Trends in Cell Biology
ReviewSignal transduction by tumor necrosis factor and its relatives
Section snippets
Receptor-proximal events
TNFα exerts its effects through two distinct receptors, TNFR1 and TNFR2 12. Binding of the inherently trimeric TNFα to TNFR1 and TNFR2 induces receptor trimerization and recruitment of several signaling proteins to the cytoplasmic domains of the receptors (Fig. 1). The first protein recruited to TNFR1 is TNFR1-associated death domain protein (TRADD), which serves as a platform to recruit at least three additional mediators, receptor-interacting protein 1 (RIP1), Fas-associated death domain
MAP kinase activation
In transient transfection experiments, TRAF2 is an efficient activator of several MAPKs, most notably JNK and p38 20, 33. Furthermore, JNK and p38 activation by TNFα is dependent on TRAF2 because activation can no longer occur in TRAF2−/− cells 29. Following its transient overexpression, TRAF2 has been reported to interact with numerous MAPK kinase kinases (MAP3Ks or MEKKs), each of which is capable of JNK and/or p38 activation 22, 34, 35, 36. Other experiments suggest that MAP3Ks, including
NF-κB activation
Although TRAF2 and RIP1 can be independently recruited to the TNFR1 complex, TNFα-mediated IKK activation might depend on an interaction between RIP1 and the IKKγ/NEMO regulatory subunit, whereas TRAF2 might be required for recruitment of the IKK complex, which also contains the IKKα and IKKβ catalytic subunits 10, to the activated TNFR1 28. However, it is still not known what leads to the activation of IKK, previously shown to depend on phosphorylation of two serines within the activation loop
Cross-talk leading to AP-1 and NF-κB activation
Although some of the details are still missing, a network of direct protein–protein interactions seems to connect TNFRs to cytosolic JNK and IKK (Fig. 2). However, NF-κB and AP-1 activation are not the simple outcome of a linear sequence of activation events.
In addition to the basic pathways discussed above, there are other ways to modulate AP-1 and NF-κB activities. For instance, the serine/threonine kinase Akt/PKB that is activated via the phosphatidylinositol 3-OH kinase [PI(3)K] signaling
Caspase activation
As mentioned above, TNFα can trigger apoptosis by more than one pathway. However, the most widely accepted pathway involves TRADD, FADD and caspase 8 (Fig. 2) 68. Indeed, FADD- and caspase 8-deficient fibroblasts are resistant to TNFR1-, Fas- and death receptor 3 (DR3)-induced apoptosis 32, 69. Upon activation through an induced proximity mechanism, the N-terminal prodomain of caspase 8 is cleaved, leading to an active heterodimeric enzyme, which in turn leads to activation of a downstream
Concluding remarks
TNFα has a unique and pivotal role in regulating the choice between pro-apoptotic and anti-apoptotic signaling pathways, and in the control of cell proliferation and inflammation. Interestingly, the suppression of apoptosis promotes inflammation. The large number of TNFα-triggered biological responses contrasts with the more restricted responses elicited by other members of the TNF family. As discussed above, our understanding of TNFα signaling is extensive but not complete, and further
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