title: Lysophosphatidic acid induces alphavbeta6 integrin-mediated TGF-beta activation via the LPA2 receptor and the small G protein G alpha(q).
abstract: Activation of latent transforming growth factor beta (TGF-beta) by alphavbeta6 integrin is critical in the pathogenesis of lung injury and fibrosis. We have previously demonstrated that the stimulation of protease activated receptor 1 promotes alphavbeta6 integrin-mediated TGF-beta activation via RhoA, which is known to modulate cell contraction. However, whether other G protein-coupled receptors can also induce alphavbeta6 integrin-mediated TGF-beta activation is unknown; in addition, the alphavbeta6 integrin signaling pathway has not yet been fully characterized. In this study, we show that lysophosphatidic acid (LPA) induces alphavbeta6-mediated TGF-beta activation in human epithelial cells via both RhoA and Rho kinase. Furthermore, we demonstrate that LPA-induced alphavbeta6 integrin-mediated TGF-beta activity is mediated via the LPA2 receptor, which signals via G alpha(q). Finally, we show that the expression levels of both the LPA2 receptor and alphavbeta6 integrin are up-regulated and are spatially and temporally associated following bleomycin-induced lung injury. Furthermore, both the LPA2 receptor and alphavbeta6 integrin are up-regulated in the overlying epithelial areas of fibrosis in patients with usual interstitial pneumonia. These studies demonstrate that LPA induces alphavbeta6 integrin-mediated TGF-beta activation in epithelial cells via LPA2, G alpha(q), RhoA, and Rho kinase, and that this pathway might be clinically relevant to the development of lung injury and fibrosis.
authors.affiliation: Centre for Respiratory Research, University of Nottingham, Nottingham, NG5 1PB, UK.
authors.forename: Ming Yan
authors.initials: MY
authors.lastname: Xu
authors.forename: Joanne
authors.initials: J
authors.lastname: Porte
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Knox
authors.forename: Paul H
authors.initials: PH
authors.lastname: Weinreb
authors.forename: Toby M
authors.initials: TM
authors.lastname: Maher
authors.forename: Shelia M
authors.initials: SM
authors.lastname: Violette
authors.forename: Robin J
authors.initials: RJ
authors.lastname: McAnulty
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
authors.forename: Gisli
authors.initials: G
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D015153:Blotting, Western; D018920:Coculture Techniques; D005355:Fibrosis; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000378:metabolism* / Q000503:physiopathology; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D016023:Integrins; D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; D054460:rho-Associated Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020742:rhoA GTP-Binding Protein; C032881:lysophosphatidic acid