Ceramide 1-phosphate mediates endothelial cell invasion via the annexin a2-p11 heterotetrameric protein complex.

Academic Article


  • The bioactive sphingolipid, ceramide 1-phosphate (C-1-P), has been implicated as an extracellular chemotactic agent directing cellular migration in hematopoietic stem/progenitor cells and macrophages. However, interacting proteins that could mediate these actions of C-1-P have, thus far, eluded identification. We have now identified and characterized interactions between ceramide 1-phosphate and the annexin a2-p11 heterotetramer constituents. This C-1-P-receptor complex is capable of facilitating cellular invasion. Herein, we demonstrate in both coronary artery macrovascular endothelial cells and retinal microvascular endothelial cells that C-1-P induces invasion through an extracellular matrix barrier. By employing surface plasmon resonance, lipid-binding ELISA, and mass spectrometry technologies, we have demonstrated that the heterotetramer constituents bind to C-1-P. Although the annexin a2-p11 heterotetramer constituents do not bind the lipid C-1-P exclusively, other structurally similar lipids, such as phosphatidylserine, sphingosine 1-phosphate, and phosphatidic acid, could not elicit the potent chemotactic stimulation observed with C-1-P. Further, we show that siRNA-mediated knockdown of either annexin a2 or p11 protein significantly inhibits C-1-P-directed invasion, indicating that the heterotetrameric complex is required for C-1-P-mediated chemotaxis. These results imply that extracellular C-1-P, acting through the extracellular annexin a2-p11 heterotetrameric protein, can mediate vascular endothelial cell invasion.
  • Authors

  • Hankins, Jody L
  • Ward, Katherine E
  • Linton, Sam S
  • Barth, Brian
  • Stahelin, Robert V
  • Fox, Todd E
  • Kester, Mark
  • Status

    Publication Date

  • July 5, 2013
  • Published In


  • Annexin
  • Annexin A2
  • Annexin a2
  • Cell Invasion
  • Cells, Cultured
  • Ceramide 1-Phosphate
  • Ceramides
  • Chemotaxis
  • Endothelial Cell
  • Endothelial Cells
  • Extracellular Matrix
  • Humans
  • Multiprotein Complexes
  • Receptor
  • S100 Proteins
  • S100A10
  • Sphingolipid
  • p11
  • Digital Object Identifier (doi)

    Start Page

  • 19726
  • End Page

  • 19738
  • Volume

  • 288
  • Issue

  • 27