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Session 8 of TNF2009 focused on the function of the RING containing proteins TRAF2 and cIAPs in TNF signaling. TNF-R1 signaling is understood to be carefully balanced between a pro-survival and pro-apoptotic response and, as might be expected for proteins containing these E3 ligase domains, much of the data and discussion revolved around the regulation of these alternative pathways by ubiquitylation. The session was also notable for talks that extended dramatically our understanding of regulation of other signaling pathways by cIAPs such as necrosis and immune responses. Furthermore there was thought provoking data looking at the role of the RIP kinase family in TNF signaling and the role they play in non-apoptotic cell death pathways initiated by TNF. [ABSTRACT FROM AUTHOR]

The ubiquitylation events leading to activation of NF-ΚB at the TNFR1 receptor have been a topic of intense study. It is believed that K63 ubiquitylation of the kinase RIPK1 is required for recruitment of the TAB2/TAB3/TAK1 and IKK1/IKK2/NEMO complexes that are in turn required to phosphorylate and degrade IΚBα allowing freed NF-ΚB dimers to nuclear translocation. The exact involvement of the E3 ligases, TRAF2, TRAF5, cIAP1, and cIAP2 in this process has been unclear. We summarize a recent study from our lab defining the roles of TRAF2 and cIAP1 s in activation of NF-ΚB downstream of TNF-R1 and report the surprising finding that RIPK1 is not essential for TNF-R1-induced NF-ΚB. Alternative mechanisms of how NF-ΚB may be activated by TNF-R1 in the light of these findings are discussed. [ABSTRACT FROM AUTHOR]

Inhibitors of apoptosis proteins (IAPs) were first identified as insect viral proteins that block host cell apoptosis. Cellular homologs bearing the characteristic baculoviral IAP repeat (BIR) domain have now been found in all metazoans and have more diverse functions than their name suggests. Some cellular IAPs do, in fact, inhibit apoptosis, in part at least by directly inhibiting cysteine proteases, called caspases, that are ultimately responsible for killing a cell. The primary aim of this chapter is to explore the intricate regulation of caspases by IAPs, and the exquisite counter regulation of IAPs by antagonist proteins. Interest in IAPs extends beyond apoptosis pathways and recent evidence suggests that IAPs modulate cell-signaling pathways that affect growth and proliferation and some of these remarkable studies will be discussed. [ABSTRACT FROM AUTHOR]