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Sci. STKE, 26 October 1999
Vol. 1999, Issue 5, p. re1
[DOI: 10.1126/stke.1999.5.re1]


The NF-{kappa}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} and karinoffice{at}

Gloss: The transcription factor nuclear factor kappa B (NF-{kappa}B) 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-{kappa}B 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-{kappa}B is sequestered in the cytoplasm of nonstimulated cells and consequently must be translocated into the nucleus to function. The subcellular location of NF-{kappa}B is controlled by a family of inhibitory proteins, the I{kappa}Bs, which noncovalently bind to NF-{kappa}B 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 I{kappa}B, which frees NF-{kappa}B 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 I{kappa}B degradation, particularly those pathways that respond to the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-1 (IL-1). The multisubunit I{kappa}B kinase (IKK) responsible for the inducible phosphorylation of I{kappa}B appears to be the point of convergence for most stimuli that activate NF-{kappa}B. IKK contains two catalytic subunits, IKKα and IKKβ, both of which phosphorylate I{kappa}B 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 I{kappa}Bα 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 I{kappa}B ubiquitinylation and degradation. Various other signaling events, including phosphorylation of NF-{kappa}B, phosphorylation of IKK, induction of I{kappa}B synthesis, and the processing of NF-{kappa}B precursors, provide additional mechanisms that modulate the level and duration of NF-{kappa}B activity.

Citation: D. M. Rothwarf, M. Karin, The NF-{kappa}B Activation Pathway: A Paradigm in Information Transfer from Membrane to Nucleus. Sci. STKE 1999, re1 (1999).

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