Activation of c-Jun N-terminal kinase and activator protein 1 by receptor activator of nuclear factor kappaB.
Receptor activator of nuclear factor kappaB (RANK), a lately identified member of the tumor necrosis factor receptor superfamily, plays important roles both in osteoclastogenesis and in lymph node development. Previously, we and others showed that RANK could stimulate the activity of c-Jun N-terminal kinase (JNK). In this study, we investigated the mechanism by which RANK activates JNK. We found that N-terminal deletion mutants of tumor necrosis factor receptor-associated factor 2 and 6 were inhibitory to RANK activation of JNK. The JNK activation by RANK was also reduced by cotransfection of kinase-inactive mutants of apoptosis signal-regulating kinase 1, MAPK/ERK kinase kinase 1, and nuclear factor kappaB-inducing kinase. In addition, dominant negative mutants of Rac and Ras decreased the RANK stimulation of JNK activity. Furthermore, we determined whether the RANK engagement of JNK signaling pathways could lead to the activation of the activator protein 1 (AP-1) transcription factor, one of the potential downstream targets of activated JNK. RANK was found to activate AP-1 in a manner dependent on the signaling molecules involved in the JNK activation by this receptor. Furthermore, the activation of JNK and ERK, but not that of p38, appeared to be involved in the AP-1 activation by RANK. Thus, RANK may use both JNK and ERK pathways to signal to the AP-1 transcription factor.
Lee
Z H
ZH
Department of Microbiology and Immunology, Chosun University Dental School, Kwangju, Korea.
Kwack
K
K
Kim
K K
KK
Lee
S H
SH
Kim
H H
HH
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D053244:Osteoprotegerin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D014162:Transfection; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D018797:Cell Cycle Proteins; D020558:GTP Phosphohydrolases; D006023:Glycoproteins; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D053244:Osteoprotegerin; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D018808:Transcription Factor AP-1; D020744:rac GTP-Binding Proteins; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; D000097782:NF-kappaB-Inducing Kinase; C506030:TNFRSF11B protein, human