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

EMBO J. 2007 Apr 4;26(7):1794-805. doi: 10.1038/sj.emboj.7601622. Epub 2007 Mar 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptosis Regulatory Proteins / deficiency
  • Apoptosis Regulatory Proteins / metabolism
  • B-Cell CLL-Lymphoma 10 Protein
  • CARD Signaling Adaptor Proteins / deficiency
  • CARD Signaling Adaptor Proteins / metabolism
  • Enzyme Activation
  • Humans
  • I-kappa B Kinase / deficiency
  • I-kappa B Kinase / metabolism*
  • Jurkat Cells
  • Lysine / metabolism
  • MAP Kinase Kinase Kinases / metabolism
  • Membrane Microdomains / metabolism
  • Mice
  • Models, Immunological
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein Kinase C / metabolism
  • Protein Transport
  • Receptors, Antigen, T-Cell / immunology
  • Signal Transduction*
  • Subcellular Fractions / metabolism
  • T-Lymphocytes / enzymology
  • Ubiquitin / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • B-Cell CLL-Lymphoma 10 Protein
  • Bcl10 protein, mouse
  • CARD Signaling Adaptor Proteins
  • Card11 protein, mouse
  • IKBKG protein, human
  • NF-kappa B
  • Receptors, Antigen, T-Cell
  • Ubiquitin
  • I-kappa B Kinase
  • Protein Kinase C
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Lysine