Platelet functional responses and signalling: the molecular relationship. Part 2: receptors.
![Alexey Martyanov](https://istore.sbpreports.com/empty.png)
Introduction
Platelets are blood cells that play a key role in the process of stopping bleeding
Hemostasis and thrombosis beyond biochemistry: roles of geometry, flow and diffusion
M. Panteleev, N. Dashkevich, F. Ataullakhanov
Thrombosis Research. 2015, 136, 699-711
Novel mouse hemostasis model for real-time determination of bleeding time and hemostatic plug composition
T. Getz, R. Piatt, B. Petrich, D. Monroe, N. Mackman, W. Bergmeier
Journal of Thrombosis and Haemostasis. 2015, 13, 417-425
Platelets and vascular integrity
C. Deppermann
Platelets. 2018, 29, 549-555
Physiological and pathophysiological aspects of blood platelet activation through CLEC-2 receptor
A. Martyanov, V. Kaneva, M. Panteleev, A. Sveshnikova
Oncohematology. 2018, 13, 83-90
How platelets safeguard vascular integrity
B. HO-TIN-NOÉ, M. DEMERS, D. WAGNER
Journal of Thrombosis and Haemostasis. 2011, 9, 56-65
Platelet ITAM signaling is critical for vascular integrity in inflammation
Yacine Boulaftali, Paul R. Hess, Todd M. Getz, Agnieszka Cholka, Moritz Stolla, Nigel Mackman, A. Phillip Owens III, Jerry Ware, Mark L. Kahn, Wolfgang Bergmeier
The Journal of Clinical Investigation. 2013, 123 (2), 908-916
Editorial: Platelets and Immune Responses During Thromboinflammation
M. Schattner, C. Jenne, S. Negrotto, B. Ho-Tin-Noe
Frontiers in Immunology. 2020, 11, None
The dual role of platelet-innate immune cell interactions in thrombo-inflammation
J. Rayes, J. Bourne, A. Brill, S. Watson
Research and Practice in Thrombosis and Haemostasis. 2020, 4, 23-35
Lipopolysaccharide Signaling without a Nucleus: Kinase Cascades Stimulate Platelet Shedding of Proinflammatory IL-1β–Rich Microparticles
G. Brown, T. McIntyre
The Journal of Immunology. 2011, 186, 5489-5496
Platelet functional responses and signalling: the molecular relationship. Part 1: responses.
A. Sveshnikova, M. Stepanyan, M. Panteleev
Systems Biology and Physiology Reports. 2021, 1, 20-28
The first response to a meeting with an activator is a change in shape. Initially, discoid cells significantly increase their surface area due to the unraveling of the membrane folds inside in the form of an open canalicular system
Platelets: production, morphology and ultrastructure
Thon JN, Italiano JE
Handbook of Experimental Pharmacology. 2012, None, 3-22
Platelet shape change and spreading
Aslan JE, Itakura A, Gertz JM, McCarty OJT
Methods in Molecular Biology. 2012, 788, 91-100
Tubulin in Platelets: When the Shape Matters
E. Cuenca-Zamora, F. Ferrer-Marín, J. Rivera, R. Teruel-Montoya
International Journal of Molecular Sciences. 2019, 20, 3484
New explanations for old observations: marginal band coiling during platelet activation
K. Sadoul
Journal of Thrombosis and Haemostasis. 2015, 13, 333-346
Actin dynamics in platelets
Bearer EL, Prakash JM, Li Z.
International Review of Cytology. 2002, 217, 137-82
Platelet shape change and spreading
Aslan JE, Itakura A, Gertz JM, McCarty OJT
Methods in Molecular Biology. 2012, 788, 91-100
Platelet shape change and spreading
Aslan JE, Itakura A, Gertz JM, McCarty OJT
Methods in Molecular Biology. 2012, 788, 91-100
Platelet Shape Changes and Cytoskeleton Dynamics as Novel Therapeutic Targets for Anti-Thrombotic Drugs
E. Shin, H. Park, J. Noh, K. Lim, J. Chung
Biomolecules & Therapeutics. 2017, 25, 223-230
The key functional response of the platelet, probably, is the transition to a proaggregant state, in which platelet integrins αIIbβ3
The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways
J. Burkhart, M. Vaudel, S. Gambaryan, S. Radau, U. Walter, L. Martens, J. Geiger, A. Sickmann, R. Zahedi
Blood. 2012, 120, e73-e82
Platelet signaling
Stalker TJ, Newman DK, Ma P, Wannemacher KM, Brass LF
Handbook of Experimental Pharmacology. 2012, None, 59-85
Regulation of Platelet Activation and Coagulation and Its Role in Vascular Injury and Arterial Thrombosis
M. Tomaiuolo, L. Brass, T. Stalker
Interventional Cardiology Clinics. 2017, 6, 1-12
RAP GTPases and platelet integrin signaling
L. Stefanini, W. Bergmeier
Platelets. 2019, 30, 41-47
Another important functional response of the platelet is granule release
Platelet functional responses and signalling: the molecular relationship. Part 1: responses.
