Human 4-1BB (CD137) Signals Are Mediated by TRAF2 and Activate Nuclear Factor-κB

• Published in: Biochemical and biophysical research communications 1998-01, Vol.242 (3), p.613-620
• Main Authors: Jang, Ihn K., Lee, Zang H., Kim, Young J., Kim, Seung H., Kwon, Byoung S.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antigens, CD; Blotting, Western; Cell Line; Electrophoresis, Polyacrylamide Gel; Genes, Reporter; Humans; Molecular Sequence Data; Mutation - genetics; NF-kappa B - metabolism; NF-kappaB-Inducing Kinase; Protein Binding; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteins - metabolism; Receptors, Nerve Growth Factor - genetics; Receptors, Nerve Growth Factor - metabolism; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Sequence Homology, Amino Acid; Signal Transduction - physiology; T-Lymphocytes - metabolism; TNF Receptor-Associated Factor 1; TNF Receptor-Associated Factor 2; TNF Receptor-Associated Factor 3; Transfection - genetics; Tumor Necrosis Factor Receptor Superfamily, Member 9
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.1997.8016

Human 4-1BB (CD137), a member of the tumor necrosis factor receptor (TNFR) superfamily, costimulates T cell activation. No apparent intrinsic kinase activity is seen with 4-1BB, which suggests that 4-1BB-associated molecules may be involved in 4-1BB-mediated signal transduction. We found that tumor necrosis factor receptor-associated factor (TRAF) 1, TRAF2, and TRAF3, all interacted with the cytoplasmic domain of 4-1BB. Mutation analysis showed that TRAF1, TRAF2, and TRAF3 were associated with one of two runs of acidic residues found in the cytoplasmic domain of 4-1BB. In addition, 4-1BB cross-linking with TCR signal in Jurkat cells and overexpression of 4-1BB in 293 cells were able to induce activation of the nuclear factor-κB (NF-κB). 4-1BB-mediated NF-κB activation was inhibited by a dominant negative-TRAF2 or -NF-κB-inducing kinase (NIK). These data suggest that 4-1BB functions may be mediated by NF-κB activation, which requires a TRAF2/NIK pathway.