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Immunol Rev. 2009 Mar;228(1):225-40. doi: 10.1111/j.1600-065X.2008.00755.x.

TNFR signaling: ubiquitin-conjugated TRAFfic signals control stop-and-go for MAPK signaling complexes.

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Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093-0723, USA.


Nearly two decades after the initial cloning and identification of the founding father of the tumor necrosis factor receptor (TNFR) family, much has been learned about the mechanisms by which these receptors signal to critical transcription factors and other targets that regulate gene expression and cellular physiology. Mitogen-activated protein kinases (MAPKs) and inhibitor of nuclear factor (NF)-kappaB (I kappaB) kinases (IKKs) were identified early on as the upstream kinases responsible for activation of activator-protein 1 (AP-1) and NF-kappaB, respectively, and later on for their ability to control life-or-death decisions in TNF-stimulated cells. Both of these critical pathways are regulated at the level of MAPK kinase kinases (MAP3Ks), after which point they diverge. Recent work, however, illustrates that protein ubiquitination cascades play a critical initiating role in TNFR signaling and account for spatial and temporal separation of IKK and MAPK signaling cascades and thereby determine biological specificity and outcome. Cellular inhibitors of apoptosis (cIAPs) 1 and 2 are ubiquitin (Ub) ligases (E3s) that mediate canonical Lys48-linked ubiquitination of TNFR-associated factor 3 (TRAF3), marking it for subsequent degradation by the proteasome. TRAF3 degradation releases the brake on TRAF2/6:MAP3K signaling complexes responsible for MAPK activation, leading to their translocation from the cytoplasmic segment of the receptor to the cytosol where they initiate MAPK phosphorylation and activation. By contrast, IKK activation proceeds considerably faster than MAPK activation, takes place at the receptor, and is independent of cIAP1/2 activity and TRAF3 degradation. This arrangement may be important for ensuring the proper delivery of NF-kappaB-dependent survival signals and conversion of JNK-promoted death signals to proliferative ones.

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