This Article Full Text Full Text (PDF) A correction has been published All Versions of this Article: 2004-0126OCv1 32/2/135    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by White, E. S. Articles by Peters-Golden, M. Search for Related Content PubMed PubMed Citation Articles by White, E. S. Articles by Peters-Golden, M.

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

This article has been cited by other articles:

				R. L. Sagana, M. Yan, A. M. Cornett, J. L. Tsui, D. A. Stephenson, S. K. Huang, B. B. Moore, M. N. Ballinger, J. Melonakos, C. D. Kontos, et al. Phosphatase and Tensin Homologue on Chromosome 10 (PTEN) Directs Prostaglandin E2-mediated Fibroblast Responses via Regulation of E Prostanoid 2 Receptor Expression J. Biol. Chem., November 20, 2009; 284(47): 32264 - 32271. [Abstract] [Full Text] [PDF]

				S. Togo, X. Liu, X. Wang, H. Sugiura, K. Kamio, S. Kawasaki, T. Kobayashi, R. F. Ertl, Y. Ahn, O. Holz, et al. PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-{beta}1-stimulated fibroblasts Am J Physiol Lung Cell Mol Physiol, June 1, 2009; 296(6): L959 - L969. [Abstract] [Full Text] [PDF]

				S. K. Huang, S. H. Wettlaufer, J. Chung, and M. Peters-Golden Prostaglandin E2 Inhibits Specific Lung Fibroblast Functions via Selective Actions of PKA and Epac-1 Am. J. Respir. Cell Mol. Biol., October 1, 2008; 39(4): 482 - 489. [Abstract] [Full Text] [PDF]

				E. S. White Erratum: Prostaglandin E2 Inhibits Fibroblast Migration by E-Prostanoid 2 Receptor-Mediated Increase in PTEN Activity Am. J. Respir. Cell Mol. Biol., August 1, 2008; 39(2): 252 - 252. [Full Text] [PDF]

				S. Togo, O. Holz, X. Liu, H. Sugiura, K. Kamio, X. Wang, S. Kawasaki, Y. Ahn, K. Fredriksson, C. M. Skold, et al. Lung Fibroblast Repair Functions in Patients with Chronic Obstructive Pulmonary Disease Are Altered by Multiple Mechanisms Am. J. Respir. Crit. Care Med., August 1, 2008; 178(3): 248 - 260. [Abstract] [Full Text] [PDF]

				S. K. Huang and M. Peters-Golden Eicosanoid Lipid Mediators in Fibrotic Lung Diseases: Ready for Prime Time? Chest, June 1, 2008; 133(6): 1442 - 1450. [Abstract] [Full Text] [PDF]

				K. E. White, Q. Ding, B. B. Moore, M. Peters-Golden, L. B. Ware, M. A. Matthay, and M. A. Olman Prostaglandin E2 Mediates IL-1 -Related Fibroblast Mitogenic Effects in Acute Lung Injury through Differential Utilization of Prostanoid Receptors J. Immunol., January 1, 2008; 180(1): 637 - 646. [Abstract] [Full Text] [PDF]

				S. K. Huang, S. H. Wettlaufer, C. M. Hogaboam, K. R. Flaherty, F. J. Martinez, J. L. Myers, T. V. Colby, W. D. Travis, G. B. Toews, and M. Peters-Golden Variable Prostaglandin E2 Resistance in Fibroblasts from Patients with Usual Interstitial Pneumonia Am. J. Respir. Crit. Care Med., January 1, 2008; 177(1): 66 - 74. [Abstract] [Full Text] [PDF]

				C. Canetti, C. H. Serezani, R. G. Atrasz, E. S. White, D. M. Aronoff, and M. Peters-Golden Activation of Phosphatase and Tensin Homolog on Chromosome 10 Mediates the Inhibition of Fc{gamma}R Phagocytosis by Prostaglandin E2 in Alveolar Macrophages J. Immunol., December 15, 2007; 179(12): 8350 - 8356. [Abstract] [Full Text] [PDF]

				P. E. Thomas, M. Peters-Golden, E. S. White, V. J. Thannickal, and B. B. Moore PGE2 inhibition of TGF-beta1-induced myofibroblast differentiation is Smad-independent but involves cell shape and adhesion-dependent signaling Am J Physiol Lung Cell Mol Physiol, August 1, 2007; 293(2): L417 - L428. [Abstract] [Full Text] [PDF]

				S. Huang, S. H. Wettlaufer, C. Hogaboam, D. M. Aronoff, and M. Peters-Golden Prostaglandin E2 inhibits collagen expression and proliferation in patient-derived normal lung fibroblasts via E prostanoid 2 receptor and cAMP signaling Am J Physiol Lung Cell Mol Physiol, February 1, 2007; 292(2): L405 - L413. [Abstract] [Full Text] [PDF]

				R. J. Soberman and P. Christmas Revisiting prostacyclin: new directions in pulmonary fibrosis and inflammation Am J Physiol Lung Cell Mol Physiol, August 1, 2006; 291(2): L142 - L143. [Full Text] [PDF]

				E. S. White, R. G. Atrasz, B. Hu, S. H. Phan, V. Stambolic, T. W. Mak, C. M. Hogaboam, K. R. Flaherty, F. J. Martinez, C. D. Kontos, et al. Negative Regulation of Myofibroblast Differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on Chromosome 10) Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 112 - 121. [Abstract] [Full Text] [PDF]

				B. B. Moore, M. N. Ballinger, E. S. White, M. E. Green, A. B. Herrygers, C. A. Wilke, G. B. Toews, and M. Peters-Golden Bleomycin-Induced E Prostanoid Receptor Changes Alter Fibroblast Responses to Prostaglandin E2 J. Immunol., May 1, 2005; 174(9): 5644 - 5649. [Abstract] [Full Text] [PDF]

				T. Sanchez, S. Thangada, M.-T. Wu, C. D. Kontos, D. Wu, H. Wu, and T. Hla PTEN as an effector in the signaling of antimigratory G protein-coupled receptor PNAS, March 22, 2005; 102(12): 4312 - 4317. [Abstract] [Full Text] [PDF]