Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets.
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.
Schwertz
Hansjörg
H
Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA.
Tolley
Neal D
ND
Foulks
Jason M
JM
Denis
Melvin M
MM
Risenmay
Ben W
BW
Buerke
Michael
M
Tilley
Rachel E
RE
Rondina
Matthew T
MT
Harris
Estelle M
EM
Kraiss
Larry W
LW
Mackman
Nigel
N
Zimmerman
Guy A
GA
Weyrich
Andrew S
AS
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*
D012322:RNA Precursors; D013925:Thromboplastin; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases