The interaction of p62 with RIP links the atypical PKCs to NF-κB activation

The two members of the atypical protein kinase C (aPKC) subfamily of isozymes (zeta PKC and lambda/iota PKC) are involved in the control of nuclear factor kappa B (NF-kappa B) through IKK beta activation, Here we show that the previously described aPKC-binding protein, p62, selectively interacts with RIP but not with TRAF2 in vitro and in vivo. p62 bridges the aPKCs to RIP, whereas the aPKCs link IKK beta to p62, In this way, a signaling cascade of interactions is established from the TNF-R1 involving TRADD/RIP/p62/aPKCs/IKK beta, These observations define a novel pathway for the activation of NF-kappa B involving the aPKCs and p62, Consistent with this model, the expression of a dominant-negative mutant lambda/iota PKC impairs RIP-stimulated NF-kappa B activation. In addition, the expression of either an N-terminal aPKC-binding domain of p62, or its C-terminal RIP-binding region are sufficient to block NF-kappa B activation. Furthermore, transfection of an antisense construct of p62 severely abrogates NF-kappa B activation, Together, these results demonstrate that the interaction of p62 with RTP serves to link the atypical PKCs to the activation of NF-kappa B by the TNF alpha signaling pathway.