title: Signal transducer and activator of transcription 3 (STAT3) regulates collagen-induced platelet aggregation independently of its transcription factor activity.
abstract: BACKGROUND
  Platelet hyperactivity induced by inflammation is a known risk factor for atherosclerosis and thrombosis, but its underlying mechanisms remain poorly understood.
  
  
  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.
authors.affiliation: Puget Sound Blood Research Institute, Seattle, WA.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Leukemia, the University of Texas M. D. Anderson Cancer Center, Houston, TX.
authors.forename: Francisca C
authors.initials: FC
authors.lastname: Gushiken
authors.affiliation: Puget Sound Blood Research Institute, Seattle, WA.
authors.forename: Doug
authors.initials: D
authors.lastname: Bolgiano
authors.affiliation: Puget Sound Blood Research Institute, Seattle, WA.
authors.forename: Breia J
authors.initials: BJ
authors.lastname: Salsbery
authors.affiliation: Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, TX.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Aghakasiri
authors.affiliation: Section of Infectious Diseases, Baylor College of Medicine, Houston, TX.
authors.forename: Naijie
authors.initials: N
authors.lastname: Jing
authors.affiliation: Puget Sound Blood Research Institute, Seattle, WA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wu
authors.affiliation: Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, TX.
authors.forename: K Vinod
authors.initials: KV
authors.lastname: Vijayan
authors.affiliation: Section of Critical Care and Pulmonary Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX.|Michael E. DeBakey VA Medical Center, Houston, TX.
authors.forename: Rolando E
authors.initials: RE
authors.lastname: Rumbaut
authors.affiliation: Pulmonary Medicine, the University of Texas M. D. Anderson Cancer Center, Houston, TX.
authors.forename: Roberto
authors.initials: R
authors.lastname: Adachi
authors.affiliation: Puget Sound Blood Research Institute, Seattle, WA.|Division of Hematology, Department of Medicine, University of Washington, School of Medicine, Seattle, WA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Lopez
authors.affiliation: Puget Sound Blood Research Institute, Seattle, WA.|General Hospital, Tianjin Medical University, Tianjin, China.|Division of Hematology, Department of Medicine, University of Washington, School of Medicine, Seattle, WA.
authors.forename: Jing-Fei
authors.initials: JF
authors.lastname: Dong
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D010974:Platelet Aggregation / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000072377:Syk Kinase; D013927:Thrombosis / Q000378:metabolism; D014657:Vasculitis / Q000378:metabolism*
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D003094:Collagen; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051966:Phospholipase C gamma