title: Cross-talk between lysophosphatidic acid receptor 1 and tropomyosin receptor kinase A promotes lung epithelial cell migration.
abstract: Lysophosphatidic acid (LPA) is a bioactive lysophospholipid, which plays a crucial role in the regulation of cell proliferation, migration, and differentiation. LPA exerts its biological effects mainly through binding to cell-surface LPA receptors (LPA1-6), which belong to the G protein-coupled receptor (GPCR) family. Recent studies suggest that cross-talk between receptor tyrosine kinases (RTKs) and GPCRs modulates GPCRs-mediated signaling. Tropomyosin receptor kinase A (TrkA) is a RTK, which mediates nerve growth factor (NGF)-induced biological functions including cell migration in neuronal and non-neuronal cells. Here, we show LPA1 transactivation of TrkA in murine lung epithelial cells (MLE12). LPA induced tyrosine phosphorylation of TrkA in both time- and dose-dependent manners. Down-regulation of LPA1 by siRNA transfection attenuated LPA-induced phosphorylation of TrkA, suggesting a cross-talk between LPA1 and TrkA. To investigate the molecular regulation of the cross-talk, we focused on the interaction between LPA1 and TrkA. We found that LPA induced interaction between LPA1 and TrkA. The LPA1/TrkA complex was localized on the plasma membrane and in the cytoplasm. The C-terminus of LPA1 was identified as the binding site for TrkA. Inhibition of TrkA attenuated LPA-induced phosphorylation of TrkA and LPA1 internalization, as well as lung epithelial cell migration. These studies provide a molecular mechanism for the transactivation of TrkA by LPA, and suggest that the cross-talk between LPA1 and TrkA regulates LPA-induced receptor internalization and lung epithelial cell migration.
authors.affiliation: Department of Anesthesia, First Hospital of Jilin University, Changchun, China; Department of Medicine, Acute Lung Injury Center of Excellence, Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Ling
authors.initials: L
authors.lastname: Nan
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Anastasia M
authors.initials: AM
authors.lastname: Jacko
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Miranda K
authors.initials: MK
authors.lastname: Culley
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, United States.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.affiliation: Department of Anesthesia, First Hospital of Jilin University, Changchun, China.
authors.forename: Haichun
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address: zhaoy3@upmc.edu.
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism*; D008168:Lung / Q000166:cytology; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D008856:Microscopy, Fluorescence; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D020239:Receptor Cross-Talk; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D014443:Tyrosine; D020917:Receptor, trkA; C032881:lysophosphatidic acid
keywords: Cell migration; GPCR; LPA; RTK; Receptor internalization; Transactivation