Figure 1

Schematic overview of the RANK-NF-κB signalling pathway. The cytokine RANK-L binds to the receptor protein RANK in an interaction antagonised by OPG-RANK-L binding. Upon receptor stimulation by RANK-L, TRAF6 associates with RANK, and the p62 adapter protein binds to TRAF6. Lys63-linked autoubiquitylation of TRAF6 is catalysed by its intrinsic E3 ubiquitin ligase activity (and may be regulated by p62). Through its N-terminal PB1 domain p62 binds aPKC, stimulating the activation of I-κB kinaseß (IKKß). Activation of the TAB1-TAB2-TAK1 complex by binding ubiquitylated TRAF6 also leads to phosphorylation and activation of IKKß. Phosphorylation of I-κB by the activated IKKß complex and subsequent Lys48-linked polyubiquitylation leads to 26S proteasomal degradation of I-κB. This allows NF-κB to enter the nucleus and activate target gene expression. VCP may regulate the proteasomal degradation of I-κB.