TAK1-dependent activation of AP-1 and c-Jun N-terminal kinase by receptor activator of NF-kappaB.

Received 25 March 2002, Accepted 18 April 2002The receptor activator of nuclear factor kappa B (RANK)is a member of the tumor necrosis factor (TNF) receptorsuperfamily. It plays a critical role in osteoclastdifferentiation, lymph node organogenesis, and mammarygland development. The stimulation of RANK causes theactivation of transcription factors NF-κB and activatorprotein 1 (AP1), and the mitogen activated protein kinase(MAPK) c-Jun N-terminal kinase (JNK). In the signaltransduction of RANK, the recruitment of the adaptormolecules, TNF receptor-associated factors (TRAFs), is aninitial cytoplasmic event. Recently, the association of theMAPK kinase kinase, transforming growth factor-β-activated kinase 1 (TAK1), with TRAF6 was shown tomediate the IL-1 signaling to NF-κB and JNK. Weinvestigated whether or not TAK1 plays a role in RANKsignaling. A dominant-negative form of TAK1 wasdiscovered to abolish the RANK-induced activation of AP1and JNK. The AP1 activation by TRAF2, TRAF5, andTRAF6 was also greatly suppressed by the dominant-negative TAK1. The inhibitory effect of the TAK1 mutanton RANK- and TRAF-induced NF-κB activation was alsoobserved, but less efficiently. Our findings indicate thatTAK1 is involved in the MAPK cascade and NF-κBpathway that is activated by RANK.Keywords: Activator protein 1, Receptor activator of NF-κB,Transforming growth factor-β-activated kinase 1, TNFreceptor-associated factor