Regulation by c-FLIP (R-HSA-3371378) [Homo sapiens]


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).

Locations in the PathwayBrowser
Additional Information
GO Biological Process regulation of extrinsic apoptotic signaling pathway via death domain receptors (1902041)
Cross References
Database Identifier
BioModels Database BIOMD0000000243, BIOMD0000000523, BIOMD0000000525, BIOMD0000000526, BIOMD0000000407, BIOMD0000000524, BIOMD0000000220
Literature References
pubMedId Title Journal Year
9217161 Inhibition of death receptor signals by cellular FLIP Nature 1997
21235526 FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity Biochem J 2011
19416807 Mechanism of procaspase-8 activation by c-FLIPL Proc. Natl. Acad. Sci. U.S.A. 2009
Inferred Entries
Orthologous events