ArticleThe Journal of biological chemistry2009
Non-redundant roles of phosphoinositide 3-kinase isoforms alpha and beta in glycoprotein VI-induced platelet signaling and thrombus formation.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 129 citations in OpenAlex.
- Article
- A computational framework for the investigation of phosphoinositide regulation.PLoS computational biology · 2025Article
- Extended Modelling of Molecular Calcium Signalling in Platelets by Combined Recurrent Neural Network and Partial Least Squares Analyses.International journal of molecular sciences · 2025Article
- Platelets and diseases: signal transduction and advances in targeted therapy.Signal transduction and targeted therapy · 2025Review
- Suppressed ORAI1-STIM1-dependent CaThe Journal of biological chemistry · 2024Article
- Platelet Activation Pathways Controlling Reversible Integrin αIIbβ3 Activation.TH open : companion journal to thrombosis and haemostasis · 2024Article
- Ultra-high throughput-based screening for the discovery of antiplatelet drugs affecting receptor dependent calcium signaling dynamics.Scientific reports · 2024Article
- Study on the Mechanism of the Adrenaline-Evoked Procoagulant Response in Human Platelets.International journal of molecular sciences · 2024Article
- Integrating Phenotypic and Chemoproteomic Approaches to Identify Covalent Targets of Dietary Electrophiles in Platelets.ACS central science · 2024Article
- Restraining of glycoprotein VI- and integrin α2β1-dependent thrombus formation by platelet PECAM1.Cellular and molecular life sciences : CMLS · 2024Article
- Article
- Current concepts and novel targets for antiplatelet therapy.Nature reviews. Cardiology · 2023Review
- The role of phosphoinositide 3-kinases in immune-inflammatory responses: potential therapeutic targets for abdominal aortic aneurysm.Cell cycle (Georgetown, Tex.) · 2022Review
- Reversible Platelet Integrin αIIbβ3 Activation and Thrombus Instability.International journal of molecular sciences · 2022Review
- Coagulation Factor XIIIa and Activated Protein C Activate Platelets via GPVI and PAR1.International journal of molecular sciences · 2022Article
- Modulation of Glycoprotein VI and Its Downstream Signaling Pathways as an Antiplatelet Target.International journal of molecular sciences · 2022Review
- Effects of Platelet Agonists and Priming on the Formation of Platelet Populations.Thrombosis and haemostasis · 2022Article
- Review
- Ultra-high-throughput CaiScience · 2022Article
- PI3K Isoform Signalling in Platelets.Current topics in microbiology and immunology · 2022Article
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Platelets are activated by adhesion to vascular collagen via the immunoglobulin receptor, glycoprotein VI (GPVI). This causes potent signaling toward activation of phospholipase Cgamma2, which bears similarity to the signaling pathway evoked by T- and B-cell receptors. Phosphoinositide 3-kinase (PI3K) plays an important role in collagen-induced platelet activation, because this activity modulates the autocrine effects of secreted ADP. Here, we identified the PI3K isoforms directly downstream of GPVI in human and mouse platelets and determined their role in GPVI-dependent thrombus formation. The targeting of platelet PI3Kalpha or -beta strongly and selectively suppressed GPVI-induced Ca(2+) mobilization and inositol 1,4,5-triphosphate production, thus demonstrating enhancement of phospholipase Cgamma2 by PI3Kalpha/beta. That PI3Kalpha and -beta have a non-redundant function in GPVI-induced platelet activation and thrombus formation was concluded from measurements of: (i) serine phosphorylation of Akt, (ii) dense granule secretion, (iii) intracellular Ca(2+) increases and surface expression of phosphatidylserine under flow, and (iv) thrombus formation, under conditions where PI3Kalpha/beta was blocked or p85alpha was deficient. In contrast, GPVI-induced platelet activation was insensitive to inhibition or deficiency of PI3Kdelta or -gamma. Furthermore, PI3Kalpha/beta, but not PI3Kgamma, contributed to GPVI-induced Rap1b activation and, surprisingly, also to Rap1b-independent platelet activation via GPVI. Together, these findings demonstrate that both PI3Kalpha and -beta isoforms are required for full GPVI-dependent platelet Ca(2+) signaling and thrombus formation, partly independently of Rap1b. This provides a new mechanistic explanation for the anti-thrombotic effect of PI3K inhibition and makes PI3Kalpha an interesting new target for anti-platelet therapy.
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