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Molecular and Cellular Biology, May 2005, p. 4010-4022, Vol. 25, No. 10
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.10.4010-4022.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The LIM Protein Ajuba Influences Interleukin-1-Induced NF-B Activation by Affecting the Assembly and Activity of the Protein Kinase C/p62/TRAF6 Signaling Complex

Departments of Medicine and Cell Biology, Washington University, St. Louis, Missouri

Received 20 September 2004/ Returned for modification 13 October 2004/ Accepted 22 February 2005

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-B 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 PKC. Ajuba recruits TRAF6 to p62 and in vitro activates PKC activity and is a substrate of PKC. Ajuba null mouse embryonic fibroblasts (MEFs) and lungs were defective in NF-B activation following IL-1 stimulation, and in lung IKK activity was inhibited. Overexpression of Ajuba in primary MEFs enhances NF-B activity following IL-1 stimulation. We propose that Ajuba is a new cytoso lic component of the IL-1 signaling pathway modulating IL-1-induced NF-B activation by influencing the assembly and activity of the aPKC/p62/TRAF6 multiprotein signaling complex.

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