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Figure 1.
Putative functions of caspase-2
Following double-strand DNA breaks (DSBs), the ataxia telangiectasia mutated (ATM) and ATM-related (ATR) kinases are activated and in turn phosphorylate and activate several target proteins, including checkpoint kinase 1 (Chk1) and Chk2. Chk2 activates the p53 response pathway, which can lead to cell cycle arrest. ATR activation leads to the activation of caspase-2 and apoptosis following irreparable DNA damage. ATR also activates Chk1, which can then act in a feedback loop to negatively regulate ATR and inhibit further activation of nuclear caspase-2. DNA-dependent protein kinase (DNA-PK) is also activated by DSBs, presumably by ATM/ATR, and forms a complex with p53-inducible protein with a death domain (PIDD) and caspase-2 (DNA-PK PIDDosome). This complex serves to phosphorylate and activate caspase-2, which is then required for the initiation of non-homologous end-joining (NHEJ) and DNA repair. Cytosolic caspase-2 is also activated by other stress signals such as reactive oxygen species (ROS), metabolic stress, cytotoxic drugs, heat shock, or endoplasmic reticulum (ER) stress. Following heat shock, RAIDD (receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain) can activate caspase-2, which is inhibited by HSP90α. Ca2+/calmodulin-dependent kinase II (CaMKII) acts to inhibit caspase-2 activation and cell death in oocytes. Activated cytosolic caspase-2 is able to cleave Bid to its truncated form (tBid), which (via Bax/Bak) can induce mitochondrial outer membrane permeability (MOMP), activation of caspase-9 and -3, and cell death. P, phosphorous; PUMA, p53-upregulated mediator of apoptosis. |
