Phosphorylation and ubiquitination of the IkappaB kinase complex by two distinct signaling pathways.

The IkappaB kinase (IKK) complex serves as the master regulator for the activation of NF-kappaB by various stimuli. It contains two catalytic subunits, IKKalpha and IKKbeta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKKalpha/beta at its activation loop and the K63-linked ...
ubiquitination of NEMO. However, the molecular mechanism by which these inducible modifications occur remains undefined. Here, we demonstrate that CARMA1, a key scaffold molecule, is essential to regulate NEMO ubiquitination upon T-cell receptor (TCR) stimulation. However, the phosphorylation of IKKalpha/beta activation loop is independent of CARMA1 or NEMO ubiquitination. Further, we provide evidence that TAK1 is activated and recruited to the synapses in a CARMA1-independent manner and mediate IKKalpha/beta phosphorylation. Thus, our study provides the biochemical and genetic evidence that phosphorylation of IKKalpha/beta and ubiquitination of NEMO are regulated by two distinct pathways upon TCR stimulation.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Apoptosis Regulatory Proteins, CARD Signaling Adaptor Proteins, Enzyme Activation, Humans, I-kappa B Kinase, Jurkat Cells, Lysine, MAP Kinase Kinase Kinases, Membrane Microdomains, Mice, Models, Immunological, NF-kappa B, Phosphorylation, Protein Kinase C, Protein Transport, Receptors, Antigen, T-Cell, Signal Transduction, Subcellular Fractions, T-Lymphocytes, Ubiquitin
EMBO J.
Date: Apr. 04, 2007
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