The LIM protein Ajuba influences interleukin-1-induced NF-kappaB activation by affecting the assembly and activity of the protein kinase Czeta/p62/TRAF6 signaling complex.
The Zyxin/Ajuba family of cytosolic LIM domain-containing proteins has the potential to shuttle from sites of cell adhesion into the nucleus and thus can be candidate transducers of environmental signals. To understand Ajuba's role in signal transduction pathways, we performed a yeast two-hybrid screen with the LIM domain region of Ajuba. We identified the atypical protein kinase C (aPKC) scaffold protein p62 as an Ajuba binding partner. A prominent function of p62 is the regulation of NF-kappaB activation in response to interleukin-1 (IL-1) and tumor necrosis factor signaling through the formation of an aPKC/p62/TRAF6 multiprotein signaling complex. In addition to p62, we found that Ajuba also interacted with tumor necrosis factor receptor-associated factor 6 (TRAF6) and PKCzeta. Ajuba recruits TRAF6 to p62 and in vitro activates PKCzeta activity and is a substrate of PKCzeta. Ajuba null mouse embryonic fibroblasts (MEFs) and lungs were defective in NF-kappaB activation following IL-1 stimulation, and in lung IKK activity was inhibited. Overexpression of Ajuba in primary MEFs enhances NF-kappaB activity following IL-1 stimulation. We propose that Ajuba is a new cytosolic component of the IL-1 signaling pathway modulating IL-1-induced NF-kappaB activation by influencing the assembly and activity of the aPKC/p62/TRAF6 multiprotein signaling complex.
Feng
Yungfeng
Y
Department of Medicine, Washington University, St. Louis, Missouri 63110, USA.
Longmore
Gregory D
GD
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase; D007375:Interleukin-1 / Q000494:pharmacology*; D060588:LIM Domain Proteins; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020798:Two-Hybrid System Techniques; D000099221:Protein Kinase C zeta
D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; D051550:I-kappa B Kinase; D007375:Interleukin-1; D060588:LIM Domain Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D000071456:Sequestosome-1 Protein; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D000099221:Protein Kinase C zeta; C485608:AJUBA protein, human; C099718:SQSTM1 protein, human; C496559:CHUK protein, human; C496564:Chuk protein, mouse; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse