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.
Sanz
L
L
Laboratorio Glaxo Wellcome-CSIC de Biología Molecular y Celular, Centro de Biología Molecular 'Severo Ochoa' (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Spain.
Sanchez
P
P
Lallena
M J
MJ
Diaz-Meco
M T
MT
Moscat
J
J
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016372:RNA, Antisense / Q000235:genetics / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D004268:DNA-Binding Proteins; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D007527:Isoenzymes; D016328:NF-kappa B; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D016372:RNA, Antisense; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D000071456:Sequestosome-1 Protein; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta; C099718:SQSTM1 protein, human; C506249:RIPK1 protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human