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

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.

Requirement of cooperative functions of two repeated death effector domains in caspase‐8 and in MC159 for induction and inhibition of apoptosis, respectively

“…Recently, we have identified a novel protein, FLASH, with binding activity to Casp8NC-DED through its DED-recruiting domain (DRD), which is involved in Fas-mediated activation of caspase-8 during apoptosis (Imai et al 1999). We have also observed that Cooperative effects of two repeated DEDs for apoptosis FLASH is included not only in Fas-induced deathinducing signalling complex (DISC) which contains Fas, FADD and caspase-8 during Fas-mediated apoptosis, but also in Casp8NC-DED-induced DEF (Y.…”

Intracellular K+ inhibits apoptosis by suppressing the Apaf-1 apoptosome formation and subsequent downstream pathways but not cytochrome c release

“…1 Among the two well-defined apoptotic pathways, receptor-mediated apoptosis is characterized by the formation of the deathinducing signaling complex (DISC). 2 On the other hand, chemical-induced apoptosis generally leads to mitochondrial damage resulting in the release of cytochrome c that associates with Apaf-1, caspase-9 and dATP to form a multiprotein complex called apoptosome. 3 The DISC and apoptosome complex activate procaspase-8 and -9, respectively.…”

CASP8AP2 (caspase 8 associated protein 2)

“…Component of the apoptosis signaling pathway required for the activation of CASP8 in Fasmediated apoptosis (Imai Y et al, 1999). Component of the machinery required for histone precursor mRNA expression and essential for 3end maturation of histone mRNAs (Barcaroli D et al, 2006;De Cola et al, 2012;Yang XC et al, 2009).…”