The CED-4-homologous protein FLASH is involved in Fas-mediated activation of caspase-8 during apoptosis.
Fas is a cell-surface receptor molecule that relays apoptotic (cell death) signals into cells. When Fas is activated by binding of its ligand, the proteolytic protein caspase-8 is recruited to a signalling complex known as DISC by binding to a Fas-associated adapter protein. A large new protein, FLASH, has now been identified by cloning of its complementary DNA. This protein contains a motif with oligomerizing activity whose sequence is similar to that of the Caenorhabditis elegans protein CED-4, and another domain (DRD domain) that interacts with a death-effector domain in caspase-8 or in the adapter protein. Stimulated Fas binds FLASH, so FLASH is probably a component of the DISC signalling complex. Transient expression of FLASH activates caspase-8, whereas overexpression of a truncated form of FLASH containing only one of its DRD or CED-4-like domains does not allow activation of caspase-8 and Fas-mediated apoptosis to occur. Overexpression of full-length FLASH blocks the anti-apoptotic effect of the adenovirus protein E1B19K. FLASH is therefore necessary for the activation of caspase-8 in Fas-mediated apoptosis.
Imai
Y
Y
Institute for Virus Research, Kyoto University, Japan.
Kimura
T
T
Murakami
A
A
Yajima
N
N
Sakamaki
K
K
Yonehara
S
S
D048868:Adaptor Proteins, Signal Transducing; D017498:Adenovirus E1 Proteins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D016384:Consensus Sequence; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein; D015801:Helminth Proteins / Q000737:chemistry*; D006801:Humans; D019169:Jurkat Cells; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D019014:fas Receptor / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D017498:Adenovirus E1 Proteins; D051017:Apoptosis Regulatory Proteins; C485604:CASP8AP2 protein, human; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C119301:Casp8ap2 protein, mouse; C089224:Ced-4 protein, C elegans; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D015801:Helminth Proteins; D046911:Macromolecular Substances; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases