Original Articles
Vol. 2 No. 3 (2023)
Restrained glycoprotein VI-induced platelet signaling by tyrosine protein phosphatases independent of phospholipase Cγ2
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Received: 18 July 2023
Accepted: 23 September 2023
Accepted: 23 September 2023
521
Views
209
Downloads
Authors
The platelet collagen receptor glycoprotein VI (GPVI) signals to activation of phospholipase Cγ2 (PLCγ2) and phosphoinositide 3-kinases (PI3K), causing platelet activation and aggregation. The non-receptor Src homology tyrosine phosphatases Shp1/2 modulate GPVI signaling in partly opposite ways, both of which are targeted by the potential drug NSC87877. Effect measurements of the Shp1/2 inhibitor NSC87877 on platelet activation via GPVI using light transmission aggregometry, Ca2+ flux assay, western blotting and flow cytometry. Effect measurements of selective PI3K inhibitor TGX221. Inhibition of Shp1/2 with NSC87877 enhanced platelet aggregation induced by the GPVI agonist, collagen-related peptide (CRP). Furthermore, NSC87877 antagonized the effects of PI3Kb inhibition, but not of Btk inhibition. Both NSC87877 and TGX221 suppressed the CRP-induced phosphorylation of PLCγ2 at activation site Tyr759. These findings indicate that drug interference of the two phosphatases Shp1/2 subtly enhances GPVI-induced platelet responses via a mechanism not involving PLCγ2 activation, even upon PI3K inhibition.
Downloads
Download data is not yet available.
Citations
Rayes J, Watson SP, Nieswandt B. Functional significance of the platelet immune receptors GPVI and CLEC-2. J Clin Invest. 2019;129:12-23. DOI: https://doi.org/10.1172/JCI122955
Van der Meijden PE, Heemskerk JW. Platelet biology and functions: new concepts and clinical perspectives. Nat Rev Cardiol. 2019;16:166-79. DOI: https://doi.org/10.1038/s41569-018-0110-0
Huang J, Zhang P, Solari FA, et al. Molecular proteomics and signalling of human platelets in health and disease. Int J Mol Sci. 2021;22:9860. DOI: https://doi.org/10.3390/ijms22189860
Watson SP, Auger JM, McCarty OJ, et al. GPVI and integrin aIIbb3 signaling in platelets. J Thromb Haemost. 2005;3:1752-62. DOI: https://doi.org/10.1111/j.1538-7836.2005.01429.x
Versteeg HH, Heemskerk JW, Levi M, et al. New fundamentals in hemostasis. Physiol Rev. 2013;93:327-58. DOI: https://doi.org/10.1152/physrev.00016.2011
Jandrot-Perrus M, Hermans C, Mezzano D. Platelet glycoprotein VI genetic quantitative and qualitative defects. Platelets. 2019;30:708-13. DOI: https://doi.org/10.1080/09537104.2019.1610166
Nagy M, Perrella G, Dalby A, et al. Flow studies on human GPVI-deficient blood under coagulating and noncoagulating conditions. Blood Adv. 2020;4:2953-61. DOI: https://doi.org/10.1182/bloodadvances.2020001761
Moraes LA, Barrett NE, Jones CI, et al. Platelet endothelial cell adhesion molecule-1 regulates collagen-stimulated platelet function by modulating the association of phosphatidylinositol 3-kinase with Grb-2-associated binding protein-1 and linker for activation of T cells. J Thromb Haemost. 2010;8:2530-341. DOI: https://doi.org/10.1111/j.1538-7836.2010.04025.x
Mazharian A, Mori J, Wang YJ, et al. Megakaryocyte-specific deletion of the protein-tyrosine phosphatases Shp1 and Shp2 causes abnormal megakaryocyte development, platelet production, and function. Blood. 2013;121:4205-20. DOI: https://doi.org/10.1182/blood-2012-08-449272
Coxon CH, Geer MJ, Senis YA. ITIM receptors: more than just inhibitors of platelet activation. Blood. 2017;129:3407-18. DOI: https://doi.org/10.1182/blood-2016-12-720185
Huang J, Swieringa F, Solari FA, et al. Assessment of a complete and classified platelet proteome from genome-wide transcripts of human platelets and megakaryocytes covering platelet functions. Sci Rep. 2021;11:12358. DOI: https://doi.org/10.1038/s41598-021-91661-x
Heemskerk JW. More than reverting tyrosine kinases. Blood. 2022;140:939-41. DOI: https://doi.org/10.1182/blood.2022017208
Ma P, Cierniewska A, Signarvic R, et al. A newly identified complex of spinophilin and the tyrosine phosphatase Shp1 modulates platelet activation by regulating G protein-dependent signaling. Blood. 2012;119:1935-45. DOI: https://doi.org/10.1182/blood-2011-10-387910
Pasquet JM, Quek L, Pasquet S, et al. Evidence of a role for Shp1 in platelet activation by the collagen receptor glycoprotein VI. J Biol Chem. 2000;275:28526-31. DOI: https://doi.org/10.1074/jbc.M001531200
Chen L, Sung SS, Yip ML, et al. Discovery of a novel Shp2 protein tyrosine phosphatase inhibitor. Mol Pharmacol. 2006;70:562-70. DOI: https://doi.org/10.1124/mol.106.025536
Song Z, Wang M, Ge Y, et al. Tyrosine phosphatase Shp2 inhibitors in tumor-targeted therapies. Acta Pharm Sin B. 2021;11:13-29. DOI: https://doi.org/10.1016/j.apsb.2020.07.010
