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: Ming Yan Xu, Joanne Porte, Alan J Knox, Paul H Weinreb, Toby M Maher, Shelia M Violette, Robin J McAnulty, Dean Sheppard, Gisli Jenkins
• Journal: The American journal of pathology (Am J Pathol) Vol. 174 Issue 4 Pg. 1264-79 (Apr 2009) ISSN: 1525-2191 [Electronic] United States
• PMID: 19147812 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Integrins
• Lysophospholipids
• Receptors, Lysophosphatidic Acid
• Transforming Growth Factor beta
• integrin alphavbeta6
• rho-Associated Kinases
• GTP-Binding Protein alpha Subunits, Gq-G11
• rhoA GTP-Binding Protein
• lysophosphatidic acid

Topics

• Animals
• Antigens, Neoplasm (metabolism)
• Blotting, Western
• Coculture Techniques
• Fibrosis
• Flow Cytometry
• Fluorescent Antibody Technique
• GTP-Binding Protein alpha Subunits, Gq-G11 (metabolism)
• Humans
• Immunohistochemistry
• Integrins (metabolism)
• Lung (metabolism, pathology)
• Lung Injury (metabolism, physiopathology)
• Lysophospholipids (metabolism, pharmacology)
• Mice
• Receptors, Lysophosphatidic Acid (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (physiology)
• Transforming Growth Factor beta (metabolism)
• rho-Associated Kinases (metabolism)
• rhoA GTP-Binding Protein (metabolism)