Activation of c-Jun N-Terminal Kinase and Activator Protein 1 by Receptor Activator of Nuclear Factor κB
- 1Department of Microbiology and Immunology (Z.H.L., H.-H.K.) and2Department of Pediatric Dentistry (S.H.L.), Chosun University Dental School, Kwangju, Korea; 3Research Institute of Medical Sciences, Chonnam University, Kwangju, Korea (K.K.K.); and 4Immunomodulation Research Center, Ulsan University, Ulsan, Korea (Z.H.L., K.K., H.-H.K.)
Abstract
Receptor activator of nuclear factor κB (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 κB-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.
Footnotes
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Send reprint requests to: Dr. Hong-Hee Kim, Department of Microbiology and Immunology, Chosun University Dental School, 375 Seosuk-Dong, Dong-Ku, Kwangju 501-759, South Korea. E-mail:hhkim{at}mail.chosun.ac.kr
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The authors acknowledge the financial support of the Korea Research Foundation made in the program year of 1998. S.H.L. was supported in part by research funds from Chosun University, 1997.
- Abbreviations:
- RANK
- receptor activator of nuclear factor κB (NF-κB)
- RANKL
- RANK ligand
- TNF
- tumor necrosis factor
- TRAF
- TNF receptor-associated factor
- JNK
- c-Jun N-terminal kinase
- AP-1
- activator protein 1
- ASK1
- apoptosis signal-regulating kinase 1
- ERK
- extracellular signal-regulated kinase
- MAPK
- mitogen-activated protein kinase
- MEKK
- MAPK/ERK kinase kinase
- NIK
- NF-κB-inducing kinase
- SEK
- SAPK (JNK)/ERK kinase
- GST
- glutathioneS-transferase
- TNFR
- tumor necrosis factor receptor
- PI
- phosphatidylinositol
- TRANCE
- TNF-related activation induced cytokine
- β-gal
- β-galactosidase
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- Received March 10, 2000.
- Accepted September 11, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
