Research ArticleCell Biology

Cellular Inhibitors of Apoptosis Are Global Regulators of NF-κB and MAPK Activation by Members of the TNF Family of Receptors

Science Signaling  20 Mar 2012:
Vol. 5, Issue 216, pp. ra22
DOI: 10.1126/scisignal.2001878

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Directing TNFR Signaling with c-IAP

Binding of ligands to tumor necrosis factor receptors (TNFRs) recruits adaptor proteins and E3 ubiquitin ligases to form signaling complexes that activate NF-κB and MAPK signaling, which are important in development and immunity. Varfolomeev et al. defined the roles of the E3 ubiquitin ligases c-IAP1 and c-IAP2, which are recruited to the TNFR1 complex by the adaptor protein TRAF2. The c-IAPs were critical for NF-κB and MAPK activation and for recruiting distal signaling components to specific TNFRs, and loss of c-IAPs resulted in diminished signaling by these TNFRs. Conversely, TNFR family members that stimulated noncanonical NF-κB signaling, which is inhibited by a complex containing c-IAP proteins, caused the translocation of c-IAP proteins from the cytosol to the plasma membrane, resulting in their degradation. Together, these data suggest that c-IAP proteins regulate canonical and noncanonical NF-κB signaling as well as MAPK activation by TNFR family members.