TRAF2-Mediated Activation of NF-κB by TNF Receptor 2 and CD40

Abstract

TNF receptor-associated factor (TRAF) proteins are candidate signal transducers that associate with the cytoplasmic domains of members of the tumor necrosis factor (TNF) receptor superfamily. The role of TRAFs in the TNF-R2 and CD40 signal transduction pathways, which result in the activation of transcription factor NF-kappa B, was investigated. Overexpression of TRAF2, but not TRAF1 or TRAF3, was sufficient to induce NF-kappa B activation. A truncated derivative of TRAF2 lacking an amino-terminal RING finger domain was a dominant-negative inhibitor of NF-kappa B activation mediated by TNF-R2 and CD40. Thus, TRAF2 is a common mediator of TNF-R2 and CD40 signaling.

From receptors to stress-activated MAP kinases

“…Overexpression studies have implicated TRAF2 in TNF-induced activation of JNK, p38 and NF-kB (Rothe et al, 1995a;Hsu et al, 1996b;Liu et al, 1996;Takeuchi et al, 1996;Natoli et al, 1997;Reinhard et al, 1997). NF-kB-inducing kinase (NIK; note: di erent from MAPKKKK NIK noted above) is a MAPKKK-related protein kinase that associates with TRAF2 and other members of the TRAF family and mediates activation of NF-kB through IKKs but does not activate JNK or p38 (Song et al, 1997).…”

“…Despite the absence of structural similarities between TNF and IL-1b receptors, ligand-induced activation of these receptors leads to overlapping, albeit non-identical, biological functions. One of the important as well as common events triggered by most of these in¯ammatory cytokine receptors is the activation of mitogenactivated protein (MAP) kinases and IkB kinases (IKKs), which ultimately activate various transcription factors such as activator protein 1(AP-1) (Brenner et al, 1989) and nuclear factor-kB (NF-kB) (Rothe et al, 1995a;Baeuerle and Baltimore, 1996;.…”

MyD genes in negative growth control

“…IRAK then dissociates from the receptor complex and interacts with TRAF6, that is required for IL-1-induced NF-kB activation (Cao et al, 1996b). Two other TRAF (TNF-receptor associated factor) proteins, TRAF2 and TRAF5, have been implicated in NF-kB activation by the superfamily of TNF receptors (Aizawa et al, 1997; Duckett et al, 1997; Hsu et al, 1996aHsu et al, , 1997Ishida et al, 1996;Nakano et al, 1996;Rothe et al, 1995), indicating that IL-1 and TNF signaling converge at the level of TRAF molecules. The kinase cascade which is distal to TRAF, and is responsible for NF-kB activation, also has been elucidated.…”

Transmembrane TNF-α, induction of apoptosis, and the efficacy of TNF-targeting therapies in Crohn's disease

“…Both TNF receptors can activate the transcription factor nuclear factor B (NF B) that induces transcription of a wide range of genes involved in inflammation. 1,2 TNFRI is a member of a family of death receptors that share a death domain that initiates programmed cell death (apoptosis). However, TNF receptor-mediated nuclear translocation of NF B protects against apoptosis, 3,4 and thus activation of TNFRI may both induce and prevent apoptosis, depending on the type and activation state of the cell.…”

“…T he management of duodenal polyps in patients with familial adenomatous polyposis (FAP) is one of the most challenging issues for clinicians. In 1981, Theodore et al 1 queried the approach to ampullary adenomas in patients with Gardner's syndrome: "What can we suggest to our 3 patients? A regular endoscopic examination with the risk of diagnosing a cancer of the ampulla too late?…”