Cell death receptors

In addition to structural roles, it is becoming increasingly apparent that a major function of IFs is to regulate the activities of cell metabolism, by serving as scaffolding for the dynamic regulation of associated proteins such as enzymes, signaling adapter molecules, stress proteins, cell death receptors, and even the endocytic machinery. 

At present, there are two relatively well-characterized cell death pathways that result in the activation of executioner caspases (Figure 2). One is receptor-mediated and the other is mitochondrial-dependent. On receiving an apoptotic stimulus, the receptor-depen-dent pathway is initiated by activation of cell death receptors such as Fas and tumor necrosis factor. The death receptor stimulation results in the formation of a death inducing signaling complex (DISC) that recruits and activates procaspase-8, which in turn cleaves and... 

There is also crosstalk between the two pathways above the mitochondria. The BH3-only protein BID is cleaved by caspase-8 and -10 which yields truncated BID (tBED), the active pro-apoptotic fragment of BID. Thereby, even in cells in which the direct apoptosis pathway which result from death receptor crosslinking is blocked, e.g. by high expression levels ofthex-linked IAP (XIAP), the activity of tBED on mitochondria can result in the activation of caspase-3 because the IAP-imposed block on full caspase-3 activation and caspase-9 activity at the apoptosome is released by Smac/ DIABLO. 

GPR4 Ovarian cancer G protein-coupled receptor 1 (OGR1, GPR68) T cell death-associated gene 8 (TDAG8, GPR65)... 

Radu CG, Cheng D, Nijagal A et al (2006) Normal immune development and glucocorticoid-induced thymocyte apoptosis in mice deficient for the T-cell death-associated gene 8 receptor. Mol Cell Biol 26 668-677... 

Two main apoptotic pathways have been identified in mammalian cells the extrinsic pathway that is activated by the binding of ligands to cell-surface death receptors, and the intrinsic pathway that involves the mitochondrial release of cytochrome cP The activation of extrinsic and intrinsic apoptotic pathways promotes the cleavage into the active form of the pro-caspase-8 and pro-caspase-9, respectively, that mainly determine the activation of effector caspase-3. ° The intrinsic pathway is the main apoptotic pathway activated by chemotherapeutic drugs, while the cytotoxic drug-induced activation of the extrinsic pathway is a more controversial issue. ... 

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