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Cited by 75Platelet Disorders and TreatmentsCytokine Signaling Pathways and InteractionsBlood Coagulation and Thrombosis Mechanisms

Signal transducer and activator of transcription 3 (STAT3) regulates collagen-induced platelet aggregation independently of its transcription factor activity

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Zhou, Zhou, Gushiken, Francisca C., Bolgiano, Doug, Salsbery, Breia J., Aghakasiri, Niloufar, Jing, Naijie, Wu, Xiaoping, Vijayan, K. Vinod +4 more·2013·Circulation
DOI 10.1161/circulationaha.112.132126PMC PMC4472638
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Abstract

BACKGROUND: Platelet hyperactivity induced by inflammation is a known risk factor for atherosclerosis and thrombosis, but its underlying mechanisms remain poorly understood. METHODS AND RESULTS: The signal transducer and activator of transcription 3 (STAT3) was activated in collagen-stimulated platelets. Activated STAT3 served as a protein scaffold to facilitate the catalytic interaction between the kinase Syk (spleen tyrosine kinase) and the substrate PLCγ2 to enhance collagen-induced calcium mobilization and platelet activation. The same interaction of STAT3 with Syk and PLCγ2 was detected in HEK293 cells transfected with cDNAs for Syk and PLCγ2 and stimulated with interleukin-6. Pharmacological inhibition of STAT3 blocked ≈50% of collagen- and a collagen-related peptide-induced but not thrombin receptor-activating peptide- or ADP-induced aggregation and ≈80% of thrombus formation of human platelets on a collagen matrix. This in vitro phenotype was reproduced in mice infused with STAT3 inhibitors and mice with platelet-specific STAT3 deficiency. By forming a complex with its soluble receptor, the proinflammatory cytokine interleukin-6 enhanced the collagen-induced STAT3 activation in human platelets. CONCLUSIONS: These data demonstrate a nontranscriptional activity of STAT3 that facilitates a crosstalk between proinflammatory cytokine and hemostasis/thrombosis signals in platelets. This crosstalk may be responsible for the platelet hyperactivity found in conditions of inflammation.

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  • STAT3 forms a complex with Syk and PLCγ2 to mediate platelet activation and aggregation.

    “STAT3 forms a complex with Syk and PLCγ2 to mediate platelet activation and 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 Zhou et al., 2013

    The Discussion reports that STAT3 interacts with Syk and PLCγ2, likely forming a three-molecule complex that enhances collagen-induced platelet activation and aggregation. The claim omits the collagen-specific condition and states complex formation more definitively than the Discussion does; the Abstract’s Methods and Results also reports no inhibition of ADP- or TRAP-induced aggregation. (LLM, conf=0.82)

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Authors
Zhou, Z., Gushiken, F. C., Bolgiano, D., Salsbery, B. J., Aghakasiri, N., Jing, N., Wu, X., Vijayan, K. V., Rumbaut, R. E., Adachi, R., Lopez, J. A., & Dong, J.-F.
Affiliations
  • Michael E. DeBakey VA Medical Center (US)
  • From the Puget Sound Blood Center Research Institute, Seattle, WA (Z.Z., D.B., B.J.S., X.W., J.A.L., J.-f.D.); Departments of Leukemia (F.C.G.) and Pulmonary Medicine (R.A.), University of Texas M.D. Anderson Cancer Center, Houston; Sections of Cardiovascular Sciences (N.A., K.V.V.), Infectious Diseases (N.J.), and Critical Care and Pulmonary Medicine (R.E.R.), Department of Medicine, Baylor College of Medicine, Houston, TX; Michael E. DeBakey VA Medical Center, Houston, TX (R.E.R.); General...
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2013-01-29
Volume
127
Issue
4
Pages
476-485
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.112.132126
PMC
PMC4472638
OpenAlex
W2063356644
Cited by
75
References
1
Citations by year
2026: 3 · 2025: 5 · 2024: 2 · 2023: 6 · 2022: 4 · 2021: 8 · 2020: 5 · 2019: 12 · 2018: 5 · 2017: 8 · 2016: 3 · 2015: 6 · 2014: 3 · 2013: 4 · 2012: 1
FWCI
2.99
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX000550)
  • National Heart, Lung, and Blood Institute (HL-081613, HL 71895, R01HL071895, R01HL081613)
  • National Cancer Institute (R01CA104035, CA104035)
Topics
  • Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
Keywords
STAT3, platelet aggregation, collagen-induced platelet activation, Syk, PLCγ2, interleukin-6, inflammation, thrombosis, atherosclerosis, thrombus formation, platelet hyperreactivity, hemostasis, STAT3 inhibitor
MeSH terms
Syk Kinase, Animals, Blood Platelets, Collagen, Humans, Mice, Inbred C57BL, Phosphorylation, Platelet Aggregation, Protein-Tyrosine Kinases, Thrombosis, Vasculitis, Signal Transduction, Interleukin-6, Mice, Knockout, Intracellular Signaling Peptides and Proteins, Atherosclerosis, STAT3 Transcription Factor, Mice, Phospholipase C gamma, HEK293 Cells

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