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

The two members of the atypical protein kinase C (aPKC) subfamily of isozym es (zeta PKC and lambda/iota PKC) are involved in the control of nuclear fa ctor kappa B (NF-kappa B) through IKK beta activation, Here we show that th e previously described aPKC-binding protein, p62, selectively interacts wit h 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/aPKC s/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 ex pression of a dominant-negative mutant lambda/iota PKC impairs RIP-stimulat ed NF-kappa B activation. In addition, the expression of either an N-termin al aPKC-binding domain of p62, or its C-terminal RIP-binding region are suf ficient to block NF-kappa B activation. Furthermore, transfection of an ant isense construct of p62 severely abrogates NF-kappa B activation, Together, these results demonstrate that the interaction of p62 with RTP serves to l ink the atypical PKCs to the activation of NF-kappa B by the TNF alpha sign aling pathway.