Caspase-2 primes cancer cells for TRAIL-mediated apoptosis by processing procaspase-8.
Although caspase-2 is believed to be involved in death receptor-mediated apoptosis, the exact function, mode of activation, and regulation of caspase-2 remain unknown. Here we show that protein kinase (PK) CK2 phosphorylates procaspase-2 directly at serine-157. When intracellular PKCK2 activity is low or downregulated by specific inhibitors, procaspase-2 is dephosphorylated, dimerized, and activated in a PIDDosome-independent manner. The activated caspase-2 then processes procaspase-8 monomers between the large and small subunits, thereby priming cancer cells for TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The processed procaspase-8 that is recruited to death-inducing signaling complex by TRAIL engagement becomes fully activated, and cancer cells undergo apoptosis. PKCK2 activity is low in TRAIL-sensitive cancer cell lines but high in TRAIL-resistant cancer cell lines. Thus, downregulating PKCK2 activity is required for TRAIL-mediated apoptosis to occur in TRAIL-resistant cancer cells. Our data provide novel insights into the regulation, mode of activation, and function of caspase-2 in TRAIL-mediated apoptosis.
Shin
Soonah
S
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Brain Korea 21 Project for Medical Science of Yonsei University, Seodaemun-gu, Seoul, Korea.
Lee
Yoonmi
Y
Kim
Wooseok
W
Ko
Hyeonseok
H
Choi
Hyeyeon
H
Kim
Kunhong
K
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053143:Caspase 2; D053181:Caspase 8; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019281:Dimerization; D004789:Enzyme Activation; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology; D009369:Neoplasms / Q000201:enzymology*; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D012694:Serine; D047390:Casein Kinase II; C505530:CASP8 protein, human; D053143:Caspase 2; D053181:Caspase 8; D020169:Caspases