e canonical Nf-kB signaling. In response to a subset of activated receptors of the tumor necrosis superfamily, the non-canonical Nf-kB signaling is triggered in a localized manner. The mammalian NF-kB family of transcription factors is composed of five members that can form homo- or heterodimers. The five components are RelA (p65), Rel (c-Rel), RelB, Nfkb1 and Nfkb2 and they all share the Rel homology domain (RHB), important for dimerization and DNA binding; a subset possess the transactivation domain. Nfkb1 and 2, which do not have the transactivation domain, are present as pro-forms - p105 and p100, respectively; their proteolytic processing giving rise to the active p50 and p52 forms (click to see a p65/p50 heterodimer in complex with DNA. In the basal state, dimers are kept inactive through their association to the inhibitory IkB proteins. The three members - alpha, beta and epsilon have ankyrin repeat domains (ARD) that interact with the DNA binding domain of Nf-kB proteins and sequester them in the cytoplasm (click the see a NF-kB dimer in complex with the ARD domain of alpha protein). Activation of the IKK complex is necessary for the stimulation of both the canonical and the non-canonical Nf-kB signaling. The IKK complex is composed of two kinases - Ikbka known as Chuck and Ikbkb, and the regulatory subunit Ikbkg known as NEMO. In the canonical (classical) NF-kB pathway, activation of Ikbkb/Ikbkg leads to phosphorylation of the inhibitory IkBs, best exemplified by Nfkbia (alpha member). Phosphorylated Nfkbia is targeted for degradation by the SCF ubiquitin complex. The released NF-kB dimers, primarily the RelA(p65)/Nfkb1(p50) complex, translocates to the nucleus to induce the activation target genes. Amongst them is Nfkbia which thus provides a negative regulatory feedback loop. The non-canonical (alternative) pathway is dependent on Map3k14 (Nik - NF-kB inducing kinase) upstream of IKK complex and is independent of Ikbkg (Nemo). Map3k14 phosphorylates and activates Chuk which then phosphorylates Nfkb2 (p100) leading to its processing to the p52 form. The Nfkb2(p52)/RelB complex then translocates to the nucleus. Activation of the IKK complex in the canonical Nf-kB signaling, is dependent upon activation of Map3k7 known as Tak1 by all three upstream pathways. Activated Tak1 phosphorylates and activates Ikbkb. In addition to phosphorylation, ubiquitination plays an essential role in the activation of Tak1 and of Nf-kB pathway. K63-linked ubiquitination by and of components of Il-1 and Toll-like receptor pathways and linear M1-linked ubiquitination by LUBAC complex of Tnf pathway components play important roles in the activation of Tak1 upstream of IKK. Tak1 is in a complex with Tab adaptor proteins - the interaction with Tab1 possibly promotes the kinase autophosphorylation (click to see a Tak1-Tab1 complex). Tab2 and 3 have ubiquitin binding domains and recruitment of K63-linked ubiquitin chain further activate the kinase (click to see Tab2 in complex with ubiquitin). LUBAC also ubiquitinates Ikbkg (NEMO), possibly the mechanism underlying its requirement for the activation of IKK (click to see the PDB entry for a NEMO domain in complex with linear ubiquitin). Deubiquitinases (DUB) such as the A20 editing complex and/or Cyld revert/modulate this post-translational modification acting as negative regulators of Nf-kB signaling mostly targeting upstream elements. Cyld removes ubiquitin from and/or inhibits ubiquitination of Ripk1; it also antagonizes ubiquitination of traf2 and the regulatory Ikbkg (Nemo). Various microRNAs (miRNAs) are targets of NF-kB and some are also providing feedback mechanisms either targeting NF-kB directly or upstream signals. Deregulated Nf-kB signaling is observed in several conditions associated with chronic inflammation as well as cancer. To see the ontology report for annotations, GViewer and download, click here...(less)