Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing*
-
Adenovirus E1 Proteins / metabolism
-
Amino Acid Sequence
-
Animals
-
Apoptosis / physiology*
-
Apoptosis Regulatory Proteins
-
Caenorhabditis elegans
-
Caenorhabditis elegans Proteins*
-
Calcium-Binding Proteins / chemistry*
-
Calcium-Binding Proteins / genetics
-
Calcium-Binding Proteins / physiology*
-
Carrier Proteins / metabolism
-
Caspase 8
-
Caspase 9
-
Caspases / metabolism*
-
Cell Line
-
Cloning, Molecular
-
Consensus Sequence
-
Enzyme Activation
-
Fas-Associated Death Domain Protein
-
Helminth Proteins / chemistry*
-
Humans
-
Jurkat Cells
-
Macromolecular Substances
-
Mice
-
Molecular Sequence Data
-
Sequence Homology, Amino Acid
-
Signal Transduction
-
fas Receptor / physiology*
Substances
-
Adaptor Proteins, Signal Transducing
-
Adenovirus E1 Proteins
-
Apoptosis Regulatory Proteins
-
CASP8AP2 protein, human
-
Caenorhabditis elegans Proteins
-
Calcium-Binding Proteins
-
Carrier Proteins
-
Casp8ap2 protein, mouse
-
Ced-4 protein, C elegans
-
FADD protein, human
-
Fadd protein, mouse
-
Fas-Associated Death Domain Protein
-
Helminth Proteins
-
Macromolecular Substances
-
fas Receptor
-
CASP8 protein, human
-
CASP9 protein, human
-
Casp8 protein, mouse
-
Casp9 protein, mouse
-
Caspase 8
-
Caspase 9
-
Caspases