Signaling to NF-κB

Abstract

The transcription factor NF-B has been the focus of intense investigation for nearly two decades. Over this period, considerable progress has been made in determining the function and regulation of NF-B, although there are nuances in this important signaling pathway that still remain to be understood. The challenge now is to reconcile the regulatory complexity in this pathway with the complexity of responses in which NF-B family members play important roles. In this review, we provide an overview of established NF-B signaling pathways with focus on the current state of research into the mechanisms that regulate IKK activation and NF-B transcriptional activity.

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…In mammalian cells, the NF-kB family is composed of five members: RelA(p65), RelB, c-Rel, p50/p105 (NF-kB1) and p52/ p100 (NF-kB2) (Gilmore, 2006). The ability of these five members to form a variety of homo-and heterodimers and, ultimately, to differentially control gene expression is regulated by signals elicited by bacterial products, cytokines, viral expression, growth factors and stress stimuli (reviewed by Hayden and Ghosh, 2004).…”

“…Upon stimulation, the IKK complex phosphorylates the IkB proteins, which then undergo rapid ubiquitination and proteasome-mediated degradation, which culminates in the release of the NF-kB complexes from their inhibitory interaction (see Scheidereit, 2006). The released complexes then accumulate in the nucleus, where they bind to target DNA sequences and regulate the expression of genes involved in the immune response, cell growth control and the regulation of cell survival (Hayden and Ghosh, 2004).…”

“…It should be noted that in addition to the wellcharacterized mechanisms of negative and positive regulation of NF-kB described above, other pathways involving different kinases, such as NF-kB-inducing kinase (NIK) and IKKe, can also lead to NF-kB activation through alternative pathways (Hayden and Ghosh, 2004;Adli and Baldwin, 2006). In addition, a variety of post-translational modifications of the NF-kB subunits or signaling components can also modulate the strength and duration of the NF-kB signal (Perkins, 2006).…”

Mutations in the NF-κB signaling pathway: implications for human disease

“…Activation of the NF-kB signaling pathway is regulated at several levels (see Hayden and Ghosh, 2004;Gilmore, 2006, this issue). Nevertheless, it is still clear that the primary regulation of the NF-kB pathway is through the association of NF-kB complexes with IkB inhibitor proteins.…”

Copine-I represses NF-κB transcription by endoproteolysis of p65

“…NF-kB is sequestered in the cytoplasm by the inhibitory protein, IkB. Upon cellular stimulation, signaling cascades are initiated that converge on the IkB kinase (IKK) complex (Hayden and Ghosh, 2004). This kinase complex phosphorylates IkB, leading to its polyubiquitination by the SCF-type E3 ligase, E3RS IkB/b-TrCP and subsequent degradation by the 26S proteosome (Karin and Ben Neriah, 2000).…”