期刊
THROMBOSIS AND HAEMOSTASIS
卷 115, 期 5, 页码 969-978出版社
GEORG THIEME VERLAG KG
DOI: 10.1160/TH15-05-0373
关键词
Fibrinogen; haemostasis; integrin; platelets; thrombin; thrombosis
资金
- National Cancer Institute [CA134671]
- National Heart, Lung, and Blood Institute [HL118246, HL118742, HL062984, HL080070]
- American Society of Hematology
- American Heart Association postdoctoral award
Adaptor proteins play a critical role in the assembly of signalling complexes after engagement of platelet receptors by agonists such as collagen, ADP and thrombin. Recently, using proteomics, the Dok (downstream of tyrosine kinase) adapter proteins were identified in human and mouse platelets. In vitro studies suggest that Dok-1 binds to platelet integrin 33, but the underlying effects of Dok-1 on alpha IIb beta 3 signalling, platelet activation and thrombosis remain to be elucidated. In the present study, using Dok-1-deficient (Dok-1(-/-)) mice, we determined the phenotypic role of Dok-1 in alpha IIb beta 3 signalling. We found that platelets from Dok-1(-/-) mice displayed normal aggregation, activation of alpha IIb beta 3 (assessed by binding of JON/A), P-selectin surface expression (assessed by anti-CD62P), and soluble fibrinogen binding. These findings indicate that Dok-1 does not affect inside-out platelet signal ling. Compared with platelets from wild-type (WT) mice, platelets from Dok-1(-/-) mice exhibited increased clot retraction (p<0.05 vs WT), increased PLC gamma 2 phosphorylation, and enhanced spreading on fibrinogen after thrombin stimulation (p <0.01 vs WT), demonstrating that Dok-1 negatively regulates alpha IIb beta 3 outside-in signalling. Finally, we found that Dok-1(-/-) mice exhibited significantly shortened bleeding times and accelerated carotid artery thrombosis in response to photochemical injury (p <0.05 vs WT mice). We conclude that Dok-1 modulates thrombosis and haemostasis by negatively regulating alpha IIb beta 3 outside-in signalling.
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