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.
MeSH terms
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Amino Acid Sequence
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Catalytic Domain / immunology
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Cell Line
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Enzyme Activation / genetics
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Enzyme Activation / immunology
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Germinal Center / enzymology*
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Germinal Center Kinases
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Humans
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JNK Mitogen-Activated Protein Kinases
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Jurkat Cells
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Mitogen-Activated Protein Kinases*
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Molecular Sequence Data
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NF-kappa B / metabolism
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Protein Biosynthesis
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / metabolism*
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Proteins / genetics
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Proteins / metabolism
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Proteins / physiology*
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / physiology*
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Sequence Deletion
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Signal Transduction / genetics
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Signal Transduction / immunology*
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / physiology*
Substances
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Germinal Center Kinases
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NF-kappa B
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Proteins
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Receptors, Tumor Necrosis Factor
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor-alpha
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases