The Catalytic Subunit of Protein Phosphatase 1 Gamma Regulates Thrombin-Induced Murine Platelet αIIbβ3 Function
Copyright policy )The Catalytic Subunit of Protein Phosphatase 1 Gamma Regulates Thrombin-Induced Murine Platelet αIIbβ3 Function
Hemostasis and thrombosis are regulated by agonist-induced activation of platelet integrin alpha(IIb)beta(3). Integrin activation, in turn is mediated by cellular signaling via protein kinases and protein phosphatases. Although the catalytic subunit of protein phosphatase 1 (PP1c) interacts with alpha(IIb)beta(3), the role of PP1c in platelet reactivity is unclear.Using gamma isoform of PP1c deficient mice (PP1cgamma(-/-)), we show that the platelets have moderately decreased soluble fibrinogen binding and aggregation to low concentrations of thrombin or protease-activated receptor 4 (PAR4)-activating peptide but not to adenosine diphosphate (ADP), collagen or collagen-related peptide (CRP). Thrombin-stimulated PP1cgamma(-/-) platelets showed decreased alpha(IIb)beta(3) activation despite comparable levels of alpha(IIb)beta(3), PAR3, PAR4 expression and normal granule secretion. Functions regulated by outside-in integrin alpha(IIb)beta(3) signaling like adhesion to immobilized fibrinogen and clot retraction were not altered in PP1cgamma(-/-) platelets. Thrombus formation induced by a light/dye injury in the cremaster muscle venules was significantly delayed in PP1cgamma(-/-) mice. Phosphorylation of glycogen synthase kinase (GSK3)beta-serine 9 that promotes platelet function, was reduced in thrombin-stimulated PP1cgamma(-/-) platelets by an AKT independent mechanism. Inhibition of GSK3beta partially abolished the difference in fibrinogen binding between thrombin-stimulated wild type and PP1cgamma(-/-) platelets.These studies illustrate a role for PP1cgamma in maintaining GSK3beta-serine9 phosphorylation downstream of thrombin signaling and promoting thrombus formation via fibrinogen binding and platelet aggregation.
- Baylor College of Medicine United States
- South Central VA Health Care Network United States
- BAYLOR COLLEGE OF MEDICINE
- Michael E. DeBakey VA Medical Center United States
Blood Platelets, Platelet Aggregation, Science, Platelet Glycoprotein GPIIb-IIIa Complex, Glycogen Synthase Kinase 3, Mice, Phosphoserine, Catalytic Domain, Protein Phosphatase 1, Animals, Glycogen Synthase Kinase 3 beta, Secretory Vesicles, Q, R, Thrombin, Fibrinogen, Thrombosis, Isoenzymes, Disease Models, Animal, Medicine, Receptors, Thrombin, Proto-Oncogene Proteins c-akt, Research Article, Signal Transduction
Blood Platelets, Platelet Aggregation, Science, Platelet Glycoprotein GPIIb-IIIa Complex, Glycogen Synthase Kinase 3, Mice, Phosphoserine, Catalytic Domain, Protein Phosphatase 1, Animals, Glycogen Synthase Kinase 3 beta, Secretory Vesicles, Q, R, Thrombin, Fibrinogen, Thrombosis, Isoenzymes, Disease Models, Animal, Medicine, Receptors, Thrombin, Proto-Oncogene Proteins c-akt, Research Article, Signal Transduction
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