Role of a JAK3-dependent biochemical signaling pathway in platelet activation and aggregation
Open accessAbstract
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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In a mouse model of thromboembolism induced by thromboplastin, treatment with WHI-P131 prolonged bleeding time and improved event-free survival.
“treatment of mice with WHI-P131 prolonged bleeding time and improved event-free survival”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Tibbles et al., 2001
Platelets from JAK3-deficient mice display reduced thrombin-induced increases in pY-STAT1 and pY-STAT3.
“platelets from JAK3-deficient mice displayed reduced thrombin-induced increases in pY-STAT1 and pY-STAT3”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Tibbles et al., 2001
Thrombin treatment activates STAT1 and STAT3.
“Thrombin treatment activates STAT1 and STAT3”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Tibbles et al., 2001
Pretreatment of human platelets with the JAK3 inhibitor WHI-P131 markedly diminishes pY-STAT1 and pY-STAT3 levels and diminishes all markers of platelet activation, including shape change, pseudopod formation, degranulation, serotonin release, and platelet aggregation.
“Pretreatment of human platelets with the JAK3 inhibitor, WHI-P131, markedly diminished pY-STAT1 and pY-STAT3 levels and diminished all markers of platelet activation, including shape change, pseudopod formation, degranulation, serotonin release, as well as platelet aggregation”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Tibbles et al., 2001
Cites
Imada, K., & Leonard, W. J. (2000) · Molecular Immunology · doi:10.1016/s0161-5890(00)00018-3 · Cited by 610 · see citing works
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“Recently, it was shown that an oxidative hepatic environment in obesity inactivates the STAT1 and STAT3 phosphatase T cell protein tyrosine phosphatase (TCPTP) and increases STAT1 and STAT3 signaling (Grohmann et al., 2018).”
BackgroundInfluentialA Role for STAT5 in the Pathogenesis of IL-2-Induced Glucocorticoid Resistance
Goleva, E., Kisich, K. O., & Leung, D. Y. M. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.10.5934 · Cited by 113 · see citing works
- Authors
- Tibbles, H. E., Vassilev, A., Wendorf, H., Schonhoff, D., Zhu, D., Lorenz, D., Waurzyniak, B., Liu, X.-P., & Uckun, F. M.
- Affiliations
- Parker Hughes Cancer Center (US)
- Corresponding author
- Uckun, Fatih M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-05
- Volume
- 276
- Issue
- 21
- Pages
- 17815-17822
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1989093949
- Cited by
- 51
- References
- 1
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 1 · 2014: 1 · 2013: 2 · 2012: 4
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- JAK3, platelet activation, platelet aggregation, thrombin, STAT1, STAT3, tyrosine phosphorylation, JAK3 inhibitors, platelet secretion, serotonin release, bleeding time, thromboembolism, antithrombotic agents
- MeSH terms
- Animals, DNA-Binding Proteins, Humans, Platelet Aggregation, Protein-Tyrosine Kinases, Quinazolines, Signal Transduction, Trans-Activators, Mice, Knockout, STAT1 Transcription Factor, STAT3 Transcription Factor, Mice, Janus Kinase 3
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