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

被引:34
作者
Alshehri, Osama M. [1 ]
Montague, Samantha [1 ]
Watson, Stephanie [1 ]
Carter, Paul [1 ]
Sarker, Najiat [1 ]
Manne, Bhanu K. [2 ]
Miller, Jeanette L. C. [3 ]
Herr, Andrew B. [3 ]
Pollitt, Alice Y. [1 ]
O'Callaghan, Chris A. [4 ]
Kunapuli, Satya [2 ]
Arman, Monica [1 ]
Hughes, Craig E. [1 ]
Watson, Steve P. [1 ]
机构
[1] Univ Birmingham, Sch Med, Inst Biomed Res, Ctr Cardiovasc Sci, Birmingham B15 2TT, W Midlands, England
[2] Temple Univ, Sol Sherry Thrombosis Res Ctr, Sch Med, Philadelphia, PA 19140 USA
[3] Cincinnati Childrens Hosp Med Ctr, Div Immunobiol, Cincinnati, OH 45229 USA
[4] Univ Oxford, Nuffield Dept Clin Med, Henry Wellcome Bldg Mol Physiol, Oxford OX3 7BN, England
基金
英国惠康基金;
关键词
C-type lectin-like receptor-2 (CLEC-2); glycoprotein VI (GPVI); histones; Src; Syk; tyrosine kinase; GAMMA-CHAIN; SIGNALING CASCADE; SYK; COLLAGEN; THROMBOSIS; HISTONES; DIMERIZATION; AGGREGATION; PEPTIDE; AGONIST;
D O I
10.1042/BJ20150192
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 gamma-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.
引用
收藏
页码:459 / 473
页数:15
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