Dynamic Protein Complexes Regulate NFkB Signaling

E. Wegener and D. Krappmann(*)

Contents

1 Two Routes to NF-kB 238

2 The IKK Complex: The Gatekeeper of NF-kB Pathways 241

2.1 Structure and Activation of the IKK Complex 241

2.2 IKKy-Binding Peptides Counteract IKK Activation 243

2.3 Chaperone HSP90 Regulates IKK Activity: Implications for Tumor Therapy . . . . 245

3 Protein Assemblies and Regulatory Ubiquitination Trigger Activation of the IKK Complex 246

3.1 Dynamic Signaling Complexes Control Activation of the Canonical

NF-kB Pathway 246

3.2 Regulatory Ubiquitin Chains Connect Upstream Events to the IKK Complex 249

3.3 IKKy Modification Triggers NF-kB Activation in Response to DNA Damage 251

4 Outlook 253

References 254

Abstract NF-kB 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 IkB kinase (IKK) complex, the gatekeeper for NF-kB activation. During recent years, considerable progress has been made in understanding the function of NF-kB 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-kB. Recently published data demonstrate that the assembly, maintenance and activity of the IKK complex determine downstream activation of NF-kB. In addition, dynamic complexes upstream of IKK

D. Krappmann

Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Toxicology, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany [email protected]

E. Klussmann, J. Scott (eds.) Protein-Protein Interactions as New Drug Targets. Handbook of Experimental Pharmacology 186, © Springer-Verlag Berlin Heidelberg 2008

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-kB activity stems from many observations that link dysregulated NF-kB 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-kB signal transduction in disease.

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