Description

Tumor necrosis factor (Tnf or Tnfa) signaling pathway plays pivotal roles in immunity, cell proliferation, differentiation and apoptosis through the activation of several downstream signaling cascades. Tumor necrosis factor and its receptors Tnfrsf1a and Tnfrsf1b (Tnfr1 and Tnfr2) belong to the tumor necrosis superfamilies of ligands and receptors of which 19 and 29 members have been so far identified in humans, respectively. Tnf signaling occurs primarily via Tnfrsf1a receptor (receptor 1), ubiquitously expressed in most tissues. The extracellular domain of Tnf receptors are characterized by the presence of cysteine-rich domains (CRD) 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 death domain (DD) 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 Fadd, Traf2 and Ripk (known as Rip1), followed by the activation of various downstream signaling pathways. Traf2, and possibly Traf5, along with Ripk are essential for the activation of the Ikb kinase (Ikk) complex. Ikk complex is the core upstream component of the Nuclear Factor Kappa B (NF-kB) signaling pathway. The Traf2/Ripk combination is essential for Ikk stimulation of the canonical or classical Nf-kB pathway. Members of Traf and/or Rip families play a role in Nf-KB pathway stimulation downstream of receptors other than Tnfr1. Of note is the role of Traf3 which negatively regulates Map3k14 (also known as Nik). 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. While NF-kB is the major pathway activated by Tnf signaling, other pathways such as c-Jun N-terminal kinase (Jnk) or p38-MAPK downstream of Traf2 and Rip1, or apoptosis downstream of Fadd, are also activated.

 

Abbreviations
Tnf – tumor necrosis factor
Tnfrsf1a – tumor necrosis factor receptor superfamily, member 1a (Tnfr1 - tumor necrosis factor receptor 1)
Tnfrsf1b – tumor necrosis factor receptor superfamily, member 1b (Tnfr2 - tumor necrosis factor receptor 2)
Adam17 – a disintegrin and metallopeptidase domain 17 (Tace – Tnf alpha converting enzyme)
Bag4 – Bcl2-associated athanogene 4 (Sodd – silencer of death domain)
Tradd – TNFRSF1A-associated via death domain
Fadd – Fas (TNFRSF6)-associated via death domain
Traf – TNF receptor-associated factor
Ripk1 – receptor (TNFRSF)-interacting serine-threonine kinase1 (Rip1 – receptor interacting protein)
Ikk – inhibitor of kappaB kinase

References
PMID:11239407, 11796220, 12655295, 15371334, 17510296,  18068998, 18267068

Import into Pathway Studio

tumor necrosis factor signaling pathway.gpp