New apoptotic complex of MK2-FADD-caspase-10 in mitochondrial cell death

다국어 초록 (Multilingual Abstract)

Mitochondrial proteins play regulatory roles in cell death after release into cytosol. Here we show that mitochondrial kinase 2(MK2) is a pro-apoptotic molecule exhibiting cytosolic translocation during cell death. Down-regulation of MK2 expression attenuated the cytotoxic drug-mediated cell death. MK2 binds to the death domain of FADD(Fas-associated protein with death domain) in vitro and in vivo after release from mitochondria during mitochondrial apoptosis. Forced expression of cytosolic MK2 is potent to induce cell death, which is blocked in FADD- or caspase-10-deficient cells, but not in caspase-8-deficient cells. The pro-apoptotic activity of MK2 is not associated with its enzymatic activity of adjusting adenine nucleotide composition but retained in the middle region of MK2. MK2 seems to dephosphorylate FADD in vitro and in vivo. Interestingly, in vitro incubation of MK2 protein with S100 HeLa cell extract induces caspase-10 activation followed by the activation of caspase-9 and-3. MK2 forms intracellular complexes with caspase-10 and FADD, and ectopic expression of MK2 leads to cell death of Apaf-1 knock-out EF cells, but not caspase-10 knock-down cells. Expression of MK2 is down-regulated in liver tumors. Taken together, these results elucidate a novel atypical mitochondrial apoptotic pathway employing MK2-FADD-caspase-10. In addition, cell-based gene high throughput screening we have performed to isolate tumor cell death will be discussed.