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 pro teolytic: protein caspase-8 is recruited to a signalling complex known as D ISC by binding to a Fas-associated adapter protein. A large new protein, FL ASH, has now been identified by cloning of its complementary DNA. This prot ein contains a motif with oligomerizing activity whose sequence is similar to that of the Caenorhabditis elegans protein CED-4, and another domain (DR D domain) that interacts with a death-effector domain in caspase-8 or in th e adapter protein. Stimulated Fas binds FLASH, so FLASH is probably a compo nent of the DISC signalling complex. Transient expression of FLASH activate s 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 cas pase-8 and Fas-mediated apoptosis to occur, Overexpression of full-length F LASH blocks the anti-apoptotic effect of the adenovirus protein E1B19K. FLA SH is therefore necessary for the activation of caspase-8 in Fas-mediated a poptosis.