Reactome | Regulation by c-FLIP

Regulation by c-FLIP

Stable Identifier

R-HSA-3371378

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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c-FLIP proteins (CASP8 and FADD-like apoptosis regulators or c-FLICE inhibitory proteins) are death effector domain (DED)-containing proteins that are recruited to the death-inducing signaling complex (DISC) to regulate activation of caspases-8. Three out of 13 distinct spliced variants of c-FLIP had been found to be expressed at the protein level, the 26 kDa short form FLIP(S), the 24 kDa form FLIP(R), and the 55 kDa long form FLIP(L) (Irmler M et al. 1997; Shu HB et al. 1997; Srinivasula SM et al. 1997; Scaffidi C et al. 1999; Golks A et al. 2005; Haag C et al. 2011)

All c-FLIP proteins carry two DEDs at their N termini, which can bind FADD and procaspase-8. In addition to two DEDs, FLIP(L) contains a large (p20) and a small (p12) caspase-like domain without catalytic activity. FLIP(S) and FLIP(R) consist of two DEDs and a small C terminus. Depending on its level of expression FLIP(L) may function as an anti-apoptotic or pro-apoptotic factor, while FLIP(S) and FLIP(R) protect cells from apoptosis by blocking the processing of caspase-8 at the receptor level (Scaffidi C et al. 1999; Golks A et al. 2005; Toivonen HT et al. 2011; Fricker N et al. 2010).

Literature References

PubMed ID	Title	Journal	Year
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
9217161	Inhibition of death receptor signals by cellular FLIP Schneider, P, Tschopp, J, Bodmer, JL, Steiner, V, Hahne, M, French, LE, Irmler, M, Rimoldi, D, Mattmann, C, Burns, K, Schröter, M, Thome, M, Hofmann, K	Nature	1997