Abstract
Objective:
Recently, mice made deficient in growth arrest-specific gene 6 product (Gas6) or in which Gas6 gene expression was inhibited were shown to have platelet dysfunction and to be less susceptible to thrombosis. The aim of this study was to define and characterize the relevant Gas6 receptor or receptors involved in platelet function.
Methods and results:
Using RT-PCR and Western blot analysis we found that mer was the predominantly expressed subtype in mouse and human platelets, whereas axl and rse were not detected. We generated mer-deficient mice by targeted disruption of the mer receptor gene. Platelets derived from mer-deficient mice had decreased platelet aggregation in responses to low concentrations of collagen, U46619, and PAR4 thrombin receptor agonist peptide in vitro. However, the response to ADP was not different from wild-type platelets. Knockout of the mer gene protected mice from collagen/epinephrine-induced pulmonary thromoembolism and inhibited ferric chloride-induced thrombosis in vivo. Tail bleeding times, coagulation parameters, and peripheral blood cell counts in mer-deficient mice were similar to wild-type mice.
Conclusions:
Our data provide the first evidence that mer, presumably through activation by its ligand Gas6, participates in regulation of platelet function in vitro and platelet-dependent thrombosis in vivo.
MeSH terms
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15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / pharmacology
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Animals
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Axl Receptor Tyrosine Kinase
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Blood Coagulation Tests
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Blood Platelets / enzymology*
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Blood Platelets / physiology
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Blotting, Western
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Chlorides
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Collagen / pharmacology
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Collagen / toxicity
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Epinephrine / toxicity
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Female
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Ferric Compounds / toxicity
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Humans
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Intercellular Signaling Peptides and Proteins / physiology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Oligopeptides / pharmacology
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Oncogene Proteins / analysis
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Platelet Aggregation / drug effects
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Receptor Protein-Tyrosine Kinases / analysis
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Receptor Protein-Tyrosine Kinases / deficiency
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / physiology*
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Receptors, Thrombin / agonists
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Reverse Transcriptase Polymerase Chain Reaction
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Thromboembolism / chemically induced
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c-Mer Tyrosine Kinase
Substances
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Chlorides
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Ferric Compounds
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Intercellular Signaling Peptides and Proteins
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Oligopeptides
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Oncogene Proteins
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Proto-Oncogene Proteins
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Receptors, Thrombin
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alanyl-tyrosyl-prolyl-glycyl-lysyl-phenylalanine
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growth arrest-specific protein 6
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15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
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Collagen
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MERTK protein, human
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Mertk protein, mouse
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Receptor Protein-Tyrosine Kinases
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TYRO3 protein, human
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c-Mer Tyrosine Kinase
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protease-activated receptor 4
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ferric chloride
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Epinephrine
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Axl Receptor Tyrosine Kinase