Induction of cell death by chimeric L-selectin-Fas receptors.
In the present study, we have established a system where engagement of an adhesion molecule triggers a death signal into cells. L-selectin, which is a well characterized adhesion receptor involved in the initial adhesion between lymphocyte and endothelium, was fused to the intracellular domain of an apoptosis-inducing molecule, Fas. Ligation of the chimeric receptors with a carbohydrate ligand for L-selectin, fucoidin or a mAb that recognizes the lectin domain of L-selectin, induced apoptosis in receptor-expressing cells. However, ligation with an anti-L-selectin mAb reactive with a non-ligand binding site did not induce apoptosis, indicating that stimulation through the lectin domain of L-selectin in the chimeric receptor leads to signal delivery. Upon activation L-selectin shows a unique proteolytic cleavage at the membrane proximal site on the extracellular (EC) domain, of which the significance is also unclear. We found that truncations in the EC domain which abrogate the proteolytic cleavage of L-selectin did not influence induction of apoptosis, suggesting that the cleavage on the EC domain itself is not important for the signaling function of the chimeric receptor. This is the first demonstration that an adhesion signal can be converted to a signal that leads to apoptotic cell death.
Ishiwatari-Hayasaka
H
H
Department of Bioregulation, Osaka University Medical School, Suita, Japan.
Kawashima
H
H
Osawa
T
T
Nagata
S
S
Miyasaka
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D003432:Cross-Linking Reagents; D006801:Humans; D019169:Jurkat Cells; D019041:L-Selectin / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D011134:Polysaccharides / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051381:Rats; D011971:Receptors, Immunologic / Q000276:immunology* / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000138:chemical synthesis / Q000494:pharmacology*; D017384:Sequence Deletion / Q000276:immunology; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics*
D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D011134:Polysaccharides; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D019041:L-Selectin; C007789:fucoidan