Activation of NF-kB complex Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.11 NF-kB is a family of transcription factors that play pivotal roles in immune, inflammatory, and antiapoptotic responses. NF-kB/Rel family include five members, p65 (RelA), RelB, c-Rel, p50/p105 (NF-kB1) and p52/p100 (NF-kB2), exist in unstimulated cells as homo or heterodimers. NF-kB is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called IkBs, which mask the nuclear localization signal of NF-kB and prevent its nuclear translocation. Various stimuli induce the activation of the IkB kinase (IKK) complex, which then phosphorylates IkBs. The phosphorylated IkBs are ubiquitinated and then degraded through the proteasome-mediated pathway. The degradation of IkBs releases NF-kB to translocate into nucleus and induces the expression of various genes. <br>The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kB signaling pathway, the activated IKK complex, predominantly acting through IKK beta in an IKK gamma-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkB-alpha or Ser19 and Ser22 of IkB-beta), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkB-alpha) and subsequent degradation by the 26S proteasome. The K-48 ubiquitination is mediated by the E2 ubiquitin ligases (or SCFs) formed by three subunits: Skp1, Cul A (Cdc53), and one of many F-box proteins. Pubmed15145317 Pubmed15371334 Pubmed17363905 Pubmed9252186 Reactome Database ID Release 43202541 Reactome, http://www.reactome.org ReactomeREACT_12399 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 has a Stoichiometric coefficient of 2 IkB(alpha):NF-kB complex NF-kB complex