NF-kappaB signaling is essential for survival of normal B lymphocytes, and dysregulated NF-kappaB activation contributes to B cell lymphoma and autoimmune disease. Our previous data indicate that the Btk/PKCbeta signaling module plays a crucial, yet highly selective role in B cell activation. PKCbeta is specifically required for B cell receptor (BCR)-mediated NF-kappaB activation. B cells from PKCbeta-deficient mice fail to recruit the lkappaB kinase (IKK) complex into lipid rafts, to activate IKK, to degrade IkappaB, and to upregulate NF-kappaB dependent survival signals. In addition, inhibition of PKCbeta promotes cell death in B lymphomas characterized by exaggerated NF-kappaB activity. Our current studies demonstrate that the MAGUK protein, CARMA1, provides an essential link between PKCbeta and NF-kappaB activation. PKCbeta specifically interacts with, and phosphorylates a highly conserved serine-rich linker within CARMA1. This interaction is predicted to trigger the assembly and activation of theCARMA1/Bcl10/IKK signalosome. In the current proposal we will: 1.) Define the molecular events mediating PKCbeta-dependent CARMA 1 activation and its functional consequences; 2.) Identify the components of the CARMA 1 signalosome; 3.) Characterize key negative regulatory signals mediated by activated PKCbeta and 4.) Determine the developmental consequences of increased dosage and activation of PKCbeta. Together, our previous and new preliminary findings highlight PKCbeta as a key candidate drug target for selected B lineage disorders. Improved understanding of the mechanisms by which PKCbeta regulates NF-kappaB activation; its major protein substrates and downstream transcriptional targets; and the developmental and functional consequences of augmented PKCbeta-dependent signaling will facilitate development of therapeutics specifically targeting these signaling events.
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