Lysophosphatidic acid induces alphavbeta6 integrin-mediated TGF-beta activation via the LPA2 receptor and the small G protein G alpha(q).
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.
Xu
Ming Yan
MY
Centre for Respiratory Research, University of Nottingham, Nottingham, NG5 1PB, UK.
Porte
Joanne
J
Knox
Alan J
AJ
Weinreb
Paul H
PH
Maher
Toby M
TM
Violette
Shelia M
SM
McAnulty
Robin J
RJ
Sheppard
Dean
D
Jenkins
Gisli
G
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
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