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TNF Superfamily Regulators

TNF superfamily receptors signal through multiple adaptor proteins including TNF receptor-associated factors (TRAFs) and death domain-containing proteins. TRAFs are a family of intracellular adaptor proteins that are defined by the presence of a TRAF domain. There are currently seven known TRAF family members (TRAF-1-7), but only TRAF-1, TRAF-2, TRAF-3, TRAF-5, and TRAF-6 have been shown to mediate TNF superfamily signaling. Signaling pathways activated downstream of the TRAF-associated TNF superfamily receptors include the Akt signaling pathway, MAP kinase signaling pathways, and both the canonical and non-canonical NF-kappa B signaling pathways. These pathways promote differentiation, proliferation, and survival in a context- and cell type-specific manner. Other TNF superfamily receptors contain intracellular death domains and recruit death domain-containing adaptor proteins such as TRADD, FADD, and RIP1 upon receptor activation. These proteins mediate the recruitment of pro-caspases to initiate the extrinsic pathway of caspase activation and apoptosis. A number of other endogenous and virally-encoded proteins can also modulate TNF superfamily signaling and activity including multiple decoy receptors, which bind and sequester TNF superfamily ligands but do not initiate intracellular signaling.