A. Sveshnikova, M. Stepanyan, M. Panteleev
Systems Biology and Physiology Reports. 2021, 1, 20-28
Platelet Secretion. In: Michelson AD, editor. Platelets (Fourth Edition)
Flaumenhaft R, Sharda A
Academic Press. 2019, None, 349-70
Sorting machineries: how platelet-dense granules differ from α-granules
Y. Chen, Y. Yuan, W. Li
Bioscience Reports. 2018, 38, None
Platelet functional responses and signalling: the molecular relationship. Part 1: responses.
A. Sveshnikova, M. Stepanyan, M. Panteleev
Systems Biology and Physiology Reports. 2021, 1, 20-28
Under certain conditions, for example, upon stimulation of platelets with the combination of thrombin and collagen, mitochondrial-dependent necrosis of a subpopulation of platelets occurs, which at the same time lose the capability to aggregate, exhibit a negatively charged phospholipid phosphatidylserine, which is one of the landing sites for tenase and prothrombinase complexes, which significantly accelerates the work of the blood plasma coagulation cascade
Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling
A. Sveshnikova, A. Balatskiy, A. Demianova, T. Shepelyuk, S. Shakhidzhanov, M. Balatskaya, A. Pichugin, F. Ataullakhanov, M. Panteleev
Journal of Thrombosis and Haemostasis. 2016, 14, 2045-2057
Procoagulant Platelets Form an α-Granule Protein-covered “Cap” on Their Surface That Promotes Their Attachment to Aggregates
A. Abaeva, M. Canault, Y. Kotova, S. Obydennyy, A. Yakimenko, N. Podoplelova, V. Kolyadko, H. Chambost, A. Mazurov, F. Ataullakhanov, A. Nurden, M. Alessi, M. Panteleev
Journal of Biological Chemistry. 2013, 288, 29621-29632
Regulating thrombus growth and stability to achieve an optimal response to injury
L. BRASS, K. WANNEMACHER, P. MA, T. STALKER
Journal of Thrombosis and Haemostasis. 2011, 9, 66-75
Clot Contraction Drives the Translocation of Procoagulant Platelets to Thrombus Surface
D. Nechipurenko, N. Receveur, A. Yakimenko, T. Shepelyuk, A. Yakusheva, R. Kerimov, S. Obydennyy, A. Eckly, C. Léon, C. Gachet, E. Grishchuk, F. Ataullakhanov, P. Mangin, M. Panteleev
Arteriosclerosis, Thrombosis, and Vascular Biology. 2019, 39, 37-47
![Different degrees of the platelet activation in hemostasis. Upon weak stimulation, platelets pass into a weakly activated state, in which there is no clustering of platelet integrins and no significant change in the shape of platelets. This weak activation is reversible, and it corresponds to the state of platelets in the outer layers (](https://astore.sbpreports.com/issues/articles/11/figures/fig_0.png?v=jimuc)
A vast network of receptors and signaling pathways of platelets regulates implementing the listed functions where and when required
Platelet functional responses and signalling: the molecular relationship. Part 1: responses.
A. Sveshnikova, M. Stepanyan, M. Panteleev
Systems Biology and Physiology Reports. 2021, 1, 20-28
![The basic scheme of signal transduction by a non-nucleated cell. From the extracellular environment comes some](https://astore.sbpreports.com/issues/articles/11/figures/fig_1.png?v=rgfb)
Secondary messengers of the platelets
The platelet receptor network can be roughly divided into several sub-networks, each controlled by its own set of secondary messengers, which may overlap in some cases. It can be argued that secondary messengers are at the center of intracellular signaling: they “collect” information from receptors and “transmit” it to functional systems. Therefore, in this review, we will look at how the concentration of the secondary messengers in the platelets is regulated. In this case, one should not forget that platelets are non-nucleated cells, i.e., they have no pathways that induce protein synthesis. Below, we briefly list the primary, secondary platelet messengers.
