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).