Tumor necrosis factor receptor-associated factor 6 (TRAF6) stimulates extracellular signal-regulated kinase (ERK) activity in CD40 signaling along a ras-independent pathway.
CD40 activates nuclear factor kappa B (NF kappa B) 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 NF kappa B activation. Here we report that transient expression of TRAF6 stimulated both ERK and NF kappa B 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 (CD40 delta 246). Transient expression of the dominant-negative H-Ras significantly suppressed ERK activation by full-length CD40, but marginally suppressed ERK activation by CD40 delta 246, compatible with the possibility that TRAF6 is a major transducer of ERK activation by CD40 delta 246, 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.
Kashiwada
M
M
Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan.
Shirakata
Y
Y
Inoue
J I
JI
Nakano
H
H
Okazaki
K
K
Okumura
K
K
Yamamoto
T
T
Nagaoka
H
H
Takemori
T
T
D019013:CD40 Antigens / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002352:Carrier Proteins / Q000276:immunology / Q000502:physiology*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007668:Kidney; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6; D018631:ras Proteins / Q000276:immunology / Q000502:physiology*
D019013:CD40 Antigens; D002352:Carrier Proteins; D016328:NF-kappa B; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D048029:TNF Receptor-Associated Factor 6; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018631:ras Proteins