cMet and Fas receptor interaction inhibits death-inducing signaling complex formation in endothelial cells.
Fas receptor is constitutively expressed on endothelial cells; however, these cells are highly resistant to Fas-mediated apoptosis. In this study, we examined death-inducing signaling complex (DISC) formation in endothelial cells after Fas receptor stimulation. Nonfunctional DISC formation was observed in human umbilical vein endothelial cells (HUVECs). Fas-associated death domain (FADD) and large amounts of FADD-like interleukin-1--converting enzyme--inhibitory protein-L were recruited to the receptor; however, no caspase 8 recruitment was observed. A role for the cell surface molecule cMet in controlling Fas sensitivity in endothelial cells was observed. Here, we report that Fas is associated with cMet in HUVECs. Such an interaction may inhibit self-association of Fas in these cells, as suggested by the fact that monomeric Fas is expressed in these cells. Endothelial cells undergoing cell matrix detachment, anoikis, are sensitive to Fas-mediated apoptosis. Despite upregulating the level of Fas receptor, endothelial cells undergoing anoikis have reduced cMet/Fas interaction, in part because of cMet being cleaved in these cells. Dimeric Fas was observed on anoikis cells. These data suggest that cMet/Fas interaction may inhibit self-association of Fas receptor such that reduced DISC formation occurs in these cells after Fas receptor ligation. cMet/Fas interaction may help explain why endothelial cells are resistant to Fas-mediated apoptosis.
Smyth
Lesley Ann
LA
Molecular Hematology and Cancer Biology Unit, Institute of Child Health, University College London, 30 Guilford St, London WC1N 1EH, United Kingdom.
Brady
Hugh J M
HJ
D023102:Anoikis / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002470:Cell Survival; D002478:Cells, Cultured; D053418:Death Domain Receptor Signaling Adaptor Proteins; D042783:Endothelial Cells / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019169:Jurkat Cells; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011940:Receptor Aggregation / Q000502:physiology; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000037:antagonists & inhibitors*; D019014:fas Receptor / Q000378:metabolism*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D053418:Death Domain Receptor Signaling Adaptor Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D019014:fas Receptor; D019859:Proto-Oncogene Proteins c-met