Mechanisms of Ubiquitin-Mediated Activation of IKK

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DESCRIPTION (provided by applicant): The transcription factor NF-KB is regulated through signal-induced phosphorylation, ubiquitination and subsequent degradation of the IicB family of inhibitory proteins. The phosphorylation of 1KB is carried out by the IKK complex, which is activated by virtually all NF-KB stimuli including the proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF). IL-1 and TNF activate IKK through TRAF2 and TRAF6, respectively. Our lab has found that TRAF2 and TRAF6 are ubiquitin ligases that function together with UbclS/UevlA to catalyze the synthesis of a unique polyubiquitin chain linked through lysine-63 of ubiquitin. This polyubiquitination mediates the activation of a protein kinase complex consisting of TAK1, TAB1 and TAB2 (or TAB3), through a proteasome-independent mechanism. Our recent studies show that TAB2 and TABS bind to K63 polyubiquitin chains through a specialized zinc finger domain, and that this binding is important for TAK1 activation. The activated TAK1 subsequently phosphorylates and activates IKK. These results set the stage for a detailed study of the mechanism of TAK1 and IKK activation by ubiquitin. In addition, our finding raises the question of whether ubiquitination may activate other protein kinases besides TAK1 and IKK. The goals of our next phase of research are to have a deeper understanding of the molecular mechanism of ubiquitin activation of protein kinases, and to begin to explore the potential generality of this mechanism. Specifically, we will strive to: 1) Elucidate the mechanism of TAK1 activation by ubiquitin; 2) Define the mechanism of IKK activation by TAK1 and ubiquitin; 3) Investigate the TAK1- independent pathway of IKK activation; 4) Dissect the TRAF6- and ubiquitin-dependent pathway of ERK activation. These studies should lead to the unraveling of the IKK activation mechanism, a central question in NF-KB research. Moreover, our research should help establish a new paradigm of signal transduction in which ubiquitin plays an important regulatory role.