Anti-FLIP-L: Rabbit FLICE-Inhibitory Proteins L Antibody

BACKGROUND FLICE-inhibitory proteins (FLIP), an antagonist of death receptors (DRs), is an endogenous inhibitor of the Fas-associated death domain (FADD)/caspase-8 proapoptotic signaling pathway. Upon stimulation, CD95 (APO-1/Fas) recruits the adapter molecule FADD/MORT1, procaspase-8, and the cellular FLIP into the death-inducing signaling complex (DISC). According to the induced proximity model, procaspase-8 is activated in the DISC in an autoproteolytic manner by two subsequent cleavage steps. FLIP proteins exist as a long (FLIP-L) and a short (FLIP-S) splice variant, both of them capable of protecting cells from death receptor-mediated apoptosis. FLIP-S contains only two tandem repeats of death effector domains and inhibits procaspase-8 activation in the DISC. In contrast, FLIP-L shares extensive homology with procaspase-8, with a C-terminal domain that is highly homologous to the procaspase-8 protease domain yet enzymatically inactive due to the lack of key active site residues.¹ In addition, it was shown that FLIP-L directly interacts with Akt and FLIP-L overexpression interferes with Gsk3-beta phosphorylation levels. Furthermore, through its effects on Gsk3beta, FLIP-L overexpression in cancer cells induced resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This effect was mediated by the regulation of p27Kip1 and caspase-3 expression.²

FLIP-L is a widely expressed molecule that confers resistance to DR-induced apoptosis in a wide range of cellular models. As an important modulator of caspase-8, FLIP-L regulates life and death in various types of normal cells and tissues. For instance, in T lymphocytes, FLIP-L interacts with different adaptor proteins to activate ERK and NF-kappaB signaling pathways. Thus, FLIP-L is a protein with dual roles displaying antiapoptotic or proliferation/differentiation properties, at least in the immune system. Moreover, FLIP-L is also a crucial factor in neurotrophin-induced control of neurite growth. It was shown that FLIP-L binds the neurotrophin receptor TrkA, but not p75NTR, during NGF stimulation.³ Overexpression of FLIP-L markedly increases neurotrophin-induced neurite outgrowth. In addition, FLIP-L renders resistance to death receptor-mediated apoptosis in many types of cancer cells. Dysregulation of c-FLIP expression has been shown to be associated with various diseases, such as cancer and autoimmune diseases, and c-FLIP might be a critical target for therapeutic intervention.⁴

 

REFERENCES  

1. Chang, D.W. et al: EMBO J. 21:3704-14, 2002
2. Quintavalle, C. et al: Cell Death Diff. 2010 (in press)
3. Moubarak, R.S. et al: J. Neurosci. 30:6094-105, 2010
4. Krueger, A. et al: J. Biol. Chem. 276:20633-4, 2001