Article Text

  1. L Nan1,2,
  2. J Wei1,
  3. J Zhao1,
  4. AM Jacko1,
  5. Y Zhao1,
  6. V Natarajan2,
  7. H Ma3
  1. 1University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  2. 2Pharmacology, University of Illinois at Chicago, Chicago, Illinois, United States
  3. 3Anesthesiology, Jilin University, Changchun, Jilin, China


Background Lysophosphatidic acid (LPA) is a bioactive lysophospholipid, which plays a crucial role in cell proliferation, migration, and differentiation. LPA exerts its biological effects mainly through 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 GPCR-mediated signaling. TrkA receptor is a RTK, which mediates nerve growth factor (NGF)-induced biological functions including cell migration in neuronal and non-neuronal tissues.

Methods and Results Here, we show that LPA treatment of the murine lung epithelial cell line (MLE-12 cells) induced tyrosine phosphorylation of TrkA in both time- and dose-dependent manners. These effects were attenuated by downregulating the LPA1 receptor. Furthermore, LPA induces interaction between LPA1 and TrkA. Co-immunoprecipitation experiment reveals that c-terminus of LPA1 contains the binding site for TrkA. Further, we found that LPA1 and phosphorylated TrkA were co-localized in both the plasma membrane and cytoplasm. Pretreatment with a TrkA inhibitor attenuated LPA-induced phosphorylation of TrkA receptor and LPA1 internalization as well as lung epithelial cell migration.

Conclusion These studies reveal 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.

This work was supported by the National Institutes of Health (R01HL091916 and R01HL112791 to Y.Z, R01GM115389 to J.Z.), American Heart Association 12SDG9050005 (J.Z.), American Lung Association Biomedical Research Grant RG350146 (J.Z.).

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