Tumor necrosis factor receptor 2 (TNFR2) signaling is negatively regulated by a novel, carboxyl-terminal TNFR-associated factor 2 (TRAF2)-binding site.
Tumor necrosis factor (TNF) superfamily receptors typically induce both NF-kappaB 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-kappaB or JNK pathways. By contrast, inactivation of T2bs-C had little effect on the amount of TRAF2 recruited but greatly enhanced ligand-dependent NF-kappaB 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.
Grech
Adrian P
AP
Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No. 6, Newtown, New South Wales 2042, Australia.
Gardam
Sandra
S
Chan
Tyani
T
Quinn
Rachel
R
Gonzales
Ruth
R
Basten
Antony
A
Brink
Robert
R
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001665:Binding Sites / Q000502:physiology; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism* / Q000502:physiology
D019013:CD40 Antigens; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; D047992:TNF Receptor-Associated Factor 2; D048031:JNK Mitogen-Activated Protein Kinases