NF-kappaB (nuclear factor-kappaB) is a collective name for inducible dimeric 
transcription factors composed of members of the Rel family of DNA-binding 
proteins that recognize a common sequence motif. NF-kappaB is found in 
essentially all cell types and is involved in activation of an exceptionally 
large number of genes in response to infections, inflammation, and other 
stressful situations requiring rapid reprogramming of gene expression. NF-kappaB 
is normally sequestered in the cytoplasm of nonstimulated cells and consequently 
must be translocated into the nucleus to function. The subcellular location of 
NF-kappaB is controlled by a family of inhibitory proteins, IkappaBs, which bind 
NF-kappaB and mask its nuclear localization signal, thereby preventing nuclear 
uptake. Exposure of cells to a variety of extracellular stimuli leads to the 
rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of 
IkappaB, which frees NF-kappaB to translocate to the nucleus where it regulates 
gene transcription. NF-kappaB activation represents a paradigm for controlling 
the function of a regulatory protein via ubiquitination-dependent proteolysis, 
as an integral part of a phosphorylationbased signaling cascade. Recently, 
considerable progress has been made in understanding the details of the 
signaling pathways that regulate NF-kappaB activity, particularly those 
responding to the proinflammatory cytokines tumor necrosis factor-alpha and 
interleukin-1. The multisubunit IkappaB kinase (IKK) responsible for inducible 
IkappaB phosphorylation is the point of convergence for most 
NF-kappaB-activating stimuli. IKK contains two catalytic subunits, IKKalpha and 
IKKbeta, both of which are able to correctly phosphorylate IkappaB. Gene 
knockout studies have shed light on the very different physiological functions 
of IKKalpha and IKKbeta. After phosphorylation, the IKK phosphoacceptor sites on 
IkappaB serve as an essential part of a specific recognition site for 
E3RS(IkappaB/beta-TrCP), an SCF-type E3 ubiquitin ligase, thereby explaining how 
IKK controls IkappaB ubiquitination and degradation. A variety of other 
signaling events, including phosphorylation of NF-kappaB, hyperphosphorylation 
of IKK, induction of IkappaB synthesis, and the processing of NF-kappaB 
precursors, provide additional mechanisms that modulate the level and duration 
of NF-kappaB activity.