Based on the previously published works
Platelet biology and functions: new concepts and clinical perspectives
P. van der Meijden, J. Heemskerk
Nature Reviews Cardiology. 2019, 16, 166-179
Computational biology analysis of platelet signaling reveals roles of feedbacks through phospholipase C and inositol 1,4,5-trisphosphate 3-kinase in controlling amplitude and duration of calcium oscillations
F. Balabin, A. Sveshnikova
Mathematical Biosciences. 2016, 276, 67-74
Dynamics of calcium spiking, mitochondrial collapse and phosphatidylserine exposure in platelet subpopulations during activation
S. Obydennyy, A. Sveshnikova, F. Ataullakhanov, M. Panteleev
Journal of Thrombosis and Haemostasis. 2016, 14, 1867-1881
Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling
A. Sveshnikova, A. Balatskiy, A. Demianova, T. Shepelyuk, S. Shakhidzhanov, M. Balatskaya, A. Pichugin, F. Ataullakhanov, M. Panteleev
Journal of Thrombosis and Haemostasis. 2016, 14, 2045-2057
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A. Martyanov, F. Balabin, J. Dunster, M. Panteleev, J. Gibbins, A. Sveshnikova
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Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling
A. Sveshnikova, A. Balatskiy, A. Demianova, T. Shepelyuk, S. Shakhidzhanov, M. Balatskaya, A. Pichugin, F. Ataullakhanov, M. Panteleev
Journal of Thrombosis and Haemostasis. 2016, 14, 2045-2057
Dynamics of calcium spiking, mitochondrial collapse and phosphatidylserine exposure in platelet subpopulations during activation
S. Obydennyy, A. Sveshnikova, F. Ataullakhanov, M. Panteleev
Journal of Thrombosis and Haemostasis. 2016, 14, 1867-1881
Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling
A. Sveshnikova, A. Balatskiy, A. Demianova, T. Shepelyuk, S. Shakhidzhanov, M. Balatskaya, A. Pichugin, F. Ataullakhanov, M. Panteleev
Journal of Thrombosis and Haemostasis. 2016, 14, 2045-2057
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Platelet biology and functions: new concepts and clinical perspectives
P. van der Meijden, J. Heemskerk
Nature Reviews Cardiology. 2019, 16, 166-179
Dynamics of calcium spiking, mitochondrial collapse and phosphatidylserine exposure in platelet subpopulations during activation
S. Obydennyy, A. Sveshnikova, F. Ataullakhanov, M. Panteleev
Journal of Thrombosis and Haemostasis. 2016, 14, 1867-1881
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M. Chalmers, M. Schell, P. Thorn
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While the primary storage for calcium ions in platelets is the endoplasmic reticulum, calcium adhesions can also pump calcium into platelet mitochondria through a calcium uniporter. Calcium can also be pumped out of mitochondria through the NCLX pump
Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling
A. Sveshnikova, A. Balatskiy, A. Demianova, T. Shepelyuk, S. Shakhidzhanov, M. Balatskaya, A. Pichugin, F. Ataullakhanov, M. Panteleev
Journal of Thrombosis and Haemostasis. 2016, 14, 2045-2057
Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling
A. Sveshnikova, A. Balatskiy, A. Demianova, T. Shepelyuk, S. Shakhidzhanov, M. Balatskaya, A. Pichugin, F. Ataullakhanov, M. Panteleev
Journal of Thrombosis and Haemostasis. 2016, 14, 2045-2057
Mechanisms of increased mitochondria-dependent necrosis in Wiskott-Aldrich syndrome platelets
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Platelet subpopulations remain despite strong dual agonist stimulation and can be characterised using a novel six-colour flow cytometry protocol
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Scientific Reports. 2018, 8, None
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IP3 is also a secondary messenger, as it is formed due to phospholipase C activity combined with diacylglycerol (DAG) from a membrane phospholipid phosphoinositide-4,5-bisphosphate (PIP2). Interestingly, the concentration of IP3 in the platelet cytosol also depends on the enzyme IP3-3 kinase (IP3K)
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Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling
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Journal of Thrombosis and Haemostasis. 2016, 14, 2045-2057
Computational biology analysis of platelet signaling reveals roles of feedbacks through phospholipase C and inositol 1,4,5-trisphosphate 3-kinase in controlling amplitude and duration of calcium oscillations
