TRAF2 and Cellular IAPs: A Critical Link in TNFR Family Signaling

  • Domagoj Vucic
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)


When first identified in the mid-1990s, cellular inhibitor of apoptosis (c-IAP1 and c-IAP2) proteins and tumor necrosis factor receptor-associated factor 2 (TRAF2) were described as putative mediators of TNFR2 signaling. The following years witnessed an immense number of studies confirming the seminal role of both cellular IAPs and of TRAF2 in transducing signaling initiated by TNF family ligands. As such, c-IAP1 and c-IAP2 suppress TNF-stimulated cell death by preventing the formation of the TNF receptor 1 (TNFR1) pro-apoptotic signaling complex. In combination with their obligatory binding partner, TRAF2, c-IAP proteins regulate pro-survival nuclear factor-kappaB (NF-κB) signaling pathways. In the TNFα-induced canonical NF-κB pathway, c-IAP1 and 2 are required for receptor interacting protein 1 (RIP1) ubiquitination and NF-κB activation. In the noncanonical NF-κB pathway, c-IAP1 and 2 ubiquitinate NF-κB-inducing kinase (NIK), leading to its proteasomal degradation and abrogation of NF-κB signaling. In addition, through the RING domain mediated ubiquitin ligase activity, c-IAP proteins regulate their own stability and the protein levels of several of their binding partners including TRAF2. Here I discuss the most recent progress in our understanding of the biological roles of c-IAPs and TRAF2, as well as the implications of targeting these molecules for therapeutic interventions.


Ring Domain BIR3 Domain Cellular IAPs Amino Acid Patch 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The author is thankful to Eugene Varfolomeev, Tatiana Goncharov, Kurt Deshayes, and Jasmin Dynek for helpful discussions and critical reading of the manuscript and to Alison Bruce and Chudi Ndubaku for assistance with figures.


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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Protein EngineeringGenentech, Inc.South San FranciscoUSA
  2. 2.Department of Protein EngineeringGenentech, Inc.South San FranciscoUSA

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