PROLIFERIN INDUCES ENDOTHELIAL-CELL CHEMOTAXIS THROUGH A G-PROTEIN-COUPLED, MITOGEN-ACTIVATED PROTEIN KINASE-DEPENDENT PATHWAY

To investigate the mechanism of action of the placental angiogenic hor mone proliferin (PLF), we analyzed the signaling components in endothe lial cells that are required for PLF-induced chemotaxis. Pertussis tox in, which inactivates G(i) proteins, inhibited PLF-induced chemotaxis of endothelial cells. G(i) proteins can lead to activation of the mito gen-activated protein kinase (MAPK) pathway; PLF was found to stimulat e MAPK activity, and this induction was blocked by both pertussis toxi n and a specific inhibitor of MAPK kinase, PD 098059. Furthermore, a b lockade of MAPK activation prevented endothelial cell movement in resp onse to PLF. As PLF functionally interacts with the insulin-like growt h factor II (IGF-II)/mannose 6-phosphate receptor, we also examined th e effects of pertussis toxin and PD 098059 on another ligand for this receptor, a mutant form of IGF-II; both inhibitors also block the acti on of this factor on endothelial cells. These data suggest that chemot axis initiated by PLF and mediated by the IGF-II/mannose 6-phosphate r eceptor occurs through a G protein-coupled pathway, and that MAPK acti vation is necessary for the chemotactic response.