFR2- RP, TNFCR, TNFRIII, OX40,  CD134, ACT35, TXGP1L, 4-1BB, CD137, ILA, Induced by Lymphocyte Activation, BAFFR, B-cell Activation Factor Receptor, BCMA, B-Cell Maturation Antigen, BCM, TACI, Transmembrane Activator and Calcium Modulator Cyclophilin Ligand Interaction, CAML interactor, RANK, TRANCER, NGFR, Nerve Growth Factor Receptor, HVEM, Herpes Virus Entry Mediator, HveA, ATAR, TR2,  LIGHTR, GITR, Glucocorticoid-Induced TNFR-Related Gene, AITR, Activation-Inducible TNFR Family Member, TNFRSF18, TROY,TAJ, EDAR, Ectodysplasin-1, Anhidrotic Receptor, XEDAR, EDA-A2R, RELT, Fn14, DcR1,Decoy Receptor-1, TRID, TRAILR3, DcR2, Decoy Receptor-2, TRUNDD, TRAILR4, DcR3, Decoy Receptor-3, Opg, Osteoprotegerin, TRAFs, TNF Receptor-Associated Factors,  NF-KappaB, Nuclear Factor-KappaB, JNK, Jun N-terminal Kinase,  ERK, Extracellular Signal Regulated Kinase, p38, PI3K, Phosphoinisitide-3 Kinase, FADD, Fas Associated Death Domain, TRADD, TNFR-Associated Death Domain protein,  Caspases, TIM, TRAF Interacting Motifs, Apoptosis, Gene Expression, CD40L, CD30L, CD27L, 4-1BBL, LT-Beta, OX40L, APRIL, RANKL, NGF.

TAK, TGF-Beta-Activating Kinase, TAB, TAK Binding Protein, MEKs, Akt, PKB, Protein Kinase-B, TNF-Alpha, TNF-Beta, Tumour Necrosis Factor-Alpha, Tumour Necrosis Factor-Beta, GITRL, EDA1, EDA2, I-KappaB, Inhibitor of Kappa Light Chain Gene Enhancer in B-Cells, I-KappaB-Alpha, I-KappaB-Beta, I-KappaB-Epsilon, Caspase1, Caspase2, Caspase3, Caspase4, Caspase5, Caspase6, Caspase7, Caspase8, Caspase9, Caspase10, I-KappaB Kinase, IKK-Alpha, IKK-Beta, IKK- Epsilon, IKK-Gamma, TRAF1, TNF Receptor-Associated Factor-1, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6.