Lysophosphatidic acid induces αvβ36 integrin-mediated TGF-β activation via the LPA2 receptor and the small G protein Gαq

Abstract

Activation of latent transforming growth factor β (TGF-β)by avβ integrin is critical in the pathogenesis of lung injury and fibrosis. We have previously demonstrated that the stimulation of protease activated receptor 1 promotes αvβ6 integrin-mediated TGF-β activation via RhoA, which is known to modulate cell contraction. However, whether other G protein-coupled receptors can also induce αvfβ6 integrin- mediated TGF-fβactivation is unknown; in addition, the αvβ 6 integrin signaling pathway has not yet been fully characterized. In this study, we show that lysophosphatidic acid (LPA) induces αvβ 6-mediated TGF-βactivation in human epithelial cells via both RhoA and Rho kinase. Furthermore, we demonstrate that LPA-induced αvβ6 integrin-mediated TGF-β activity is mediated via the LPA2 receptor, which signals via Gαq. Finally, we show that the expression levels of both the LPA2 receptor and αvβ 6 integrin are up-regulated and are spatially and temporally associated following bleomycin-induced lung injury. Furthermore, both the LPA2 receptor and αvβ 6 integrin are up-regulated in the overlying epithelial areas of fibrosis in patients with usual interstitial pneumonia. These studies demonstrate that LPA induces αvβ6 inte- grin-mediated TGF-βactivation in epithelial cells via LPA2, Gαq, RhoA, and Rho kinase, and that this pathway might be clinically relevant to the development of lung injury and fibrosis. Copyright © American Society for Investigative Pathology.