regulation of canonical NF-kappaB signal transduction

Definition

Target type: biologicalprocess

Any process that modulates the canonical NF-kappaB signaling cascade. [GOC:jl, PMID:12773372]

The canonical NF-κB signaling pathway is a critical regulator of cellular processes, including inflammation, immunity, and cell survival. It is a complex cascade of events that begins with the activation of the IκB kinase (IKK) complex, which phosphorylates the inhibitor of NF-κB (IκB) protein. Phosphorylation of IκB leads to its ubiquitination and degradation by the proteasome, releasing NF-κB. NF-κB then translocates to the nucleus, where it binds to specific DNA sequences called κB sites and activates the transcription of target genes.

The canonical NF-κB pathway is activated by a variety of stimuli, including pro-inflammatory cytokines (TNF-α, IL-1β), pathogen-associated molecular patterns (PAMPs), and stress signals (UV radiation, oxidative stress). These stimuli activate a cascade of signaling molecules, ultimately leading to the activation of the IKK complex.

The IKK complex is a trimeric protein complex consisting of IKKα, IKKβ, and NEMO (NF-κB essential modulator). Activation of the IKK complex is triggered by the phosphorylation of its catalytic subunits, IKKα and IKKβ. This phosphorylation is mediated by upstream kinases such as TAK1 (transforming growth factor-β-activated kinase 1) and RIP1 (receptor-interacting protein 1), which are themselves activated by different signaling pathways.

Once activated, the IKK complex phosphorylates IκB, which is a family of proteins that bind to and sequester NF-κB in the cytoplasm, preventing its nuclear translocation. Phosphorylation of IκB leads to its polyubiquitination by an E3 ligase complex called SCFβ-TrCP. Polyubiquitination targets IκB for degradation by the proteasome, a cellular machine that degrades proteins.

The degradation of IκB releases NF-κB, allowing it to translocate to the nucleus. NF-κB is a heterodimer consisting of two subunits, typically p50 and p65 (RelA). NF-κB dimers bind to specific DNA sequences called κB sites in the promoter regions of target genes. Once bound, NF-κB activates the transcription of these genes, leading to the production of proteins involved in various cellular processes, such as inflammation, immunity, cell survival, and proliferation.

The regulation of the NF-κB pathway is crucial for maintaining cellular homeostasis and preventing aberrant activation that can lead to chronic inflammation and disease. Several mechanisms are in place to tightly control NF-κB activity, including negative feedback loops, deubiquitinating enzymes, and protein phosphatases. These mechanisms ensure that NF-κB activation is transient and specific to the appropriate stimuli.'
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Proteins (7)

Compounds (148)