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NF-κB Signaling

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NF-κB Signaling

Pathway Description:

Nuclear factor-κB (NF-κB)/Rel proteins include NF-κB2 p52/p100, NF-κB1 p50/p105, c-Rel, RelA/p65, and RelB. These proteins function as dimeric transcription factors that regulate the expression of genes influencing a broad range of biological processes including innate and adaptive immunity, inflammation, stress responses, B-cell development, and lymphoid organogenesis. In the classical (or canonical) pathway, NF-κB/Rel proteins are bound and inhibited by IκB proteins. Proinflammatory cytokines, LPS, growth factors, and antigen receptors activate an IKK complex (IKKβ, IKKα, and NEMO), which phosphorylates IκB proteins. Phosphorylation of IκB leads to its ubiquitination and proteasomal degradation, freeing NF-κB/Rel complexes. Active NF-κB/Rel complexes are further activated by post-translational modifications (phosphorylation, acetylation, glycosylation) and translocate to the nucleus where, either alone or in combination with other transcription factors including AP-1, Ets, and Stat, they induce target gene expression. In the alternative (or noncanonical) NF-κB pathway, NF-κB2 p100/RelB complexes are inactive in the cytoplasm. Signaling through a subset of receptors, including LTβR, CD40, and BR3, activates the kinase NIK, which in turn activates IKKα complexes that phosphorylate C-terminal residues in NF-κB2 p100. Phosphorylation of NF-κB2 p100 leads to its ubiquitination and proteasomal processing to NF-κB2 p52. This creates transcriptionally competent NF-κB p52/RelB complexes that translocate to the nucleus and induce target gene expression. Only a subset of NF-κB agonists and target genes are shown here.

Selected Reviews:

We would like to thank Prof. Thomas D. Gilmore, Boston University, Boston, MA, for contributing to this diagram.

created July 2009

revised May 2014

Acetylase
Acetylase
Metabolic Enzyme
Metabolic Enzyme
Adaptor
Adaptor
Methyltransferase or G-protein
Methyltransferase or G-protein
Adaptor
Apoptosis/Autophagy Regulator
Phosphatase
Phosphatase
Cell Cycle Regulator
Cell Cycle Regulator
Protein Complex
Protein Complex
Deacetylase or Cytoskeletal Protein
Deacetylase or Cytoskeletal Protein
Ubiquitin/SUMO Ligase or Deubiquitinase
Ubiquitin/SUMO Ligase or Deubiquitinase
Growth Factor/Cytokine/Development Protein
Growth Factor/Cytokine/Development Protein
Transcription Factor or Translation Factor
Transcription Factor or Translation Factor
GTPase/GAP/GEF
GTPase/GAP/GEF
Receptor
Receptor
Kinase
Kinase
Other
Other
 
Direct Process
Direct Process
Tentative Process
Tentative Process
Translocation Process
Translocation Process
Stimulatory Modification
Stimulatory Modification
Inhibitory Modification
Inhibitory Modification
Transcriptional Modification
Transcriptional Modification
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