Gilio K, Munnix IC, Mangin P, et al. Non-redundant roles of phosphoinositide 3-kinase isoforms a and b in glycoprotein VI-induced platelet signaling and thrombus formation. J Biol Chem. 2009;285:33750-62. DOI: https://doi.org/10.1074/jbc.M109.048439
Jooss NJ, De Simone I, Provenzale I, et al. Role of platelet glycoprotein VI and tyrosine kinase Syk in thrombus formation on collagen-like surfaces. Int J Mol Sci. 2019;20:2788. DOI: https://doi.org/10.3390/ijms20112788
Izquierdo I, Barrachina MN, Hermida-Nogueira L, et al. A comprehensive tyrosine phosphoproteomic analysis reveals novel components of the platelet CLEC-2 signaling cascade. Thromb Haemost. 2020;120:262-76. DOI: https://doi.org/10.1055/s-0039-3400295
García A. Two-dimensional gel electrophoresis in platelet proteomics research. Methods Mol Med. 2007;139:339-53. DOI: https://doi.org/10.1007/978-1-59745-571-8_23
Fernández DI, Provenzale I, Cheung HY, et al. Ultra-high-throughput Ca2+ assay in platelets to distinguish ITAM-linked and G-protein-coupled receptor activation. iScience. 2022;25:103718. DOI: https://doi.org/10.1016/j.isci.2021.103718
Zou J, Wu J, Roest M, et al. Long-term platelet priming after glycoprotein VI stimulation in comparison to protease-activating receptor (PAR) stimulation. PLoS One. 2021;16:e0247425. DOI: https://doi.org/10.1371/journal.pone.0247425
Ozdener F, Dangelmaier C, Ashby B, et al. Activation of phospholipase Cg2 by tyrosine phosphorylation. Mol Pharmacol. 2002;62:672-9. DOI: https://doi.org/10.1124/mol.62.3.672
Fernández DI, Kuijpers MJ, Heemskerk JW. Platelet calcium signaling by G-protein coupled and ITAM-linked receptors regulating anoctamin-6 and procoagulant activity. Platelets. 2021;32:863-71. DOI: https://doi.org/10.1080/09537104.2020.1859103
Estevez B, Du X. New concepts and mechanisms of platelet activation signaling. Physiology (Bethesda). 2017;32:162-77. DOI: https://doi.org/10.1152/physiol.00020.2016
Bye AP, Unsworth AJ, Vaiyapuri S, et al. Ibrutinib inhibits platelet integrin αIIbβ3 outside-in signaling and thrombus stability but not adhesion to collagen. Arterioscler Thromb Vasc Biol. 2015;35:2326-635. DOI: https://doi.org/10.1161/ATVBAHA.115.306130
Supporting Agencies
EU Horizon 2020 grant no. 766118How to Cite
1.
Huang J, Fernández DI, Zou J, Wang X, Heemskerk JW, García Ángel. Restrained glycoprotein VI-induced platelet signaling by tyrosine protein phosphatases independent of phospholipase Cγ2. Bleeding Thromb Vascul Biol [Internet]. 2023 Oct. 11 [cited 2025 Nov. 10];2(3). Available from: https://www.btvb.org/btvb/article/view/93
Copyright (c) 2023 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Share
Similar Articles
- Roger Lijnen, Désiré Collen, The key to fibrinolysis and thrombolysis , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. 3 (2025)
- Boris Shenkman, Ivan Budnik, Yulia Einav, Interaction between adenosine diphosphate receptors and protein-kinase C isoforms in platelet adhesion under flow condition , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 1 (2023)
- PO50 | Treatment with BTK inhibitors in patients affected by chronic lymphocytic leukemia: safety and hemostasis , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- CS07 | Endothelial dysfunction and impaired angiogenesis in Hermansky-Pudlak syndrome (HPS) type 1: studies with endothelial colony forming cells , Bleeding, Thrombosis and Vascular Biology: Special issues
- CO43 | Early platelet dysfunction in sepsis: an ICU pilot study , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- CO25 | Thromboinflammation and ros accumulation in individuals with high lipoprotein(a) levels , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- Rita Carlotta Santoro, Roberto Minici, Marzia Leotta, Mariapia Falbo, Lucia Concetta Elia, Francesca Leo, Antonella Ierardi, Alessandra Strangio, Simona Prejanò, Vaccine-induced immune thrombotic thrombocytopenia following ChAdOx1 nCoV-19 vaccine: report of two cases , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 2 (2022)
- PO03 | Enlarged platelets with reduced GP IB/IX can indicate disorders other than Bernard-Soulier syndrome , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- Bianca Clerici, Mariangela Scavone, Gian Marco Podda, Recent advances in classic heparin-induced thrombocytopenia (HIT), autoimmune HIT, spontaneous HIT, and vaccine-induced immune thrombotic thrombocytopenia , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. 2 (2024)
- Luca Barcella, Chiara Ambaglio, Paolo Gritti, Francesca Schieppati, Varusca Brusegan, Eleonora Sanga, Marina Marchetti, Luca Lorini, Anna Falanga, Long-term persistence of high anti-PF4 antibodies titer in a challenging case of AZD1222 vaccine-induced thrombotic thrombocytopenia , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 2 (2023)
1-10 of 171
Next
You may also start an advanced similarity search for this article.
