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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.

Original publication

DOI

10.1042/BJ20150192

Type

Journal article

Journal

Biochem J

Publication Date

15/06/2015

Volume

468

Pages

459 - 473

Keywords

C-type lectin-like receptor-2 (CLEC-2), Src, Syk, glycoprotein VI (GPVI), histones, tyrosine kinase, Air Pollutants, Animals, CD36 Antigens, 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