F. Balabin, A. Sveshnikova
Mathematical Biosciences. 2016, 276, 67-74
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H. XIA, G. YANG
Cell Research. 2005, 15, 83-91
A secondary messenger comparable in importance to calcium is the membrane concentration of the phospholipid phosphoinositide-3,4,5-triphosphate (phosphoinositide-3,4,5-trisphosphate, PIP3). Phosphorylated residues of inositide — phosphoinositides — account for 10–15% of the lipid composition of the inner layer of the plasma membrane of platelets
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Blood. 2013, 122, 1358-1365
Regulation of platelet plug formation by phosphoinositide metabolism
S. Min, C. Abrams
Blood. 2013, 122, 1358-1365
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Academic Press. 2019, None, 329-48
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Platelets lacking PIP5KIγ have normal integrin activation but impaired cytoskeletal-membrane integrity and adhesion
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The last secondary mediator of platelet signaling is the cytosolic concentration of cyclic nucleotides - cAMP and cGMP
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J. Burkhart, M. Vaudel, S. Gambaryan, S. Radau, U. Walter, L. Martens, J. Geiger, A. Sickmann, R. Zahedi
Blood. 2012, 120, e73-e82
G-protein coupled receptors (GPCRs)
Approximately half of the platelet receptors are serpentine receptors, otherwise called 7TM receptors or G-protein coupled receptors (GPCR)
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Due to the importance of calcium signaling, we start with phospholipase Cβ (phospholipase C, PLCβ), which hydrolyzes PIP2 to inositol 3,4,5 triphosphate (IP3) and diacylglycerol (DAG). PLCβ activation consists in its localization at the plasma membrane close to its substrates
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T. Bondeva
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Synergistic Activation of Phospholipase C-β3 by Gαq and Gβγ Describes a Simple Two-State Coincidence Detector
F. Philip, G. Kadamur, R. Silos, J. Woodson, E. Ross
Current Biology. 2010, 20, 1327-1335
Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling
A. Sveshnikova, A. Balatskiy, A. Demianova, T. Shepelyuk, S. Shakhidzhanov, M. Balatskaya, A. Pichugin, F. Ataullakhanov, M. Panteleev
Journal of Thrombosis and Haemostasis. 2016, 14, 2045-2057
Synergistic Activation of Phospholipase C-β3 by Gαq and Gβγ Describes a Simple Two-State Coincidence Detector
F. Philip, G. Kadamur, R. Silos, J. Woodson, E. Ross
Current Biology. 2010, 20, 1327-1335
The actin-binding protein profilin binds to PIP2 and inhibits its hydrolysis by phospholipase C
P. Goldschmidt-Clermont, L. Machesky, J. Baldassare, T. Pollard
Science. 1990, 247, 1575-1578
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M. Rebecchi, S. Pentyala
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M. Rebecchi, S. Pentyala
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The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways
J. Burkhart, M. Vaudel, S. Gambaryan, S. Radau, U. Walter, L. Martens, J. Geiger, A. Sickmann, R. Zahedi
Blood. 2012, 120, e73-e82
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A. Moroi, S. Watson
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Kramer IjM.
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The second enzyme activated by G proteins is called phosphoinositide 3 kinase γ (PI3Kγ). The most characterized members of the PI3K family are PI3K class I, which are heterodimeric proteins: they consist of a catalytic subunit (p110α, p110β or p110δ) linked to an SH2-containing regulatory subunit (five types, with p85α being the most common). p110β associates with the plasma membrane via the Gβγ subunits. PI3K class IB (PI3Kγ) consists of the p110γ catalytic subunit associated with the regulatory subunit (p84), which is also activated by binding to the Gβγ subunit
Heterodimeric Phosphoinositide 3-Kinase Consisting of p85 and p110β Is Synergistically Activated by the βγ Subunits of G Proteins and Phosphotyrosyl Peptide
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RAP GTPases and platelet integrin signaling
L. Stefanini, W. Bergmeier
Platelets. 2019, 30, 41-47
Platelet Signal Transduction. In: Michelson AD, editor. Platelets (Fourth Edition)
Lee RH, Stefanini L, Bergmeier W.
