title: Autotaxin induces lung epithelial cell migration through lysoPLD activity-dependent and -independent pathways.
abstract: Lung cell migration is a crucial step for re-epithelialization that in turn is essential for remodelling and repair after lung injury. In the present paper we hypothesize that secreted ATX (autotaxin), which exhibits lysoPLD (lysophospholipase D) activity, stimulates lung epithelial cell migration through LPA (lysophosphatidic acid) generation-dependent and -independent pathways. Release of endogenous ATX protein and activity was detected in lung epithelial cell culture medium. ATX with V5 tag overexpressed conditional medium had higher LPA levels compared with control medium and stimulated cell migration through G(αi)-coupled LPA receptors, cytoskeleton rearrangement, phosphorylation of PKC (protein kinase C) δ and cortactin at the leading edge of migrating cells. Inhibition of PKCδ attenuated ATX-V5 overexpressed conditional medium-mediated phosphorylation of cortactin. In addition, a recombinant ATX mutant, lacking lysoPLD activity, or heat-inactived ATX also induced lung epithelial cell migration. Extracelluar ATX bound to the LPA receptor and integrin β4 complex on A549 cell surface. Finally, intratracheal administration of LPS (lipopolysaccharide) into the mouse airway induced ATX release and LPA production in BAL (bronchoalveolar lavage) fluid. These results suggested a significant role for ATX in lung epithelial cell migration and remodelling through its ability to induce LPA production-mediated phosphorylation of PKCδ and cortactin. In addition we also demonstrated association of ATX with the epithelial cell-surface LPA receptor and integrin β4.
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Donghong
authors.initials: D
authors.lastname: He
authors.forename: Evgeny
authors.initials: E
authors.lastname: Berdyshev
authors.forename: Mintao
authors.initials: M
authors.lastname: Zhong
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Susan S
authors.initials: SS
authors.lastname: Smyth
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D006801:Humans; D047468:Immunoprecipitation; D039663:Integrin beta4 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000099189:Lysophospholipase D
chemical_list: D039663:Integrin beta4; D008070:Lipopolysaccharides; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid