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

David M. Rothwarf and Michael Karin

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA. drothwar{at}ucsd.edu and karinoffice{at}ucsd.edu

Abstract: Nuclear factor kappa B (NF-B)/Rel proteins are dimeric, sequence-specific transcription factors involved in the 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. In unstimulated cells, NF-B is sequestered in an inactive form in the cytoplasm bound to inhibitory IB proteins. Stimulation leads to the rapid phosphorylation, ubiquitinylation, and ultimately proteolytic degradation of IB, which frees NF-B to translocate to the nucleus and activate the transcription of its target genes. The multisubunit IB kinase (IKK) responsible for the inducible phosphorylation of IB appears to be the initial point of convergence for most stimuli that activate NF-B. IKK contains two catalytic subunits, IKK and IKKß, both of which phosphorylate IB at sites phosphorylated in vivo. Gene knockout studies indicate that IKKß is primarily responsible for the activation of NF-B in response to proinflammatory stimuli, whereas IKK is essential for keratinocyte differentiation. The activity of IKK is regulated by phosphorylation. IKK contains a regulatory subunit, IKK, which is critical for activation of IKK and is postulated to serve as a recognition site for upstream activators. When phosphorylated, the IKK recognition site on IB serves as a specific recognition site for the -TrCP-like component of a Skp1-Cullin-F-box-type E3 ubiquitin-protein ligase. A variety of other signaling events, including phosphorylation of NF-B, phosphorylation of IKK, new synthesis of IBs, and the processing of NF-B precursors provide mechanisms of modulating the amount and duration of NF-B activity.

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