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 initia l adhesion between lymphocyte and endothelium, was fused to the intrac ellular domain of an apoptosis-inducing molecule, Fas. Ligation of the chimeric receptors with a carbohydrate ligand for L-selectin, fucoidi n or a mAb that recognizes the lectin domain of L-selectin, induced ap optosis in receptor-expressing cells. However, ligation with an anti-L -selectin mAb reactive with a non-ligand binding site did not induce a poptosis, indicating that stimulation through the lectin domain of L-s electin in the chimeric receptor leads to signal delivery. Upon activa tion L-selectin shows a unique proteolytic cleavage at the membrane pr oximal site on the extracellular (EC) domain, of which the significanc e is also unclear. We found that truncations in the EC domain which ab rogate the proteolytic cleavage of L-selectin did not influence induct ion 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 conver ted to a signal that leads to apoptotic cell death.