Tumor Necrosis Factor Receptor 2 (TNFR2) Signaling Is Negatively Regulated by a Novel, Carboxyl-terminal TNFR-associated Factor 2 (TRAF2)-binding Site

• Published in: The Journal of biological chemistry Vol. 280; no. 36; pp. 31572 - 31581
• Main Authors: Grech, Adrian P., Gardam, Sandra, Chan, Tyani, Quinn, Rachel, Gonzales, Ruth, Basten, Antony, Brink, Robert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.09.2005; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; Animals; Apoptosis - physiology; Binding Sites - physiology; CD40 Antigens - genetics; CD40 Antigens - metabolism; Cell Line; Down-Regulation - physiology; Humans; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - physiology; Mice; Molecular Sequence Data; NF-kappa B - antagonists & inhibitors; NF-kappa B - physiology; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; Receptors, Tumor Necrosis Factor, Type II - genetics; Receptors, Tumor Necrosis Factor, Type II - metabolism; Receptors, Tumor Necrosis Factor, Type II - physiology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Signal Transduction - physiology; TNF Receptor-Associated Factor 2 - metabolism; TNF Receptor-Associated Factor 2 - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M504849200

Tumor necrosis factor (TNF) superfamily receptors typically induce both NF-κB and JNK activation by recruiting the TRAF2 signal transduction protein to their cytoplasmic domain. The type 2 TNF receptor (TNFR2), however, is a poor activator of these signaling pathways despite its high TRAF2 binding capability. This apparent paradox is resolved here by the demonstration that TNFR2 carries a novel carboxyl-terminal TRAF2-binding site (T2bs-C) that prevents the delivery of activation signals from its conventional TRAF2-binding site (T2bs-N). T2bs-C does not conform to canonical TRAF2 binding motifs and appears to bind TRAF2 indirectly via an as yet unidentified intermediary. Specific inactivation of T2bs-N by site-directed mutagenesis eliminated most of the TRAF2 recruited to the TNFR2 cytoplasmic domain but had no effect on ligand-dependent activation of the NF-κB or JNK pathways. By contrast, inactivation of T2bs-C had little effect on the amount of TRAF2 recruited but greatly enhanced ligand-dependent NF-κB and JNK activation. In wild-type TNFR2 therefore, T2bs-C acts in a dominant fashion to attenuate signaling by the intrinsically more active T2bs-N but not by preventing TRAF2 recruitment. This unique uncoupling of TRAF2 recruitment and signaling at T2bs-N may be important in the modulation by TNFR2 of signaling through coexpressed TNFR1.