The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation.
The two members of the atypical protein kinase C (aPKC) subfamily of isozymes (zetaPKC and lambda/iotaPKC) are involved in the control of nuclear factor kappaB (NF-kappaB) through IKKbeta 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 IKKbeta to p62. In this way, a signaling cascade of interactions is established from the TNF-R1 involving TRADD/RIP/p62/aPKCs/IKKbeta. These observations define a novel pathway for the activation of NF-kappaB involving the aPKCs and p62. Consistent with this model, the expression of a dominant-negative mutant lambda/iotaPKC impairs RIP-stimulated NF-kappaB 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-kappaB activation. Furthermore, transfection of an antisense construct of p62 severely abrogates NF-kappaB activation. Together, these results demonstrate that the interaction of p62 with RIP serves to link the atypical PKCs to the activation of NF-kappaB by the TNFalpha signaling pathway.
Mesh Terms:
Antigens, CD, Binding Sites, Cell Line, DNA-Binding Proteins, Enzyme Activation, Gene Expression Regulation, Humans, I-kappa B Kinase, I-kappa B Proteins, Isoenzymes, Mutation, NF-kappa B, Precipitin Tests, Protein Binding, Protein Kinase C, Protein-Serine-Threonine Kinases, Proteins, RNA, Antisense, RNA-Binding Proteins, Receptor-Interacting Protein Serine-Threonine Kinases, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, TNF Receptor-Associated Factor 1, TNF Receptor-Associated Factor 2, Transfection, Tumor Necrosis Factor-alpha
Antigens, CD, Binding Sites, Cell Line, DNA-Binding Proteins, Enzyme Activation, Gene Expression Regulation, Humans, I-kappa B Kinase, I-kappa B Proteins, Isoenzymes, Mutation, NF-kappa B, Precipitin Tests, Protein Binding, Protein Kinase C, Protein-Serine-Threonine Kinases, Proteins, RNA, Antisense, RNA-Binding Proteins, Receptor-Interacting Protein Serine-Threonine Kinases, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, TNF Receptor-Associated Factor 1, TNF Receptor-Associated Factor 2, Transfection, Tumor Necrosis Factor-alpha
EMBO J.
Date: Jun. 01, 1999
PubMed ID: 10356400
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