XB-IMG-138134
Xenbase Image ID: 138134
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FIG. 1. Scheme of the vertebrate apoptotic pathway. In a viable cell, the proapoptotic proteins Bax and Bak of the B-cell lymphoma 2
(Bcl2) family are repressed by the antiapoptotic proteins Bcl2, Mcl1 and BclXL. Proapoptotic stimuli such as cytokine deprivation or endoplasmic
reticulum stress trigger the induction of the BH3-only proteins. BH3-only proteins counteract the effect of Bcl2 and Bcl-XL, a process
that leads to the release of Bax and Bak. Bax and Bak are then inserted and activated at the outer mitochondrial membrane where
they promote the formation of pores. A key event in the induction of death is the release of cytochrome c and SMAC/Diablo from the mitochondrial
intermembranous space to the cytoplasm. SMAC/Diablo inhibits the IAP proteins, whereas cytochrome c recruits APAF-1 to form
the apoptosome. Caspase-9 is activated by the apoptosome that leads to the cleavage of the effector caspases, caspase-3 and caspase-
7, and to irreversible death. In parallel to this intrinsic pathway, the stimulation of death receptors leads to the recruitment of the adaptor
proteins such as TRADD and FADD through their death domain. Caspase-8 is then recruited to the membrane dimerizes and can directly
activate caspase-3 and caspase-7. Crosstalk between the extrinsic and the intrinsic pathway depends on the caspase-8 cleavage of the
BH3-only protein BH3-interacting domain death agonist BID. The product of this cleavage t-BID (truncated BID) inhibits Bcl2, Mcl1 and
Bcl-XL and promotes the accumulation of Bax and Bak. Both pathways can be activated through p53 stimulation resulting from DNA damage.
Another pathway is linked to the absence of the survival factor Shh that leads to the stimulation of the proapoptotic function of its
receptor patched. In the absence of its ligand, patched forms a protein complex with the adaptor protein DRAL (downregulated in rhabomuosarcoma
LIM-domain protein) and one caspase recruitment (CARD)-domain containing protein, either TUCAN (family member, 8) or
NALP (NLR family, pyrin domain containing 1). Apical caspase-9 is then recruited to this complex and activated by patched, which leads to
activation of the effector caspases. Image published in: Juraver-Geslin HA and Durand BC (2015) Copyright © 2015. Image reproduced with permission of the Publisher, John Wiley & Sons. Larger Image Printer Friendly View |