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

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Advances in TNF Family Research

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 691))

Abstract

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.

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Acknowledgments

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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  1. Department of Protein Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Domagoj Vucic

  2. Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, 94080, USA

    Domagoj Vucic

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  1. Domagoj Vucic
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Correspondence to Domagoj Vucic .

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  1. Dept. Biological Chemistry, Weizmann Institute of Science, 1 Herzl Street, Rehovot, 76100, Israel

    David Wallach

  2. Dept. Biological Chemistry, Weizmann Institute of Science, 1 Herzl Street, Rehovot, 76100, Israel

    Andrew Kovalenko

  3. Kennedy Institute of Rheumatology, Imperial College London, Aspenlea Rd. 1, London, W6 8LH, United Kingdom

    Marc Feldmann

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Vucic, D. (2011). TRAF2 and Cellular IAPs: A Critical Link in TNFR Family Signaling. In: Wallach, D., Kovalenko, A., Feldmann, M. (eds) Advances in TNF Family Research. Advances in Experimental Medicine and Biology, vol 691. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6612-4_7

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