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The NF-{kappa}B Activation Pathway: A Paradigm in Information Transfer from Membrane to Nucleus

The transcription factor nuclear factor kappa B (NF-κB) is a somewhat heterogeneous collection of dimeric DNA-binding proteins composed of subunits that belong to the Rel family and recognize a common sequence motif. NF-κB is found in essentially all cell types and is involved in activation of an exceptionally large number of genes in response to inflammation, viral and bacterial infections, and other stressful situations requiring rapid reprogramming of gene expression. NF-κB is sequestered in the cytoplasm of nonstimulated cells and consequently must be translocated into the nucleus to function. The subcellular location of NF-κB is controlled by a family of inhibitory proteins, the IκBs, which noncovalently bind to NF-κB and mask its nuclear localization signal, thereby preventing nuclear uptake. Exposure of cells to various extracellular stimuli leads to the rapid phosphorylation, ubiquitinylation, and ultimately proteolytic degradation of IκB, which frees NF-κB to translocate to the nucleus, where it regulates gene transcription. Recently, considerable progress has been made in understanding the details of the signaling pathways that regulate and mediate inducible IκB degradation, particularly those pathways that respond to the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-1 (IL-1). The multisubunit IκB kinase (IKK) responsible for the inducible phosphorylation of IκB appears to be the point of convergence for most stimuli that activate NF-κB. IKK contains two catalytic subunits, IKKα and IKKβ, both of which phosphorylate IκB at sites phosphorylated in vivo. However, gene knockout studies have revealed that IKKα and IKKβ have very different physiological functions. After phosphorylation, the IKK phosphoacceptor site on IκBα serves as a specific recognition site for the β-TrCP-like component of a Skp1-Cullin-F-box (SCF)-type E3 ubiquitin-protein ligase, thereby explaining how IKK controls IκB ubiquitinylation and degradation. Various other signaling events, including phosphorylation of NF-κB, phosphorylation of IKK, induction of IκB synthesis, and the processing of NF-κB precursors, provide additional mechanisms that modulate the level and duration of NF-κB activity.

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Resource Type: Bibliography, Diagram, Illustration, Journal article/Issue, Review
Audience Level: Undergraduate upper division 15-16, Graduate, Professional (degree program)

Author and Copyright

Authors and Editors: David M. Rothwarf of University of California, Michael Karin of San Diego
Publisher: American Association for the Advancement of Science
Format: application/pdf, image/gif, image/jpeg, text/html
Copyright and other restrictions: Yes
Cost: Yes


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