ously expressed in most tissues. The extracellular domain of Tnf receptors are characterized by the presence of CCGs (Cysteine-rich domain) that contribute to the specific ligand-receptor interaction. Tnf, a type II transmembrane protein is processed by Adam17 (known as Tace - Tnf alpha converting enzyme). Binding of soluble, trimeric Tnf to the receptor triggers the trimerization of the receptor and the release of the inhibitory Bag4 protein (known as Sodd) from the receptor intracellular domain. The exposure of the hitherto masked DD (death domain) of the receptor allows for interactions with other DD containing proteins. Tradd uses its DD domain to bind to the Tnf-R1 complex where it acts as a scaffold to recruit Traf proteins and Fadd. A Tradd-Traf2 complex shows a 3:3 stoichiometry (click to see a crystal structure of Tradd-Traf complex). Recruitment of Traf2 and possibly Traf5, and of Birc2 and 3, known as c-Iap1 and 2, respectively results in a receptor signaling complex that leads to the recruitment and activation of Ripk1 (there is no Traf5 rat gene, human shown). Traf and Birc proteins are E3 ubiquitin ligases involved in the synthesis and attachment of K63-linked polyubiquitin chains; Birc enzymes may also promote K11-linked ubiquitination. Recruitment and ubiquitination of Ripk1 activates this kinase which then activates Map3k7, known as Tak1. Tak1, activated by Tnf signaling and also by interleukin-1 and Toll-like receptors pathways, phosphorylates components of the IKK complex which then activates signaling by Nuclear Factor kappa B (NF-kB). Tak1 is in a complex with Tab adaptor proteins - the interaction with Tab1 possibly promotes the kinase autophosphorylation (click to see a Tak1-Tab complex). Tab2 and 3 have ubiquitin binding domains and recruitment of K63-linked ubiquitin chain further activate the kinase (click to see a Tab2-ubiquitin complex). The multi-protein Tnf-R1 associated complex also recruits LUBAC - a protein complex with E3 ligase activity that is involved in the synthesis and attachment of linear M1-linked ubiquitin chains. LUBAC ubiquitinates Ripk1 as well as the regulatory subunit of the IKK complex. Deubiquitinases (DUB) such as the A20 editing complex and Cyld revert/modulate this post-translational modification acting as negative regulators of Tnf signaling and of NF-kB, downstream of it. Cyld removes ubiquitin from and/or inhibits ubiquitination of Ripk1. A20 does not have strong DUB activity for K63 ubiquitin but promotes K48-linked ubiquitination of Ripk1 and also inhibits the interaction of E3 ligases Traf and Birc with their E2 partners thus preventing the ubiquitination and activation of Ripk1. K48-ubiquitination of proteins targets them for proteasomal degradation. Tradd can also form a complex with Fadd and procaspase-8; processing of procaspase to its mature Casp8 can trigger the extrinsic apoptotic pathway. However, in vivo Tnf-mediated apoptosis appears to play a minor role. While Nf-kB is a major pathway activated by Tnf signaling, other pathways such as p38 and c-Jun N terminal kinase (Jnk) MAPK signaling can be activated downstream of Traf2 and Ripk1; Map3k7 is one of the MAPKKKs for the two pathways. Members of Traf and/or Rip families play a role in Nf-KB pathway stimulation downstream of receptors other than Tnfrfs1. Of note is the role of Traf3 which negatively regulates Map3k14 (also known as Nik) - not shown. Upon activation of a subset of tumor receptor superfamily, Traf3 is signal-dependent degraded. This event leads to the activation of Map3k14 and subsequent activation of Ikk alpha component which triggers the non-canonical or alternative NF-kB pathway. Tnf promotes inflammatory responses and deregulation of the pathway has been associated with several autoimmune disorders. To see the ontology report for annotations, Gviewer and download, click here [click to see the ontology report for associated GO term GO:0033209 and entry at Reactome - REACT_1432.1]...(less)