Caspase-8 and FLIP(L) processing at DISC

Stable Identifier
Reaction [omitted]
Homo sapiens
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In the presence of FLIP(L), both caspase-8 and FLIP(L) are recruited and partially processed at the death-inducing signaling complex (DISC). The partially processed proteins stay bound to the DISC.

The long cellular FLIP (FLIP(L) or c-FLIPL) has two death effector domains (DED) and a caspase-like domain that lacks catalytic activity due to absence of a cysteine residue. Processing of FLIP(L) occurs at the DISC and depends on caspase-8 activity (zymogen and mature form). Upon activation FLIP(L) is cleaved to generate N-terminal FLIP(p43) and C-terminal FLIP(p12)(Irmler M et al. 1997; Jong WY et al. 2009). Processed FLIP(L) can enhance the proteolytic activity of procaspase-8 (Chang DW et al. 2002; Jong WY et al. 2009; Pop C et al. 2011). However, the increased FLIP(L) protein levels in cells have been found to limit caspase-8 activity and inhibit apoptotic signaling pathway,

Literature References
PubMed ID Title Journal Year
19278658 Structural and biochemical studies on procaspase-8: new insights on initiator caspase activation

Zerbe, O, Keller, N, Grütter, MG, Mares, J

Structure 2009
19416807 Mechanism of procaspase-8 activation by c-FLIPL

Shi, Y, Jeffrey, PD, Yu, JW

Proc. Natl. Acad. Sci. U.S.A. 2009
21235526 FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity

Drag, M, Van Raam, BJ, Oberst, A, Green, DR, Riedl, SJ, Salvesen, GS, Pop, C

Biochem J 2011
20696707 Model-based dissection of CD95 signaling dynamics reveals both a pro- and antiapoptotic role of c-FLIPL

Richter, P, Lavrik, IN, Beaudouin, J, Fricker, N, Eils, R, Krammer, PH

J. Cell Biol. 2010
10837247 The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways

Hahne, M, Irmler, M, Budd, RC, Martinon, F, Thome, M, Kovacsovics, M, Kataoka, T, Tschopp, J, Burns, K, Holler, N, Kennedy, N

Curr. Biol. 2000
15024054 N-terminal fragment of c-FLIP(L) processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-kappaB signaling pathway

Kataoka, T, Tschopp, J

Mol. Cell. Biol. 2004
Catalyst Activity

cysteine-type endopeptidase activity of active caspase-8 [cytosol]

Orthologous Events
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