title: TNF-mediated activation of the stress-activated protein kinase pathway: TNF receptor-associated factor 2 recruits and activates germinal center kinase related.
abstract: TNF-induced activation of stress activated protein kinases (SAPKs, Jun NH2-terminal kinases) requires TNF receptor associated factor 2 (TRAF2). TRAF2 is a potent activator of a 95-kDa serine/threonine kinase termed germinal center kinase related (GCKR, also referred to as KHS1), which signals activation of the SAPK pathway. Consistent with a role for GCKR in TNF- induced SAPK activation, a kinase-inactive mutant of GCKR is a dominant negative inhibitor of TRAF2-induced SAPK activation. Here we show that TRAF2 interacts with GCKR. This interaction depended upon the TRAF domain of TRAF2 and the C-terminal 150 aa of GCKR. The full activation of GCKR by TRAF2 required the TRAF2 RING finger domain. TNF treatment of a T cell line, Jurkat, increased both GCRK and SAPK activity and enhanced the coimmunoprecipitation of GCKR with TRAF2. Similar results were found with the B cell line HS-Sultan. These findings are consistent with a model whereby TNF signaling results in the recruitment and activation of GCKR by TRAF2, which leads to SAPK activation.
authors.affiliation: B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Disease, Bethesda, MD 20892, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Shi
authors.forename: A
authors.initials: A
authors.lastname: Leonardi
authors.forename: J
authors.initials: J
authors.lastname: Kyriakis
authors.forename: U
authors.initials: U
authors.lastname: Siebenlist
authors.forename: J H
authors.initials: JH
authors.lastname: Kehrl
mesh_terms: D000595:Amino Acid Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D020134:Catalytic Domain / Q000276:immunology; D002460:Cell Line; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D018858:Germinal Center / Q000201:enzymology*; D000081410:Germinal Center Kinases; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
chemical_list: D000081410:Germinal Center Kinases; D016328:NF-kappa B; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases