title: 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.
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.
authors: Centre for Cardiovascular Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham B15 2TT, U.K.
authors: Osama M
authors: OM
authors: Alshehri
authors: Centre for Cardiovascular Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham B15 2TT, U.K.
authors: Samantha
authors: S
authors: Montague
authors: Centre for Cardiovascular Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham B15 2TT, U.K. s.p.watson@bham.ac.uk.
authors: Stephanie
authors: S
authors: Watson
authors: Centre for Cardiovascular Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham B15 2TT, U.K.
authors: Paul
authors: P
authors: Carter
authors: Centre for Cardiovascular Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham B15 2TT, U.K.
authors: Najiat
authors: N
authors: Sarker
authors: Sol Sherry Thrombosis Research Center, Temple University Medical School, 3420 North Broad Street, Philadelphia, PA 19140, U.S.A.
authors: Bhanu K
authors: BK
authors: Manne
authors: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, U.S.A.
authors: Jeanette L C
authors: JL
authors: Miller
authors: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, U.S.A.
authors: Andrew B
authors: AB
authors: Herr
authors: Centre for Cardiovascular Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham B15 2TT, U.K.
authors: Alice Y
authors: AY
authors: Pollitt
authors: Nuffield Department of Clinical Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, U.K.
authors: Chris A
authors: CA
authors: O'Callaghan
authors: Sol Sherry Thrombosis Research Center, Temple University Medical School, 3420 North Broad Street, Philadelphia, PA 19140, U.S.A.
authors: Satya
authors: S
authors: Kunapuli
authors: Centre for Cardiovascular Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham B15 2TT, U.K.
authors: Mònica
authors: M
authors: Arman
authors: Centre for Cardiovascular Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham B15 2TT, U.K.
authors: Craig E
authors: CE
authors: Hughes
authors: Centre for Cardiovascular Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham B15 2TT, U.K. s.p.watson@bham.ac.uk.
authors: Steve P
authors: SP
authors: Watson
mesh_terms: D000393:Air Pollutants / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D018955:CD36 Antigens / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002645:Chickens; D003029:Coagulants / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003433:Crosses, Genetic; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D019169:Jurkat Cells; D037181:Lectins, C-Type / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D008822:Mice, Transgenic; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015202:Protein Engineering; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: D000393:Air Pollutants; D018955:CD36 Antigens; C529518:CLEC-2 protein, mouse; C104778:CLEC2B protein, human; D003029:Coagulants; D037181:Lectins, C-Type; D008024:Ligands; D008562:Membrane Glycoproteins; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D001335:Vehicle Emissions
keywords: C-type lectin-like receptor-2 (CLEC-2); Src; Syk; glycoprotein VI (GPVI); histones; tyrosine kinase