FLIP(L) and procaspase-8 form heterodimer in TNF signaling

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Reaction [binding]
Homo sapiens
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Following recruitment to the death-inducing signaling complex (DISC) and called complex II in the TNFR1 signalling pathway, cellular FLICE-like inhibitory protein (cFLIP) forms a heterodimer with procaspase-8. The presence of cFLIP in complex II determines if and how cells die. cFLIP is encoded by the CFLAR gene and is expressed in two major isoforms cFLIP long (FLIP(L)) and cFLIP short (FLIP(S)). While both FLIP(L) and FLIP(S) form heterodimers with procaspase-8, they differentially control caspase-8 activation. FLIP(L) interacts with procaspase-8 through both death effector domain (DED) and caspase-like domain (CLD). The procaspase-8 catalytic domain prefers heterodimerization with the CLD of FLIP(L) over homodimerization with catalytic domains of other procaspase-8 molecules (Boatright KM et al. 2004; Yu JW et al. 2009). Heterodimerization to FLIP(L) rearranges the catalytic site of procaspase-8, producing a conformation that renders the heterodimer highly active even in the absence of proteolytic processing of either caspase-8 or cFLIPL (Micheau O et al. 2002; Yu JW et al. 2009; reviewed in Tummers B & Green DR 2017). In addition, FLIP(L) can also regulate TNFR1 signaling via interaction with the DED of FADD (Majkut J et al. 2014). However, other studies showed that FLIP(L) is only weakly able to bind FADD (Hughes MA et al. 2016; Fu TM et al. 2016; Schleich K et al. 2016). The regulatory function of FLIP(L) has been found to differ depending on its expression levels. FLIP(L) was shown to inhibit death receptor (DR)-mediated apoptosis only when expressed at high levels, while low cell levels of FLIP(L) enhanced DR signaling to apoptosis (Boatright KM et al. 2004; Okano H et al. 2003; Yerbes R et al. 2011; Hughes MA et al. 2016). The FLIP(S) protein lacks CLD and contains only two tandem DEDs and a short C-terminal tail. FLIP(S) blocks DISC-dependent procaspase-8 activation. The expression levels of cFLIP proteins were shown to be regulated by NFkappaB signaling pathway (Micheau O et a. 2001; Kreuz S et al 2001).

Literature References
PubMed ID Title Journal Year
18256533 TNF signaling gets FLIPped off: TNF-induced regulation of FLIP

Langa, S, Taylor, A, Rushworth, SA, MacEwan, DJ

Cell Cycle 2008
20218968 c-FLIP is involved in erythropoietin-mediated protection of erythroid-differentiated cells from TNF-alpha-induced apoptosis

Chamorro, ME, Vittori, D, Nesse, A, Vota, D, Callero, M

Cell Biol. Int. 2010
12620240 Insights into the regulatory mechanism for caspase-8 activation

Grütter, MG, Briand, C, Mac Sweeney, A, Donepudi, M

Mol. Cell 2003
18838202 Differential responses of FLIPLong and FLIPShort-overexpressing human myeloid leukemia cells to TNF-alpha and TRAIL-initiated apoptotic signals

Abbassi, N, Spaulding, EY, Deeg, HJ, Seal, S, Kiem, HP, Hockenbery, DM

Exp. Hematol. 2008
12887920 Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes

Micheau, O, Tschopp, J

Cell 2003
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Orthologous Events
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