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Published ahead of print on November 11, 2004, doi:10.1165/rcmb.2004-0126OC

Am. J. Respir. Cell Mol. Biol., Volume 32, Number 2, February 2005, 135-141

A more recent version of this article appeared on February 1, 2005
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Submitted on April 21, 2004
Revised on November 10, 2004

Prostaglandin E2 inhibits fibroblast migration by EP2 receptor-mediated increase in PTEN activity

Eric S White1*, Rachelle G Atrasz1, Emily G Dickie1, David M Aronoff2, Vuk Stambolic3, Tak W Mak3, Bethany B Moore1, and Marc Peters-Golden1

1 Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan, Ann Arbor, MI, USA, 2 Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, MI, USA, 3 University Health Network, Ontario Cancer Institute, University of Toronto, Ontario, Toronto, Canada

* To whom correspondence should be addressed. E-mail: docew{at}umich.edu.

An increased migratory phenotype exists in lung fibroblasts derived from patients with fibroproliferative lung disease. Prostaglandin E2 (PGE2[[infinity]]) 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 can not be inhibited by PGE2 or butaprost, confirming the central role of EP2 in mediating these effects. Our previous data suggested that phosphatase and tensin homologue 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, since 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.




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