Wan-Jung Lu1, Kao-Chang Lin2, Shih-Yi Huang3, Philip Aloysius Thomas4, Yu-Hua Wu5, Hsu-Chu Wu5, Kuan-Hung Lin6, Joen-Rong Sheu7. 1. 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. 2. 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. 3. School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan. 4. Department of Microbiology, Institute of Ophthalmology, Joseph Eye Hospital, Tiruchirappalli, Tamil Nadu, India. 5. Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan. 6. 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. 7. Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: sheujr@tmu.edu.tw.
Abstract
INTRODUCTION: 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. CONCLUSION: 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.
INTRODUCTION: 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. CONCLUSION: 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: Sokha Nhek; Robert Clancy; Kristen A Lee; Nicole M Allen; Tessa J Barrett; Emanuela Marcantoni; Janet Nwaukoni; Sara Rasmussen; Maya Rubin; Jonathan D Newman; Jill P Buyon; Jeffrey S Berger Journal: Arterioscler Thromb Vasc Biol Date: 2017-02-02 Impact factor: 8.311
Authors: Iván Parra-Izquierdo; Alexander R Melrose; Jiaqing Pang; Hari Hara Sudhan Lakshmanan; Stéphanie E Reitsma; Sai Hitesh Vavilapalli; Mark K Larson; Joseph J Shatzel; Owen J T McCarty; Joseph E Aslan Journal: Platelets Date: 2021-06-07 Impact factor: 4.236