title: Distinct phospholipase C-β isozymes mediate lysophosphatidic acid receptor 1 effects on intestinal epithelial homeostasis and wound closure.
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.
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Sei-Jung
authors.initials: SJ
authors.lastname: Lee
authors.forename: Giovanna
authors.initials: G
authors.lastname: Leoni
authors.forename: Philipp-Alexander
authors.initials: PA
authors.lastname: Neumann
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.forename: Asma
authors.initials: A
authors.lastname: Nusrat
authors.forename: C Chris
authors.initials: CC
authors.lastname: Yun
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004386:Duodenum / Q000166:cytology / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology*; D059585:G1 Phase Cell Cycle Checkpoints; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D015870:Gene Expression; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000166:cytology / Q000502:physiology; D007527:Isoenzymes / Q000378:metabolism; D008246:Lysophospholipids / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000378:metabolism; D054799:Phospholipase C beta / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D015398:Signal Transduction; D014945:Wound Healing; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
chemical_list: D018797:Cell Cycle Proteins; D007527:Isoenzymes; D008246:Lysophospholipids; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D049368:Receptors, Lysophosphatidic Acid; D054799:Phospholipase C beta; C518034:Plcb1 protein, mouse; C518037:Plcb2 protein, mouse; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein