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Dynamic Protein Complexes Regulate NF-κB Signaling

  • E. Wegener
  • D. Krappmann
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 186)

Abstract

NF-κB is a major regulator of the first-line defense against invading pathogens, antigen-specific adaptive immune responses or chemical stress. Stimulation either by extracellular ligands (e.g., inflammatory cytokines, microbial pathogens, peptide antigens) or by intracellular Stressors (e.g., genotoxic drugs) initiates signal-specific pathways that all converge at the IκB kinase (IKK) complex, the gatekeeper for NF-κB activation. During recent years, considerable progress has been made in understanding the function of NF-κB in the regulation of cell growth, survival and apoptosis. In this review, we will focus on the regulation of large signaling complexes on the route to NF-κB. Recently published data demonstrate that the assembly, maintenance and activity of the IKK complex determine downstream activation of NF-κB. In addition, dynamic complexes upstream of IKK are formed in response to tumor necrosis factor (TNF), antigenic peptides or DNA-damaging agents. Clustering of signaling adaptors promotes the association and activation of ubiquitin ligases that trigger the conjugation of regulatory ubiquitin to target proteins. Ubiquitination serves as a platform to recruit the IKK complex and potentially other protein kinases to trigger IKK activation. These findings support a concept whereby protein complex assembly induces regulatory ubiquitination, which in turn recruits and activates protein kinases. Notably, the great interest in a detailed description of the mechanisms that regulate NF-κB activity stems from many observations that link dysregulated NF-κB signaling with the onset or progression of various diseases, including cancer, chronic inflammation, cardiovascular disorders and neurodegenerative diseases. Thus, the formation of large signaling clusters and regulatory ubiquitin chains represents promising targets for pharmacological intervention to modulate NF-κB signal transduction in disease.

Keywords

Polyubiquitin Chain Ubiquitin Chain IkappaB Kinase Dynamic Protein Complex Proximal Signaling Event 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • E. Wegener
    • 1
  • D. Krappmann
    • 2
  1. 1.Institute of ToxicologyGSF – Research Center for Environment and HealthNeuherbergGermany
  2. 2.Institute of ToxicologyHelmholtz Zentrum München - German Research Center for Environmental HealthNeuherbergGermany

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