Role of a JAK3-dependent biochemical signaling pathway in platelet activation and aggregation.
Here we provide experimental evidence that identifies JAK3 as one of the regulators of platelet function. Treatment of platelets with thrombin induced tyrosine phosphorylation of the JAK3 target substrates STAT1 and STAT3. Platelets from JAK3-deficient mice displayed a decrease in tyrosine phosphorylation of STAT1 and STAT3. In accordance with these data, pretreatment of human platelets with the JAK3 inhibitor WHI-P131 markedly decreased the base-line enzymatic activity of constitutively active JAK3 and abolished the thrombin-induced tyrosine phosphorylation of STAT1 and STAT3. Following thrombin stimulation, WHI-P131-treated platelets did not undergo shape changes indicative of activation such as pseudopod formation. WHI-P131 inhibited thrombin-induced degranulation/serotonin release as well as platelet aggregation. Highly effective platelet inhibitory plasma concentrations of WHI-P131 were achieved in mice without toxicity. WHI-P131 prolonged the bleeding time of mice in a dose-dependent manner and improved event-free survival in a mouse model of thromboplastin-induced generalized and invariably fatal thromboembolism. To our knowledge, WHI-P131 is the first anti-thrombotic agent that prevents platelet aggregation by inhibiting JAK3.
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HE
Parker Hughes Cancer Center, Departments of Hematology, Parker Hughes Institute, St. Paul, Minnesota, 55113, USA.
Vassilev
A
A
Wendorf
H
H
Schonhoff
D
D
Zhu
D
D
Lorenz
D
D
Waurzyniak
B
B
Liu
X P
XP
Uckun
F M
FM
D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D053616:Janus Kinase 3; D051379:Mice; D018345:Mice, Knockout; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011799:Quinazolines / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology
D004268:DNA-Binding Proteins; D011799:Quinazolines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C116180:WHI P131; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3