Diacylglycerol kinase ζ is a negative regulator of GPVI-mediated platelet activation. Blood Adv 2019 Apr 09;3(7):1154-1166
Date
04/11/2019Pubmed ID
30967391Pubmed Central ID
PMC6457232DOI
10.1182/bloodadvances.2018026328Scopus ID
2-s2.0-85068307036 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
Diacylglycerol kinases (DGKs) are a family of enzymes that convert diacylglycerol (DAG) into phosphatidic acid (PA). The ζ isoform of DGK (DGKζ) has been reported to inhibit T-cell responsiveness by downregulating intracellular levels of DAG. However, its role in platelet function remains undefined. In this study, we show that DGKζ was expressed at significant levels in both platelets and megakaryocytes and that DGKζ-knockout (DGKζ-KO) mouse platelets were hyperreactive to glycoprotein VI (GPVI) agonists, as assessed by aggregation, spreading, granule secretion, and activation of relevant signal transduction molecules. In contrast, they were less responsive to thrombin. Platelets from DGKζ-KO mice accumulated faster on collagen-coated microfluidic surfaces under conditions of arterial shear and stopped blood flow faster after ferric chloride-induced carotid artery injury. Other measures of hemostasis, as measured by tail bleeding time and rotational thromboelastometry analysis, were normal. Interestingly, DGKζ deficiency led to increased GPVI expression on the platelet and megakaryocyte surfaces without affecting the expression of other platelet surface receptors. These results implicate DGKζ as a novel negative regulator of GPVI-mediated platelet activation that plays an important role in regulating thrombus formation in vivo.
Author List
Moroi AJ, Zwifelhofer NM, Riese MJ, Newman DK, Newman PJAuthors
Debra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinDebra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBlood Platelets
Diacylglycerol Kinase
Hemostasis
Humans
Megakaryocytes
Mice
Mice, Knockout
Platelet Activation
Platelet Membrane Glycoproteins
Thrombosis
