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

AbstractBACKGROUND:
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.
AuthorsZhou Zhou, Francisca C Gushiken, Doug Bolgiano, Breia J Salsbery, Niloufar Aghakasiri, Naijie Jing, Xiaoping Wu, K Vinod Vijayan, Rolando E Rumbaut, Roberto Adachi, Jose A Lopez, Jing-Fei Dong
JournalCirculation (Circulation) Vol. 127 Issue 4 Pg. 476-485 (Jan 29 2013) ISSN: 1524-4539 [Electronic] United States
PMID23266857 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • IL6 protein, human
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Collagen
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Syk protein, mouse
  • Phospholipase C gamma
Topics
  • Animals
  • Atherosclerosis (metabolism)
  • Blood Platelets (cytology, drug effects, metabolism)
  • Collagen (metabolism, pharmacology)
  • HEK293 Cells
  • Humans
  • Interleukin-6 (metabolism)
  • Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phospholipase C gamma (metabolism)
  • Phosphorylation (physiology)
  • Platelet Aggregation (physiology)
  • Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
  • STAT3 Transcription Factor (genetics, metabolism)
  • Signal Transduction (physiology)
  • Syk Kinase
  • Thrombosis (metabolism)
  • Vasculitis (metabolism)

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