Fig. 8.

Autocrine TNF signaling. Membrane-bound TNF (mTNF) is released from the plasma membrane by the protease TACE. Soluble (sTNF) or membrane-anchored TNF interacts with receptors of the TNF receptor (TNF-R) family. Interaction with death domain (DD)-containing receptors such as FAS, TRAIL-R1, and TRAIL-R2 recruits FADD and caspase-8 to the receptor and activates caspase-8. Other DD-containing receptors such as TNF-R1, DR3, and DR6 activate caspase-8 in a complex with TRADD. Conformational changes in the cytosolic domains of TNF-R1 induced by TNF binding release the inhibitory protein SODD from the cytosolic effector domains of the receptor. Binding of TRAF2 to the receptor TRADD complex either recruits cIAP to inhibit caspase-8 activation, or recruits IKK kinase and MAPKKKs such as ASK1 to activate NF-κB and the MAPK p38 and JNK. TRAF2-associated proteins such as RIP contribute to modulation of the outcome of TNF-R1 signaling. TNF-Rs with a cytosolic TRAF-interacting motif (TIM) domain directly associate with TRAF2 to activate IKK, p38, and JNK. TNF-R2 is preferentially activated by mTNF. Decoy receptors lack cytosolic effector domains and inhibit TNF signaling (Dempsey et al. 2003; Wajant and Scheurich 2001). Abbreviation: DED—Death effector domain