Journal article
Dok-1 Negatively Regulates Platelet Integrin αIIbβ3 Outside-in Signaling and Inhibits Thrombosis in Mice
Thrombosis and haemostasis, Vol.115(5), pp.969-978
05/02/2016
DOI: 10.1160/TH15-05-0373
PMCID: PMC4854776
PMID: 26790499
Abstract
Adaptor proteins play a critical role in the assembly of signaling 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 β3, but the underlying effects of Dok-1 on αIIbβ3 signaling, 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 αIIbβ3 signaling. We found that platelets from
Dok-1
−/−
mice displayed normal aggregation, activation of αIIbβ3 (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 signaling. Compared with platelets from wild-type (WT) mice, platelets from
Dok-1
−/−
mice exhibited increased clot retraction (
P
< 0.05 vs WT), increased PLCγ2 phosphorylation, and enhanced spreading on fibrinogen after thrombin stimulation (
P
< 0.01 vs. WT), demonstrating that Dok-1 negatively regulates αIIbβ3 “outside-in” signaling. 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 hemostasis by negatively regulating αIIbβ3 outside-in signaling.
Details
- Title: Subtitle
- Dok-1 Negatively Regulates Platelet Integrin αIIbβ3 Outside-in Signaling and Inhibits Thrombosis in Mice
- Creators
- Masaru Niki - Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IAManasa K Nayak - Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IAHong Jin - Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IANeha Bhasin - Department of Pediatrics, The University of Iowa Carver College of Medicine, Iowa City, IAEdward F Plow - Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OHPier Paolo Pandolfi - Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MAPaul B Rothman - Johns Hopkins University School of Medicine, Baltimore, MDAnil K Chauhan - Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IASteven R Lentz - Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA
- Resource Type
- Journal article
- Publication Details
- Thrombosis and haemostasis, Vol.115(5), pp.969-978
- DOI
- 10.1160/TH15-05-0373
- PMID
- 26790499
- PMCID
- PMC4854776
- NLM abbreviation
- Thromb Haemost
- ISSN
- 0340-6245
- eISSN
- 2567-689X
- Grant note
- DOI: 10.13039/100000054, name: National Cancer Institute, award: CA134671; DOI: 10.13039/100000050, name: National Heart, Lung, and Blood Institute, award: HL118246 and HL118742 to AKC, HL062984 to SRL, and HL080070
- Language
- English
- Date published
- 05/02/2016
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094370102771
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