Potentiation of Fas-mediated apoptosis by an engineered glycosylphosphatidylinositol-linked Fas

Cell Death Differ. 2002 Mar;9(3):329-39. doi: 10.1038/sj.cdd.4400960.


FasL and TRAIL are apoptotic ligands of the TNF-like cytokines family, acting via activation of the transmembrane death domain containing receptors Fas for FasL, and DR4 or DR5 for TRAIL. A glycosylphosphatidylinositol-linked TRAIL receptor called DcR1 behaves as a decoy receptor inhibiting TRAIL-mediated cell death in several cellular systems. We engineered and stably expressed a chimeric GPI-linked Fas receptor (Fas-GPI) in T-lymphocyte cell lines constitutively expressing functional transmembrane Fas. Surprisingly, despite lacking the death domain region of functional Fas, Fas-GPI was able to significantly increase Fas-mediated cell death triggered by membrane bound or soluble FasL, whereas engagement of Fas-GPI alone did not trigger apoptosis. This potentiating effect, but not transmembrane Fas activation, was selectively inhibited by protein kinase C activation with phorbol esters, demonstrating that Fas-GPI activated a specific synergistic signal transduction pathway. Fas-GPI and transmembrane Fas were localized in distinct membrane compartments, since Fas-GPI, but not transmembrane Fas, was found in the glycolipid-rich membrane microdomains. These results suggest that apoptosis induced by members of this ligand/receptors family may be differentially modulated through other and parallel signalling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism
  • Cells, Cultured
  • DNA Fragmentation / physiology
  • Enzyme Activation / drug effects
  • Fas Ligand Protein
  • Glycosylphosphatidylinositols / metabolism*
  • Humans
  • Jurkat Cells
  • Membrane Glycoproteins / metabolism*
  • Membrane Microdomains / metabolism
  • Mice
  • Protein Engineering
  • Protein Kinase C / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / physiology
  • Tetradecanoylphorbol Acetate / pharmacology*
  • Tumor Cells, Cultured
  • fas Receptor / physiology*


  • FASLG protein, human
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Glycosylphosphatidylinositols
  • Membrane Glycoproteins
  • Recombinant Fusion Proteins
  • fas Receptor
  • Protein Kinase C
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Casp3 protein, mouse
  • Casp8 protein, mouse
  • Casp9 protein, mouse
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases
  • Tetradecanoylphorbol Acetate