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Masaki Kashiwada^*, Yumiko Shirakata^*, Jun-Ichiro Inoue, Hiroyasu Nakano, Kenji Okazaki^||, Ko Okumura, Tadashi Yamamoto, Hitoshi Nagaoka^*, and Toshitada Takemori^*

^* Department of Immunology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162, Japan; Department of Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shiroganedai, Minato-ku, Tokyo 108, Japan; Department of Immunology, School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113, Japan; ^|| CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Corporation (JST), and ^¶ Department of Molecular Biology, Biomolecular Engineering Research Institute, 6-2-3 Furuedai, Suita-shi, Osaka-fu 565, Japan

CD40 activates nuclear factor kappa B (NFB) and the mitogen-activated protein kinase (MAPK) subfamily, including extracellular signal–regulated kinase (ERK). The CD40 cytoplasmic tail interacts with tumor necrosis factor receptor–associated factor (TRAF)2, TRAF3, TRAF5, and TRAF6. These TRAF proteins, with the exception of TRAF3, are required for NFB activation. Here we report that transient expression of TRAF6 stimulated both ERK and NFB activity in the 293 cell line. Coexpression of the dominant-negative H-Ras did not affect TRAF6-mediated ERK activity, suggesting that TRAF6 may activate ERK along a Ras-independent pathway. The deletion mutant of TRAF6 lacking the NH₂-terminal domain acted as a dominant-negative mutant to suppress ERK activation by full-length CD40 and suppress prominently ERK activation by a deletion mutant of CD40 only containing the binding site for TRAF6 in the cytoplasmic tail (CD40246). Transient expression of the dominant-negative H-Ras significantly suppressed ERK activation by full-length CD40, but marginally suppressed ERK activation by CD40246, compatible with the possibility that TRAF6 is a major transducer of ERK activation by CD40246, whose activity is mediated by a Ras-independent pathway. These results suggest that CD40 activates ERK by both a Ras-dependent pathway and a Ras-independent pathway in which TRAF6 could be involved.

¹ Abbreviations used in this paper: β-gal, β-galactosidase; aa, amino acids; DN, dominant negative; ERK, extracellular signal–regulated kinase; GST, glutathione-S-transferase; Jak, Janus kinase; JNK, c-jun NH₂-terminal kinase; MAPK, mitogen-activated protein kinase; MBP, myelin basic protein; MEK, MAPK/ERK-activating kinase; NFB, nuclear factor kappa B; TRAF, TNFR-associated factor; TRAF-C, TRAF-COOH; TRAF-N, TRAF-NH₂.

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