The CED-4-homologous protein FLASH is involved in Fas-mediated activation of caspase-8 during apoptosis

Nature. 1999 Apr 29;398(6730):777-85. doi: 10.1038/19709.


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*


  • 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

Associated data

  • GENBANK/AF132726