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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

Alshehri, Osama M.; Montague, Samantha; Watson, Stephanie; Carter, Paul; Sarker, Najiat; Manne, Bhanu K.; Miller, Jeanette L.C.; Herr, Andrew B.; Pollitt, Alice Y.; O'Callaghan, Chris A.; Kunapuli, Satya; Arman, Monica; Hughes, Craig E.; Watson, Steve P.

Authors

Osama M. Alshehri

Samantha Montague

Stephanie Watson

Paul Carter

Najiat Sarker

Bhanu K. Manne

Jeanette L.C. Miller

Andrew B. Herr

Alice Y. Pollitt

Chris A. O'Callaghan

Satya Kunapuli

Monica Arman

Craig E. Hughes

Steve P. Watson



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 glycoproteinVI (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.

Journal Article Type Article
Publication Date Jun 15, 2015
Journal Biochemical Journal
Print ISSN 1470-8728
Electronic ISSN 1470-8728
Publisher Portland Press
Peer Reviewed Peer Reviewed
Volume 468
Issue 3
Pages 459-473
APA6 Citation Alshehri, O. M., Montague, S., Watson, S., Carter, P., Sarker, N., Manne, B. K., …Watson, S. P. (2015). 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. Biochemical Journal, 468(3), 459-473. https://doi.org/10.1042/BJ20150192
DOI https://doi.org/10.1042/BJ20150192
Keywords C-type lectin-like receptor-2 (CLEC-2); glycoprotein VI (GPVI); histones; Src; Syk; tyrosine kinase
Publisher URL http://www.biochemj.org/content/468/3/459
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