Distinct Phospholipase C-β Isozymes Mediate Lysophosphatidic Acid Receptor 1 Effects on Intestinal Epithelial Homeostasis and Wound Closure

• Type of Material: Article
• Authors: Sei-Jung Lee, Emory University; Giovanna Leoni, Emory University; Philipp-Alexander Neumann, Emory University; Jerold Chun, The Scripps Research Institute; Asma Nusrat, Emory University; Chris Yun, Emory University
• Language: English
• Date: 2013-05
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2013, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://mcb.asm.org/content/33/10/2016
• Title of Journal or Parent Work: Molecular and Cellular Biology
• ISSN: 0270-7306
• Volume: 33
• Issue: 10
• Start Page: 2016
• End Page: 2028
• Grant/Funding Information: The microscopy core was supported by grant DK064399.; This work was supported by a Senior Research Award from the Crohn's and Colitis Foundation of America, the National Institutions of Health grants DK071597; to C.C.Y., DK055679; to A.N., and MH51699; and NS082092 to J.C., and the German Research Foundation (DFG; NE1834/1-1;) to P.-A.N.
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology

Abstract

Maintenance of the epithelial barrier in the intestinal tract is necessary to protect the host from the hostile luminal environment. Phospholipase C-β (PLC-β) has been implicated to control myriad signaling cascades. However, the biological effects of selective PLC-β isozymes are poorly understood. We describe novel findings that lysophosphatidic acid (LPA) regulates PLC-β1 and PLC-β2 via two distinct pathways to enhance intestinal epithelial cell (IEC) proliferation and migration that facilitate wound closure and recovery of the intestinal epithelial barrier. LPA acting on the LPA1 receptor promotes IEC migration by facilitating the interaction of Gαq with PLC-β2. LPA-induced cell proliferation is PLC-β1 dependent and involves translocation of Gαq to the nucleus, where it interacts with PLC-β1 to induce cell cycle progression. An in vivo study using LPA1-deficient mice (Lpar1−/−) shows a decreased number of proliferating IECs and migration along the crypt-luminal axis. Additionally, LPA enhances migration and proliferation of IECs in an LPA1-dependent manner, and Lpar1−/− mice display defective mucosal wound repair that requires cell proliferation and migration. These findings delineate novel LPA1-dependent lipid signaling that facilitates mucosal wound repair via spatial targeting of distinct PLC-βs within the cell.