title: Role of a Janus kinase 2-dependent signaling pathway in platelet activation.
abstract: BACKGROUND
  Janus kinases (JAKs) are intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals through a pathway mediated by JAK and the signal transducer and activator of transcription (STAT) proteins. The JAK-STAT pathway is involved in immune response, inflammation, and tumorigenesis. Platelets are anuclear blood cells that play a central role in hemostasis.
  
  
  METHODS
  The aggregometry, immunoblotting, and platelet functional analysis used in this study.
  
  
  RESULTS
  We found that the JAK2 inhibitor AG490 (25 and 50μM) attenuated collagen-induced platelet aggregation and calcium mobilization in a concentration-dependent manner. In the presence of AG490, the phosphorylation of PLCγ2, protein kinase C (PKC), Akt or JNK in collagen-activated aggregation of human platelets was also inhibited. In addition, we found that various inhibitors, such as the PLCγ2 inhibitor U73122, the PKC inhibitor Ro318220, the phospoinositide 3-kinase inhibitor LY294002, the p38 mitogen-activated protein kinase inhibitor SB203580, the ERK inhibitor PD98059, and the JNK inhibitor SP600125, had no effects on collagen-induced JAK2 activity. However, U73122, Ro318220 and SP600125 significantly diminished collagen-induced STAT3 phosphorylation. These findings suggest that PLCγ2-PKC and JNK are involved in JAK2-STAT3 signaling in collagen-activated platelets.
  
  
  CONCLUSIONS
  Our results demonstrate that the JAK2-STAT3 pathway is involved in collagen-induced platelet activation through the activation of JAK2-JNK/PKC-STAT3 signaling. The inhibition of JAK2 may represent a potential therapeutic strategy for the preventing or treating thromboembolic disorders.
authors.affiliation: Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wan-Jung
authors.initials: WJ
authors.lastname: Lu
authors.affiliation: Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Neurology, Chi Mei Medical Center, Tainan, Taiwan.
authors.forename: Kao-Chang
authors.initials: KC
authors.lastname: Lin
authors.affiliation: School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shih-Yi
authors.initials: SY
authors.lastname: Huang
authors.affiliation: Department of Microbiology, Institute of Ophthalmology, Joseph Eye Hospital, Tiruchirappalli, Tamil Nadu, India.
authors.forename: Philip Aloysius
authors.initials: PA
authors.lastname: Thomas
authors.affiliation: Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Wu
authors.affiliation: Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hsu-Chu
authors.initials: HC
authors.lastname: Wu
authors.affiliation: Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan; Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan. Electronic address: d102092002@tmu.edu.tw.
authors.forename: Kuan-Hung
authors.initials: KH
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: sheujr@tmu.edu.tw.
authors.forename: Joen-Rong
authors.initials: JR
authors.lastname: Sheu
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000097:blood*; D020935:MAP Kinase Signaling System; D051379:Mice; D010766:Phosphorylation; D015539:Platelet Activation / Q000502:physiology*; D011493:Protein Kinase C / Q000097:blood; D050796:STAT3 Transcription Factor / Q000097:blood; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D011493:Protein Kinase C
keywords: AG490; JAK2; JNK; PKC; Platelet activation