A caspase-8-independent signaling pathway activated by Fas ligation leads to exposure of the Bak N terminus.
Bak is a pro-apoptotic member of the Bcl-2 family that is activated by apoptotic stimulation: its activation is characterized by conformational changes such as exposure of the N terminus and oligomerization. In death receptor-mediated apoptosis, the activation of Bak depends on activation of caspase-8. However, we found that exposure of the N terminus of Bak (but not oligomerization) can occur in the absence of active caspase-8. Although exposure of the N terminus of Bak without oligomerization is not sufficient to release cytochrome c from the mitochondria and commit cells to apoptosis, this change sensitizes the mitochondria to apoptotic signals (including Bid) and thus sensitizes cells to apoptotic death. Fas-induced, caspase-8-independent exposure of the N terminus of Bak is blocked by staurosporine, a pan protein kinase inhibitor. These results suggest that Fas stimulation not only activates caspase-8, but also a distinct signaling pathway involving protein kinase(s) to induce exposure of the N terminus of Bak.
Zhang
Lilin
L
Laboratory of Molecular Genetics, Department of Post-Genomics and Diseases, Osaka University Medical School and Solution-Oriented Research for Science and Technology, Japan Science and Technology Corp., 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Shimizu
Shigeomi
S
Sakamaki
Kazuhiro
K
Yonehara
Shin
S
Tsujimoto
Yoshihide
Y
D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis; D053181:Caspase 8; D020169:Caspases / Q000172:deficiency / Q000378:metabolism*; D003432:Cross-Linking Reagents; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008164:Luminescent Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection; D050998:bcl-2 Homologous Antagonist-Killer Protein; D019014:fas Receptor / Q000378:metabolism* / Q000494:pharmacology
D000911:Antibodies, Monoclonal; C494772:BAK1 protein, human; C494773:Bak1 protein, mouse; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D008164:Luminescent Proteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D019014:fas Receptor; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; D011494:Protein Kinases; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases; D019311:Staurosporine