Figure 2

p62 in osteoclast signaling and protein trafficking. The binding of RANKL to the receptor protein RANK at the plasma membrane induces the formation of a trimer, triggering the recruitment of a series of adaptor proteins. TRAF6 catalyses Lys63-linked autoubiquitination via intrinsic E3 ubiquitin ligase activity, which is regulated by the UBA domain of p62, and eventually deubiquitinated post-recruitment of CYLD to p62. In the interim, this ubiquitination permits activation of the TAB1-TAB2-TAK1 complex, in turn activating the MAP kinases, as well as NF-κB-inducing kinase (NIK), which leads to phosphorylation and activation of IKKβ. Activation of TRAF6 and p62 also leads to activation of the Akt/PKB pathway. Simultaneously, p62 binds aPKC through its N-terminal PB1, allowing for the phosphorylation of IKKβ by the aPKC. Once activated, IKKβ phosphorylates IκB, which is subsequently ubiquitinated, and degraded through the proteasome system, liberating NF-κB to translocate to the nucleus and interact with transcription promoters.