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Prostaglandin E₂ Inhibits Fibroblast Migration by E-Prostanoid 2 Receptor–Mediated Increase in PTEN Activity

Division of Pulmonary and Critical Care Medicine and Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; and University Health Network, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to Eric S. White, M.D., Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, 6301 MSRB III/0642, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0642. E-mail: docew{at}umich.edu

An increased migratory phenotype exists in lung fibroblasts derived from patients with fibroproliferative lung disease. Prostaglandin E₂ (PGE₂) suppresses fibroblast migration, but the receptor(s) and mechanism(s) mediating this action are unknown. Our data confirm that treatment of human lung fibroblasts with PGE₂ inhibits migration. Similar effects of butaprost, an E-prostanoid (EP) 2 receptor–specific ligand, implicate the EP2 receptor in migration-inhibitory signaling. Further, migration in fibroblasts deficient for the EP2 receptor cannot be inhibited by PGE₂ or butaprost, confirming the central role of EP2 in mediating these effects. Our previous data suggested that phosphatase and tensin homolog on chromosome ten (PTEN), a phosphatase that opposes the actions of phosphatidylinositol-3-kinase (PI3K), may be important in regulating lung fibroblast motility. We now report that both PGE₂ and butaprost increase PTEN phosphatase activity, without a concomitant increase in PTEN protein levels. This contributes to EP2-mediated migration inhibition, because migration in PTEN-null fibroblasts is similarly unaffected by EP2 receptor signaling. Increased PTEN activity in response to EP2 stimulation is associated with decreased tyrosine phosphorylation on PTEN, a mechanism known to regulate enzyme activity. Collectively, these data describe the novel mechanistic finding that PGE₂, via the EP2 receptor, decreases tyrosine phosphorylation on PTEN, resulting in increased PTEN enzyme activity and inhibition of fibroblast migration.

Key Words: fibroblast • eicosanoid • phosphatase • cell migration