Research Papers:

A TRAF2 binding independent region of TNFR2 is responsible for TRAF2 depletion and enhancement of cytotoxicity driven by TNFR1

Lucía Cabal-Hierro, Noelia Artime, Julián Iglesias, Miguel A. Prado, Lorea Ugarte-Gil, Pedro Casado, Belén Fernández-García, Bryant G. Darnay and Pedro S. Lazo _

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Oncotarget. 2014; 5:224-236. https://doi.org/10.18632/oncotarget.1492

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Lucía Cabal-Hierro1,3, Noelia Artime1, Julián Iglesias1, Miguel A. Prado1,4, Lorea Ugarte-Gil1, Pedro Casado1,5, Belén Fernández-García1, Bryant G. Darnay2 and Pedro S. Lazo1.

1 Departamento de Bioquímica y Biología Molecular and Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.

2 University of Texas. MD Anderson Cancer Center. Houston, Texas, USA.

3 Present address: Abramson Cancer Center. Perelman School of Medicine, University of Pennsylvania Philadelphia, PA. USA.

4 Present address: Department of Cell Biology. Harvard Medical School. Boston, MA. USA.

5 Present address: Institute of Cancer, Barts Cancer Institute. Queen Mary University of London. London, UK


Pedro S. Lazo, email:

Keywords: TNF receptors; Death Receptors; TRAF2; Apoptosis; NF-kappaB

Received: October 11, 2013 Accepted: November 27, 2013 Published: November 29, 2013


Tumor Necrosis Factor (TNF) interacts with two receptors known as TNFR1 and TNFR2. TNFR1 activation may result in either cell proliferation or cell death. TNFR2 activates Nuclear Factor-kappaB (NF-kB) and c-Jun N-terminal kinase (JNK) which lead to transcriptional activation of genes related to cell proliferation and survival. This depends on the binding of TNF Receptor Associated Factor 2 (TRAF2) to the receptor. TNFR2 also induces TRAF2 degradation. In this work we have investigated the structural features of TNFR2 responsible for inducing TRAF2 degradation and have studied the biological consequences of this activity. We show that when TNFR1 and TNFR2 are co-expressed, TRAF2 depletion leads to an enhanced TNFR1 cytotoxicity which correlates with the inhibition of NF-kB. NF-kB activation and TRAF2 degradation depend of different regions of the receptor since TNFR2 mutants at amino acids 343-349 fail to induce TRAF2 degradation and have lost their ability to enhance TNFR1-mediated cell death but are still able to activate NF-kB. Moreover, whereas NF-kB activation requires TRAF2 binding to the receptor, TRAF2 degradation appears independent of TRAF2 binding. Thus, TNFR2 mutants unable to bind TRAF2 are still able to induce its degradation and to enhance TNFR1-mediated cytotoxicity. To test further this receptor crosstalk we have developed a system stably expressing in cells carrying only endogenous TNFR1 the chimeric receptor RANK-TNFR2, formed by the extracellular region of RANK (Receptor activator of NF-kB) and the intracellular region of TNFR2.This has made possible to study independently the signals triggered by TNFR1 and TNFR2. In these cells TNFR1 is selectively activated by soluble TNF (sTNF) while RANK-TNFR2 is selectively activated by RANKL. Treatment of these cells with sTNF and RANKL leads to an enhanced cytotoxicity.

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