title: VAMP-7 links granule exocytosis to actin reorganization during platelet activation.
abstract: Platelet activation results in profound morphologic changes accompanied by release of granule contents. Recent evidence indicates that fusion of granules with the plasma membrane during activation provides auxiliary membrane to cover growing actin structures. Yet little is known about how membrane fusion is coupled with actin reorganization. Vesicle-associated membrane protein (VAMP)-7 is found on platelet vesicles and possesses an N-terminal longin domain capable of linking exocytosis to cytoskeletal remodeling. We have evaluated platelets from VAMP-7(-/-) mice to determine whether this VAMP isoform contributes to granule release and platelet spreading. VAMP-7(-/-) platelets demonstrated a partial defect in dense granule exocytosis and impaired aggregation. α Granule exocytosis from VAMP-7(-/-) platelets was diminished both in vitro and in vivo during thrombus formation. Consistent with a role of VAMP-7 in cytoskeletal remodeling, spreading on matrices was decreased in VAMP-7(-/-) platelets compared to wild-type controls. Immunoprecipitation of VAMP-7 revealed an association with VPS9-domain ankyrin repeat protein (VARP), an adaptor protein that interacts with both membrane-bound and cytoskeleton proteins and with Arp2/3. VAMP-7, VARP, and Arp2/3 localized to the platelet periphery during spreading. These studies demonstrate that VAMP-7 participates in both platelet granule secretion and spreading and suggest a mechanism whereby VAMP-7 links granule exocytosis with actin reorganization.
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;
authors.forename: Secil
authors.initials: S
authors.lastname: Koseoglu
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;
authors.forename: Christian G
authors.identifier: http://orcid.org/0000-0003-1857-2093
authors.initials: CG
authors.lastname: Peters
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Fitch-Tewfik
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;
authors.forename: Omozuanvbo
authors.initials: O
authors.lastname: Aisiku
authors.affiliation: Institut Jacques Monod, Unité Mixte de Recherche 7592, Centre National de la Recherche Scientifique, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; and INSERM Equipe de recherche labellisée U950, Membrane Traffic in Neuronal and Epithelial Morphogenesis, Paris, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Danglot
authors.affiliation: Institut Jacques Monod, Unité Mixte de Recherche 7592, Centre National de la Recherche Scientifique, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; and INSERM Equipe de recherche labellisée U950, Membrane Traffic in Neuronal and Epithelial Morphogenesis, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Galli
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;
authors.forename: Robert
authors.initials: R
authors.lastname: Flaumenhaft
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D051376:Actin-Related Protein 2-3 Complex / Q000097:blood; D000818:Animals; D001792:Blood Platelets / Q000502:physiology / Q000648:ultrastructure; D003594:Cytoplasmic Granules / Q000502:physiology; D005089:Exocytosis / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000097:blood; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000097:blood; D015539:Platelet Activation / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology; D050683:R-SNARE Proteins / Q000097:blood* / Q000172:deficiency / Q000235:genetics
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D020662:Guanine Nucleotide Exchange Factors; D019007:P-Selectin; D050683:R-SNARE Proteins; C496927:Sybl1 protein, mouse; C121241:VAMP7 protein, human; C512038:VPS9-ankyrin-repeat protein, mouse