TAK1-dependent activation of AP-1 and c-Jun N-terminal kinase by receptor activator of NF-kappaB.
The receptor activator of nuclear factor kappa B (RANK) is a member of the tumor necrosis factor (TNF) receptor superfamily. It plays a critical role in osteoclast differentiation, lymph node organogenesis, and mammary gland development. The stimulation of RANK causes the activation of transcription factors NF-kappaB and activator protein 1 (AP1), and the mitogen activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK). In the signal transduction of RANK, the recruitment of the adaptor molecules, TNF receptor-associated factors (TRAFs), is an initial cytoplasmic event. Recently, the association of the MAPK kinase kinase, transforming growth factor-beta-activated kinase 1 (TAK1), with TRAF6 was shown to mediate the IL-1 signaling to NF-kappaB and JNK. We investigated whether or not TAK1 plays a role in RANK signaling. A dominant-negative form of TAK1 was discovered to abolish the RANK-induced activation of AP1 and JNK. The AP1 activation by TRAF2, TRAF5, and TRAF6 was also greatly suppressed by the dominant negative TAK1. The inhibitory effect of the TAK1 mutant on RANK- and TRAF-induced NF-kappaB activation was also observed, but less efficiently. Our findings indicate that TAK1 is involved in the MAPK cascade and NF-kappaB pathway that is activated by RANK.
Lee
Soo Woong
SW
National Research Laboratory for Bone Metabolism, Chosun University, Gwangju, Korea.
Han
Sang-In
SI
Kim
Hong-Hee
HH
Lee
Zang Hee
ZH
D002460:Cell Line; D004789:Enzyme Activation; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D053244:Osteoprotegerin; D011506:Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014162:Transfection; D000099151:MAP Kinase Kinase Kinase 7
D006023:Glycoproteins; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D053244:Osteoprotegerin; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D018808:Transcription Factor AP-1; D000099151:MAP Kinase Kinase Kinase 7; C506030:TNFRSF11B protein, human