Published online before print January 15, 2009

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Copyright © 2009 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2009.080160

Accepted for publication October 31, 2008.

Article

Lysophosphatidic Acid Induces v6 Integrin-Mediated TGF- Activation via the LPA2 Receptor and the Small G Protein G_q

Ming Yan Xu^*, Joanne Porte^*, Alan J. Knox^*, Paul H. Weinreb, Toby M. Maher, Shelia M. Violette, Robin J. McAnulty, Dean Sheppard, and R. Gisli Jenkins^*@

From the Centre for Respiratory Research,* the University of Nottingham, United Kingdom; the Lung Biology Center, University of California at San Francisco, San Francisco, California; Biogen Idec, Cambridge, Massachusetts; and the Centre for Respiratory Research, University College London, United Kingdom

^@ To whom correspondence should be addressed. E-mail: Gisli.Jenkins{at}Nottingham.ac.uk.

	Abstract

Activation of latent transforming growth factor (TGF-) by v6 integrin is critical in the pathogenesis of lung injury and fibrosis. We have previously demonstrated that the stimulation of protease activated receptor 1 promotes v6 integrin-mediated TGF- activation via RhoA, which is known to modulate cell contraction. However, whether other G protein-coupled receptors can also induce v6 integrin-mediated TGF- activation is unknown; in addition, the v6 integrin signaling pathway has not yet been fully characterized. In this study, we show that lysophosphatidic acid (LPA) induces v6-mediated TGF- activation in human epithelial cells via both RhoA and Rho kinase. Furthermore, we demonstrate that LPA-induced v6 integrin-mediated TGF- activity is mediated via the LPA2 receptor, which signals via G_q. Finally, we show that the expression levels of both the LPA2 receptor and v6 integrin are up-regulated and are spatially and temporally associated following bleomycin-induced lung injury. Furthermore, both the LPA2 receptor and v6 integrin are up-regulated in the overlying epithelial areas of fibrosis in patients with usual interstitial pneumonia. These studies demonstrate that LPA induces v6 integrin-mediated TGF- activation in epithelial cells via LPA2, G_q, RhoA, and Rho kinase, and that this pathway might be clinically relevant to the development of lung injury and fibrosis.