Abstract 2151: Activation of NF-kB and MAP kinases by TNF Family Receptors is regulated by cellular IAPs

Abstract

Abstract Activation of NF-kB, JNK and p38 MAPK signaling pathways is innermost activity of TNF receptor protein signaling complexes that is important for proper function of the immune system. However, excessive activation of these signaling pathways may result in tumor development and progression. Therefore, elucidation of the detailed molecular mechanisms of TNF receptor signaling should gain advantage in our understanding of the tumor biology and invention of the novel anticancer therapies. The formation of TNF receptor complexes, as well structural and functional associations between different signaling molecules is regulated by ubiquitination in TRAF-dependent fashion. TNF receptors employ several proteins possessing ubiquitin E3 ligase activities including cellular Inhibitor of Apoptosis, c-IAP1 and c-IAP2 proteins. We demonstrate that c-IAPs are required for canonical NF-kB and MAPK activation by TNF receptors. By regulating the recruitment of Nemo, IKK2 and HOIP to TNFR signaling complexes c-IAPs promote induction of gene expression by TNF ligands. We also found that TNF receptors that stimulate the noncanonical NF-kB pathway trigger c-IAPs, TRAF2 and TRAF3 intracellular translocation followed by their proteasomal and lysosomal degradation. Finally, we establish that BR3-induced cytosolic depletion of TRAF3 results in noncanonical NF-κB activation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2151. doi:1538-7445.AM2012-2151