Fas/FasL-mediated apoptosis. (A) Binding of 3 FasL molecules with Fas leads to cell surface oligomerization, recruitment of the adapter protein FADD (Fas-associated protein with death domain), and procaspase-8 via its death effector domain (DED) into a death-inducing signaling complex (DISC). Activation of procaspase-8 by autocatalysis results in the initiation of extrinsic apoptosis by converting inactive effector procaspases-3, -6, and -7 into active enzymes via transproteolysis and intrinsic apoptosis via cleavage of Bid, release of cytochrome c, and activation of caspase-9 (not shown). (B) FasL is synthesized and stored as a membranous protein in vesicles by selected cell types. Upon activation by various physiologic stimuli, these vesicles are excreted from the cell and cause apoptosis of Fas-positive cells. (C) Wild-type FasL is cleaved from the cell surface by matrix metalloproteinases (MMPs) and accumulates as a soluble protein (sFasL). (D) sFasL may transiently interact with proteins on the cell surface or the extracellular matrix (ECM) to form oligomeric structures with apoptotic activity. (E) sFasL as a soluble homotrimer cannot induce oligomerization of Fas and as such blocks apoptosis by competing with the membranous form for Fas binding.