title: Gas6 receptors Axl, Sky and Mer enhance platelet activation and regulate thrombotic responses.
abstract: Gas6 (encoded by growth arrest-specific gene 6) is a vitamin-K dependent protein highly homologous to coagulation protein S that is secreted from platelet alpha-granules and has recently been demonstrated to participate in platelet thrombus formation. The current study evaluated the contribution of each of the three known Gas6 receptors (Axl, Sky and Mer) in human and mouse platelet function. Flow cytometry analyses confirmed that all three receptors are present on both human and mouse platelets. Pre-incubation of human platelets with either an anti-Gas6 antibody or blocking antibodies to Sky or Mer inhibited platelet aggregation and degranulation responses to both ADP and the PAR-1 activating peptide, SFLLRN, by more than 80%. In contrast, a stimulatory anti-Axl antibody increased activation responses to these agonists, suggesting a potentiating role for Gas6 in platelet activation. Moreover, in a mouse model of thrombosis, administration of Gas6 or Sky blocking antibodies resulted in a decrease in thrombus weight similar to clopidogrel but, unlike clopidogrel, produced no increase in template bleeding. Thus, Gas6 enhances platelet degranulation and aggregation responses through its known receptors, promoting platelet activation and mediating thrombus formation such that its inhibition prevents thrombosis without increasing bleeding.
authors.affiliation: Pfizer Global Research and Development, Department of Cardiovascular Pharmacology, Ann Arbor, MI, USA.
authors.forename: W R
authors.initials: WR
authors.lastname: Gould
authors.forename: S M
authors.initials: SM
authors.lastname: Baxi
authors.forename: R
authors.initials: R
authors.lastname: Schroeder
authors.forename: Y W
authors.initials: YW
authors.lastname: Peng
authors.forename: R J
authors.initials: RJ
authors.lastname: Leadley
authors.forename: J T
authors.initials: JT
authors.lastname: Peterson
authors.forename: L A
authors.initials: LA
authors.lastname: Perrin
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry; D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism; D000077144:Clopidogrel; D005434:Flow Cytometry; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry; D015513:Oncogene Proteins / Q000502:physiology*; D010455:Peptides / Q000737:chemistry; D015539:Platelet Activation; D010974:Platelet Aggregation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D013927:Thrombosis / Q000378:metabolism*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D036341:Intercellular Signaling Peptides and Proteins; D009842:Oligopeptides; D015513:Oncogene Proteins; D010455:Peptides; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D029701:Saccharomyces cerevisiae Proteins; D013988:Ticlopidine; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C462999:PAR-1-activating peptide; C490216:SKY1 protein, S cerevisiae; C097072:MERTK protein, human; C084944:TYRO3 protein, human