Caspase Cascade
Apoptosis is a normal cellular process involving physiologically relevant cell death that is essential for cell selection, tissue homeostasis, morphogenesis, and host defense in multi-cellular organisms. Apoptosis is initiated and promoted by a wide variety of intra- and extra-cellular stimuli. It can be triggered by cell surface “death” receptors, by the action of the cytotoxic T-cell proteins granzyme-B and perforin or by an intrinsic pathway that involves the release of cytochrome C from the mitochondria (mitochondrial apoptosis).
Apoptotic signals are propagated by members of a family of regulated proteolytic enzymes called caspases. Caspases are aspartate-specific cysteine (interleukin-1beta converting enzyme/CED-3) proteases present in cells as inactive or low activity proenzymes (zymogens) that are sequentially activated to promote apoptosis. The caspases most often associated with apoptosis are caspases 2, 3, 6, 7, 8, 9 and 10. Caspase cascades are composed of upstream (initiator) caspases (caspase 2, caspase 8, caspase 10), which are activated by death receptor signalosomes (DISC); caspase 9, which is activated by the mitochondrial cytochrome C/Apaf-1 derived apoptosome; and downstream (effector) caspases (caspase 3, caspase 6, caspase 7) that cleave proteins involved in programmed cell death events.
Caspase 2, caspase 8 and caspase 10 are activated by death receptor signalosomes (death-inducing signaling complex (DISC)). In addition to activating caspase-3, caspase-6 or caspase-7 directly, caspases 8 or 10 activates pro-apoptotic factors such as BID that induce the release of cytochrome c from the mitochondria. Caspase 9 is activated by the mitochondrial release of cytochrome C. Cytosolic cytochrome c binds and induces oligomerization of apoptotic protease activating factor 1 (APAF-1) followed by recruitment of procaspase-9 to form an apoptosome. Apoptosome-associated procaspase-9 self-activates and then activates downstream caspase 3 and/or caspase 7.
The downstream executioner caspases (3,6,7) cleave: proteins involved with DNA processing such as DNA fragmentation factor (DFF-45); the DNA repair enzymes poly(ADP-ribose) polymerase (PARP); and DNA fragmentation factor 45 kDa subunit (ICAD); signaling molecules such as the Rho-GTPase GDP dissociation inhibitor (D4-GDI); enzymes protein kinase Cd (PKCd), cytosolic phospholipase A2 (cPLA2); sterol-regulatory element-binding proteins (SREBP); p21-activated kinase 2 (PAK2); and DNA-dependent protein kinase catalytic subunit (DNA-PKcs); and structural proteins such as a-fodrin, actin, and lamin.
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