Tumor Necrosis Factors (TNF) Signaling Pathways

The intracellular regions of tumor necrosis factors receptors (TNFR) associate with either of two adapter protein types. One is death domain (DD) adapter proteins and another is TNF receptor-associated factors (TRAF).

TNF receptors that directly recruit TRAFs involve a TRAF interaction motif (TIM), a short cytoplasmic sequence with an extended conformation. In humans, TRAF2 is the best characterized one of TRAF. Once TNFR and TRAF2 combine, the Jun N-terminal kinases (JNK) pathway and NF-KB pathway is triggered, leading to diverse functions including cell differentiation, proliferation and inflammatory response. Structural studies about TRAF2 reveal that the molecule forms a stable trimer in solution. Therefore, it is likely that upon engagement with ligands, the trimerized TNF receptors bind a trimeric intracellular TRAF adapter protein with high avidity. After recruitment by the TNF receptors, TRAF2 activates protein kinases that start the JNK pathway or the NF-KB pathway. TRAFs are major signal transducers for the TNF superfamily as well as the IL-1 family proteins.

TNFRs that recruit DD adapter proteins contain a cytoplasmic DD-binding module, composed of 6 a-helices. These receptor DDs form homotypic interactions with the structurally conserved DDs in adapter proteins such as Fas-associated DD protein (FADD) and TNFR-associated DD protein (TRADD). FADD is recruited by receptors, such as Fas, DR4 and DR5. These interactions lead the formation of the death-inducing signaling complex (DISC), and activate the cleavage of caspases 8 and 10, and induce apoptosis. Other TNFRs including TNFR1 and DR3 bind TRADD. TRADD is capable of recruiting FADD through the DD interactions and transmits pro-apoptotic signaling. Alternatively, TRADD can recruit TRAF2 and a serine/threonine kinase receptor-interacting protein (RIP). These two proteins function synergistically to activate the NF-KB pathway, which suppresses apoptotic signaling, promoting cellular proliferation, and initiates inflammatory responses.


Related literatures

1. Ashkenazi A. Targeting death and decoy receptors of the tumour necrosis factor superfamily[J]. Nature Reviews Cancer, 2002, 2(6): 420-430.

2. Hsu H, Xiong J, Goeddel D V. The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation[J]. Cell, 1995, 81(4): 495-504.

3. Bradley J R, Pober J S. Tumor necrosis factor receptor-associated factors (TRAFs)[J]. Oncogene, 2001, 20(44): 6482-6491.


TNF receptors-CD molecules