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

Gloss: The transcription factor nuclear factor kappa B (NF-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-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-B is sequestered in the cytoplasm of nonstimulated cells and consequently must be translocated into the nucleus to function. The subcellular location of NF-B is controlled by a family of inhibitory proteins, the IBs, which noncovalently bind to NF-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 IB, which frees NF-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 IB degradation, particularly those pathways that respond to the proinflammatory cytokines tumor necrosis factor (TNF-) and interleukin-1 (IL-1). The multisubunit IB kinase (IKK) responsible for the inducible phosphorylation of IB appears to be the 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. However, gene knockout studies have revealed that IKK and IKKß have very different physiological functions. After phosphorylation, the IKK phosphoacceptor site on IB serves as a specific recognition site for the ß-TrCP-like component of a Skp1-Cullin-F-box (SCF)-type E3 ubiquitin-protein ligase, thereby explaining how IKK controls IB ubiquitinylation and degradation. Various other signaling events, including phosphorylation of NF-B, phosphorylation of IKK, induction of IB synthesis, and the processing of NF-B precursors, provide additional mechanisms that modulate the level and duration of NF-B activity.

The editors suggest the following Related Resources on Science sites:

In Science Signaling

EDITORS' CHOICE
Immunology
Turning NF-B On and Off

Wei Wong (10 March 2009)
Sci. Signal. 2 (61), ec91. [DOI: 10.1126/scisignal.261ec91]
 |  Abstract »

EDITORS' CHOICE
Apoptosis
Of Arsenic and NF-B

Elizabeth M. Adler (28 November 2006)
Sci. STKE 2006 (363), tw402. [DOI: 10.1126/stke.3632006tw402]
 |  Abstract »

PERSPECTIVES
TRAF2: A Double-Edged Sword?

Zong-Ping Xia and Zhijian J. Chen (22 February 2005)
Sci. STKE 2005 (272), pe7. [DOI: 10.1126/stke.2722005pe7]
 |  Abstract »  |  Full Text »  |  PDF »

EDITORS' CHOICE
INTERACTION DOMAINS
Building Signaling Complexes with Ubiquitin

(7 September 2004)
Sci. STKE 2004 (249), tw316. [DOI: 10.1126/stke.2492004tw316]
 |  Abstract »

EDITORS' CHOICE
APOPTOSIS
Context Matters

(30 March 2004)
Sci. STKE 2004 (226), tw113. [DOI: 10.1126/stke.2262004TW113]
 |  Abstract »

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES: