Major Apoptotic pathways

Major Apoptotic pathways. The extrinsic pathway is driven by Fas-type death receptors. Upon engagement with their ligands, these receptors trimerize and the death adaptor protein FADD is recruited to the intracellular death domain of Fas. FADD then recruits pro-capsase-8 into this complex completing the formation of the death-inducing signaling complex (DISC). The induced juxtaposition of pro-caspase-8 results in autocatalytic cleavage and activation of caspase-8. Caspase-8 then dissociates from the receptor and enters the cytoplasm to initiate the cleavage other caspases or cellular proteins. The intrinsic pathway (activated by cytotoxic drugs, radiation or reactive oxygen species) involves the damage of mitochondrion. The Bcl2 and Bax proteins counteract each other in steady sate. Signal-induced rise in Bax and/or dissociation of Bcl2:Bax complex by Bak results in the formation of Bax:Bax or Bax:Bak oligomers, which insert into the mitochondrial membrane and open permeability transition pores (PTP). This leads to the release of many apoptotic inducing factors such as AIF, HtrA2, Endonuclease G (EndoG), Smac/Diablo and cytochrome-c. Cytochrome-c associates with apoptosis-activating factor-1 (APAF1) and pro-caspase-9 leading to formation of ‘Apoptosome’. Activated caspase-9 from this complex activates other caspases, which dismantle the cellular proteins required for viability. Although thought to operate independently, in some cell types, the intrinsic and extrinsic pathways cross regulate each other. In these scenarios, caspase-8 from the DISC cleaves the pro-apoptotic Bcl2-like protein, Bid, to generate a truncated version, t-Bid. The latter causes mitochondrial damage, which amplifies the apoptotic response through the formation of Apoptosome. A number of proteins in this pathway are controlled by IFNs and other cytokines.

Publication

Cytokine-induced tumor suppressors: a GRIM story. () Dhan V Kalvakolanu, et al. Cytokine. ;52(1-2):128-142. Figure: F1. Homo sapiens

Disease mentions