Induction of cell death by chimeric L-selectin-Fas receptors

In the present study, we have established a system where engagement of anadhesion molecule triggers a death signal into cells. L-selectin, which isa well characterized adhesion receptor involved in the initial adhesionbetween lymphocyte and endothelium, was fused to the intracellular domainof an apoptosis-inducing molecule, Fas. Ligation of the chimeric receptorswith a carbohydrate ligand for L-selectin, fucoidin or a mAb thatrecognizes the lectin domain of L-selectin, induced apoptosis inreceptor-expressing cells. However, ligation with an anti-L-selectin mAbreactive with a non-ligand binding site did not induce apoptosis,indicating that stimulation through the lectin domain of L-selectin in thechimeric receptor leads to signal delivery. Upon activation L-selectinshows a unique proteolytic cleavage at the membrane proximal site on theextracellular (EC) domain, of which the significance is also unclear. Wefound that truncations in the EC domain which abrogate the proteolyticcleavage of L-selectin did not influence induction of apoptosis, suggestingthat the cleavage on the EC domain itself is not important for thesignaling function of the chimeric receptor. This is the firstdemonstration that an adhesion signal can be converted to a signal thatleads to apoptotic cell death.