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

Abstract

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-κB 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-b-activated kinase 1 (TAK1), with TRAF6 was shown to mediate the IL-1 signaling to NF-κB 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-κB activation was also observed, but less efficiently. Our findings indicate that TAK1 is involved in the MAPK cascade and NF-κB pathway that is activated by RANK. © BSRK & Springer-Verlag 2002.