he major death ligands activating the extrinsic apoptotic pathway. Note that the primary role of Tnf is pro-inflammatory and pro-growth via downstream activation of Nuclear Factor Kappa B signaling. If NF-kB is not activated, the formation of a second complex can trigger Tnf mediated apoptosis. However, in vivo Tnf-mediated apoptosis appears to play a minor role. The receptors contain an extracellular CCG (cysteine rich domain) that plays a role in the interaction with ligands, and a cytoplasmic DD (death domain) involved in receptor-adapter interactions. Assembly of a trimeric ligand-receptor complex and subsequent receptor-adapter interactions, result in the formation of DISC (death-inducing signaling complex). Fadd, the major adapter molecule, via its second functional domain DED (death effector domain) recruits the initiator caspase Casp8 and when present, Casp10 to the DISC where they are activated. Note that in the case of Tnf mediated apoptosis, the receptor is indirectly linked to Fadd via Tradd. Like Fadd, Casp8 and 10 posses a DED domain. Casp9, the initiator caspase of the intrinsic apoptotic pathway possesses a CARD (caspase recruitment domain); of note is that the three domains DD, DED and CARD adopt a similar structural fold. The molecular mechanism of caspase activation at the DISC is not well understood; three models currently attempt to explain it. Activated Casp8 can then activate the effector/executioner caspases; this is the case of type I cells. In type II cells, amplification via the intrinsic, mitochondrial pathway is necessary for full activation of the executioner caspases. In this case, activated Casp8 cleaves Bid to the active t-Bid form. Bid is a member of the pro-apoptotic BH3-only group of the Bcl family. Cflar protein (known as Flip) can also be recruited to the DISC where it antagonizes the activation of Casp8. DED-DED interactions mediate the recruitment; the inhibition is thought to be due to competition for Fadd binding. There are several Cflar variants resulting from alternative mRNA splicing of which three are expressed at the protein level. While the anti-apoptotic effect is well documented, a pro-apoptotic function for one of the variants has been observed for the FasL system, under certain conditions. The receptors and other members of DISC are subject to several types of post-translational modifications that modulate their function. The role of lipid rafts and protein clustering in the formation of an active DISC have been documented for the FasL system. FasL and Trail can also elicit noncytotoxic signals; how these other pathways enfold is currently being investigated. The major components and steps of the extrinsic apoptotic pathways have been established but much remains to be determined regarding their fine-tuning and individual details....(less)