title: Kindlin-3 is essential for integrin activation and platelet aggregation.
abstract: Integrin-mediated platelet adhesion and aggregation are essential for sealing injured blood vessels and preventing blood loss, and excessive platelet aggregation can initiate arterial thrombosis, causing heart attacks and stroke. To ensure that platelets aggregate only at injury sites, integrins on circulating platelets exist in a low-affinity state and shift to a high-affinity state (in a process known as integrin activation or priming) after contacting a wounded vessel. The shift is mediated through binding of the cytoskeletal protein Talin to the beta subunit cytoplasmic tail. Here we show that platelets lacking the adhesion plaque protein Kindlin-3 cannot activate integrins despite normal Talin expression. As a direct consequence, Kindlin-3 deficiency results in severe bleeding and resistance to arterial thrombosis. Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis.
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Siegfried
authors.initials: S
authors.lastname: Ussar
authors.forename: Miroslava
authors.initials: M
authors.lastname: Pozgajova
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
mesh_terms: D000818:Animals; D002678:Chimera; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D022781:Hepatocytes / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D010024:Osteoporosis; D010974:Platelet Aggregation / Q000502:physiology*
chemical_list: D003598:Cytoskeletal Proteins; D016023:Integrins; C527818:kindlin-3 protein, mouse