TNF superfamily proteins consisting of 19 members that signal through 29 receptors. These ligands, while regulating normal functions such as immune responses, hematopoiesis, and morphogenesis, have also been implicated in tumorigenesis, transplant rejection, septic shock, viral replication, bone resorption, rheumatoid arthritis, and diabetes, indicating their role as ‘double-edged swords’. These cytokines induce cellular proliferation, survival, differentiation, or apoptosis. The 19 ligands mediate their cellular response through 29 receptors that belong to the TNF receptor (TNFR) superfamily, and they are characterized by the presence of a cysteine-rich domain (CRD) in the extracellular portion [1,2]. Based upon their cytoplasmic sequences and signaling properties, these TNF receptors can be classified into three major groups [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 [3].

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. 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) [4]. 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 [5].

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 through 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. The TNFR superfamily contains a large number of proteins that regulate a very broad array of developmental and differentiating processes. Indeed, a number of biologic TNF blocking therapies are being used now to inhibit the inflammation associated with Crohn’s disease and rheumatoid arthritis. 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 [6].


Pathway

TNF Superfamily Pathway

Key

Pathway Key
References
  1. Mathew SJ, Haubert D, Krönke M, et al. (2009) Looking beyond death: a morphogenetic role for the TNF signalling pathway. J Cell Sci 122(Pt 12):1939-46.
  2. Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3(9):745-56. Review.
  3. Daniel D, Yang B, Lawrence DA, et al. (2007) Cooperation of the proapoptotic receptor agonist rhApo2L/TRAIL with the CD20 antibody rituximab against non-Hodgkin lymphoma xenografts. Blood 110(12):4037-46. Epub 2007 Aug 27.
  4. Morlon A, Munnich A, Smahi A (2005) TAB2, TRAF6 and TAK1 are involved in NF-kappaB activation induced by the TNF-receptor, Edar and its adaptator Edaradd. Hum Mol Genet 14(23):3751-7. Epub 2005 Oct 26.
  5. Amm HM, Zhou T, Steg AD, et al. (2011) Mechanisms of drug sensitization to TRA-8, an agonistic death receptor 5 antibody, involve modulation of the intrinsic apoptotic pathway in human breast cancer cells.  Mol Cancer Res 9(4):403-17. Epub 2011 Feb 25.
  6. Aggarwal BB, Gupta SC, Kim JH (2011) Historical perspectives on tumor necrosis factor and its superfamily: twenty-five years later, a golden journey. Blood 2011 Nov 8.