title: Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets.
abstract: Tissue factor (TF) is an essential cofactor for the activation of blood coagulation in vivo. We now report that quiescent human platelets express TF pre-mRNA and, in response to activation, splice this intronic-rich message into mature mRNA. Splicing of TF pre-mRNA is associated with increased TF protein expression, procoagulant activity, and accelerated formation of clots. Pre-mRNA splicing is controlled by Cdc2-like kinase (Clk)1, and interruption of Clk1 signaling prevents TF from accumulating in activated platelets. Elevated intravascular TF has been reported in a variety of prothrombotic diseases, but there is debate as to whether anucleate platelets-the key cellular effector of thrombosis-express TF. Our studies demonstrate that human platelets use Clk1-dependent splicing pathways to generate TF protein in response to cellular activation. We propose that platelet-derived TF contributes to the propagation and stabilization of a thrombus.
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schwertz
authors.forename: Neal D
authors.initials: ND
authors.lastname: Tolley
authors.forename: Jason M
authors.initials: JM
authors.lastname: Foulks
authors.forename: Melvin M
authors.initials: MM
authors.lastname: Denis
authors.forename: Ben W
authors.initials: BW
authors.lastname: Risenmay
authors.forename: Michael
authors.initials: M
authors.lastname: Buerke
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Tilley
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Rondina
authors.forename: Estelle M
authors.initials: EM
authors.lastname: Harris
authors.forename: Larry W
authors.initials: LW
authors.lastname: Kraiss
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.forename: Guy A
authors.initials: GA
authors.lastname: Zimmerman
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Weyrich
mesh_terms: D001777:Blood Coagulation / Q000276:immunology*; D001792:Blood Platelets / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D015539:Platelet Activation / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013925:Thromboplastin / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D012322:RNA Precursors; D013925:Thromboplastin; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases