Fig. (1).

TRAIL signaling pathway and regulatory proteins. Binding of the TRAIL ligand to TRAIL-R1 or TRAIL-R2 (1) induces the recruitment of FADD and caspase-8 to these receptors, forming the membrane DISC or complex I (2), in which pro-caspase-8 is activated, leading to the release of the active caspase-8 in the cytosol (3) and allowing the engagement of the apoptotic cascade (4). The mitochondrial amplification loop (5) can be required in some cells to induce the activation of the effector caspase-3. A second complex has recently been described (6), which induces activation of survival signaling pathways leading to transcription factors, which can result in cytokine secretion and increase levels of the inhibitory protein c-FLIP. Regulatory processes of the TRAIL pathway can be divided into three groups: receptor level, proximal, and distal regulation. Inhibitory proteins are shown in red.