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Proliferin Induces Endothelial Cell Chemotaxis through a G Protein-Coupled, Mitogen-Activated Protein Kinase-Dependent Pathway¹

Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University (J.C.G., D.I.H.L.), Evanston, Illinois 60208; and the Department of Signal Transduction, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co. (L.-J.S., A.R.S.), Ann Arbor, Michigan 48105

Address all correspondence and requests for reprints to: Dr. Daniel I. H. Linzer, Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, 2153 Sheridan Road, Evanston, Illinois 60208. E-mail: dlinzer{at}nwu.edu

To investigate the mechanism of action of the placental angiogenic hormone proliferin (PLF), we analyzed the signaling components in endothelial cells that are required for PLF-induced chemotaxis. Pertussis toxin, which inactivates G_i proteins, inhibited PLF-induced chemotaxis of endothelial cells. G_i proteins can lead to activation of the mitogen-activated protein kinase (MAPK) pathway; PLF was found to stimulate MAPK activity, and this induction was blocked by both pertussis toxin and a specific inhibitor of MAPK kinase, PD 098059. Furthermore, a blockade of MAPK activation prevented endothelial cell movement in response to PLF. As PLF functionally interacts with the insulin-like growth factor II (IGF-II)/mannose 6-phosphate receptor, we also examined the effects of pertussis toxin and PD 098059 on another ligand for this receptor, a mutant form of IGF-II; both inhibitors also block the action of this factor on endothelial cells. These data suggest that chemotaxis initiated by PLF and mediated by the IGF-II/mannose 6-phosphate receptor occurs through a G protein-coupled pathway, and that MAPK activation is necessary for the chemotactic response.

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