title: NF-kappaB signal triggering and termination by tumor necrosis factor receptor 2.
abstract: Tumor necrosis factor receptor 2 (TNFR2) activates transcription factor κB (NF-κB) and c-Jun N-terminal kinase (JNK). The mechanisms mediating these activations are dependent on the recruitment of TNF receptor-associated factor 2 (TRAF2) to the intracellular region of the receptor. TNFR2 also induces TRAF2 degradation. We show that in addition to the well characterized TRAF2 binding motif 402-SKEE-405, the human receptor contains another sequence located at the C-terminal end (amino acids 425-439), which also recruits TRAF2 and activates NF-κB. In addition to that, human TNFR2 contains a conserved region (amino acids 338-379) which is responsible for TRAF2 degradation and therefore of terminating NF-κB signaling. TRAF2 degradation and the lack of NF-κB activation when both TNFR1 and TNFR2 are co-expressed results in an enhanced ability of TNFR1 to induce cell death, showing that the cross-talk between both receptors is of a great biological relevance. Induction of TRAF2 degradation appears to be independent of TRAF2 binding to the receptor. Amino acids 343-TGSSDSS-349 are essential for inducing TRAF2 degradation because deletion mutants of this region or point mutations at serine residues 345 and 346 or 348 and 349 obliterate the ability of TNFR2 to induce TRAF2 degradation.
authors.affiliation: Departamento de Bioquímica y Biología Molecular and Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, 33071 Oviedo, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Rodríguez
authors.forename: Lucía
authors.initials: L
authors.lastname: Cabal-Hierro
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Carcedo
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Iglesias
authors.forename: Noelia
authors.initials: N
authors.lastname: Artime
authors.forename: Bryant G
authors.initials: BG
authors.lastname: Darnay
authors.forename: Pedro S
authors.initials: PS
authors.lastname: Lazo
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D047992:TNF Receptor-Associated Factor 2; D048670:MAP Kinase Kinase 4