Lee Soo Woong, Han Sang-In, Kim Hong-Hee, Lee Zang Hee
National Research Laboratory for Bone Metabolism, Chosun University, Gwangju, Korea.
J Biochem Mol Biol. 2002 Jul 31;35(4):371-6. doi: 10.5483/bmbrep.2002.35.4.371.
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.
核因子κB受体激活剂（RANK）是肿瘤坏死因子（TNF）受体超家族的成员。它在破骨细胞分化、淋巴结器官发生和乳腺发育中起关键作用。RANK的刺激导致转录因子NF-κB和激活蛋白1（AP1）以及丝裂原活化蛋白激酶（MAPK）c-Jun氨基末端激酶（JNK）的激活。在RANK的信号转导中，衔接分子肿瘤坏死因子受体相关因子（TRAFs）的募集是最初的细胞质事件。最近，有研究表明，丝裂原活化蛋白激酶激酶激酶转化生长因子-β激活激酶1（TAK1）与TRAF6的结合介导了IL-1向NF-κB和JNK的信号传导。我们研究了TAK1是否在RANK信号传导中起作用。发现TAK1的显性负性形式可消除RANK诱导的AP1和JNK的激活。显性负性TAK1也大大抑制了TRAF2、TRAF5和TRAF6对AP1的激活。还观察到TAK1突变体对RANK和TRAF诱导的NF-κB激活的抑制作用，但效率较低。我们的研究结果表明，TAK1参与了由RANK激活的MAPK级联反应和NF-κB途径。
