Activation of glycoprotein VI (GPVI) and C-type lectin-like receptor-2 (CLEC-2) underlies platelet activation by diesel exhaust particles and other charged/hydrophobic ligands

Research output: Contribution to journalArticle

Authors

  • Osama M Alshehri
  • Samantha Montague
  • Stephanie Watson
  • Paul Carter
  • Najiat Sarker
  • Bhanu K Manne
  • Jeanette L C Miller
  • Andrew B Herr
  • Chris A O'Callaghan
  • Satya Kunapuli
  • Mònica Arman

Colleges, School and Institutes

Abstract

Platelets are activated by a range of stimuli that share little or no resemblance in structure to each other or to recognized ligands, including diesel exhaust particles (DEP), small peptides [4N1-1, Champs (computed helical anti-membrane proteins), LSARLAF (Leu-Ser-Ala-Arg-Leu-Ala-Phe)], proteins (histones) and large polysaccharides (fucoidan, dextran sulfate). This miscellaneous group stimulate aggregation of human and mouse platelets through the glycoprotein VI (GPVI)-FcR γ-chain complex and/or C-type lectin-like receptor-2 (CLEC-2) as shown using platelets from mice deficient in either or both of these receptors. In addition, all of these ligands stimulate tyrosine phosphorylation in GPVI/CLEC-2-double-deficient platelets, indicating that they bind to additional surface receptors, although only in the case of dextran sulfate does this lead to activation. DEP, fucoidan and dextran sulfate, but not the other agonists, activate GPVI and CLEC-2 in transfected cell lines as shown using a sensitive reporter assay confirming a direct interaction with the two receptors. We conclude that this miscellaneous group of ligands bind to multiple proteins on the cell surface including GPVI and/or CLEC-2, inducing activation. These results have pathophysiological significance in a variety of conditions that involve exposure to activating charged/hydrophobic agents.

Details

Original languageEnglish
Pages (from-to)459-73
Number of pages15
JournalBiochem J
Volume468
Issue number3
Publication statusPublished - 15 Jun 2015

Keywords

  • Air Pollutants, Animals, Antigens, CD36, Cell Line, Chickens, Coagulants, Crosses, Genetic, Genes, Reporter, Humans, Hydrophobic and Hydrophilic Interactions, Jurkat Cells, Lectins, C-Type, Ligands, Membrane Glycoproteins, Mice, Transgenic, Molecular Conformation, Peptides, Phosphorylation, Platelet Activation, Platelet Aggregation Inhibitors, Protein Engineering, Protein Processing, Post-Translational, Recombinant Proteins, Vehicle Emissions