title: TRAF-mediated modulation of NF-kB AND JNK activation by TNFR2.
abstract: Tumor Necrosis Factor Receptor 2 (TNFR2) activates transcription factor κB (NF-κB) and c-Jun N-terminal kinase (JNK). Most of the biological activities triggered by TNFR2 depend on the recruitment of TNF Receptor-Associated Factor 2 (TRAF2) to the intracellular region of the receptor. The intracellular region of TNFR2 contains five highly conserved amino acid sequences, three of which appear implicated in receptor signaling. In this work we have studied the interaction of TNFR2 with TRAF proteins as well as the functional consequences of this interaction. We show that TRAF1, TRAF2 and TRAF3 bind to the receptor through two different binding sites located at conserved modules IV and V of its intracellular region, respectively. We also show that TRAF1 and TRAF3 have opposite effects to TRAF2 on NF-κB and JNK activation by TNFR2. Moreover, we show that TNFR2 is able to induce JNK activation in a TRAF2-independent fashion. This new receptor activity relies on a sequence located in the conserved module III. This region is also responsible for the ability of TNFR2 to induce TRAF2 degradation, thus emphasizing the role of conserved module III (amino acids 338-379) on receptor signaling and regulation. We show that only TNFR2 can induce TRAF2 degradation while TRAF1 or TRAF3 is not subjected to this regulatory mechanism and that TRAF1, but not TRAF3, is able to inhibit TRAF2 degradation.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33071 Oviedo, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Cabal-Hierro
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33071 Oviedo, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Rodríguez
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33071 Oviedo, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Artime
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33071 Oviedo, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Iglesias
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33071 Oviedo, Spain.
authors.forename: Lorea
authors.initials: L
authors.lastname: Ugarte
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33071 Oviedo, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Prado
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33071 Oviedo, Spain. Electronic address: pslazo@uniovi.es.
authors.forename: Pedro S
authors.initials: PS
authors.lastname: Lazo
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000502:physiology; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D047889:Receptors, Tumor Necrosis Factor, Type II; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Apoptosis; Death Receptors; JNK; NF-κB; TNF receptors; TRAF proteins