Academic Press. 2019, None, 329-48
G12/13 - activates RhoA (GTPases Ras homolog gene family, member A) and Rho kinases. Activated Rho-kinase stimulates the phosphorylation of myosin light chains MLC (Myosin Light Chain)
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Platelet signaling
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The last protein controlled by the platelet G-proteins, paradoxically, is adenylate cyclase (AC)
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L. Hines, B. Tabakoff
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Fueling Platelets
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Arteriosclerosis, Thrombosis, and Vascular Biology. 2017, 37, 1592-1594
Signaling through Gi Family Members in Platelets
J. Yang, J. Wu, H. Jiang, R. Mortensen, S. Austin, D. Manning, D. Woulfe, L. Brass
Journal of Biological Chemistry. 2002, 277, 46035-46042
One of the interesting features of GPCR receptors is the possibility of their desensitization as a result of contact with an activator
G-Protein Coupled Receptor Resensitization - Appreciating the Balancing Act of Receptor Function
M. L. Mohan, N. T. Vasudevan, M. K. Gupta, E. E. Martelli, S. V. Naga Prasad
Current Molecular Pharmacology. 2013, 5, 350-361
Heterogeneity of Integrin αIIbβ3 Function in Pediatric Immune Thrombocytopenia Revealed by Continuous Flow Cytometry Analysis
A. Martyanov, D. Morozova, M. Sorokina, A. Filkova, D. Fedorova, S. Uzueva, E. Suntsova, G. Novichkova, P. Zharkov, M. Panteleev, A. Sveshnikova
International Journal of Molecular Sciences. 2020, 21, 3035
G-Protein Coupled Receptor Resensitization - Appreciating the Balancing Act of Receptor Function
M. L. Mohan, N. T. Vasudevan, M. K. Gupta, E. E. Martelli, S. V. Naga Prasad
Current Molecular Pharmacology. 2013, 5, 350-361
G-Protein Coupled Receptor Resensitization - Appreciating the Balancing Act of Receptor Function
M. L. Mohan, N. T. Vasudevan, M. K. Gupta, E. E. Martelli, S. V. Naga Prasad
Current Molecular Pharmacology. 2013, 5, 350-361
G-Protein Coupled Receptor Resensitization - Appreciating the Balancing Act of Receptor Function
M. L. Mohan, N. T. Vasudevan, M. K. Gupta, E. E. Martelli, S. V. Naga Prasad
Current Molecular Pharmacology. 2013, 5, 350-361
G-Protein Coupled Receptor Resensitization - Appreciating the Balancing Act of Receptor Function
M. L. Mohan, N. T. Vasudevan, M. K. Gupta, E. E. Martelli, S. V. Naga Prasad
Current Molecular Pharmacology. 2013, 5, 350-361
Heterogeneity of Integrin αIIbβ3 Function in Pediatric Immune Thrombocytopenia Revealed by Continuous Flow Cytometry Analysis
A. Martyanov, D. Morozova, M. Sorokina, A. Filkova, D. Fedorova, S. Uzueva, E. Suntsova, G. Novichkova, P. Zharkov, M. Panteleev, A. Sveshnikova
International Journal of Molecular Sciences. 2020, 21, 3035
Platelet activation by thrombin
Thrombin is one of the key platelet activators and the key enzyme of the blood coagulation system. Thrombin activates platelets by binding to PAR (Protease-Activated Receptors). On the surface of platelets, there are two kinds of these GPCRs: PAR1 and PAR4 in humans and PAR3 and PAR4 in mice. Thrombin cuts off a small oligopeptide from the N-terminus of these receptors, which subsequently activates the corresponding receptor
Domains specifying thrombin–receptor interaction
T. Vu, V. Wheaton, D. Hung, I. Charo, S. Coughlin
Nature. 1991, 353, 674-677
Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling
A. Sveshnikova, A. Balatskiy, A. Demianova, T. Shepelyuk, S. Shakhidzhanov, M. Balatskaya, A. Pichugin, F. Ataullakhanov, M. Panteleev
Journal of Thrombosis and Haemostasis. 2016, 14, 2045-2057
RhoA downstream of Gq and G12/13 pathways regulates protease-activated receptor-mediated dense granule release in platelets
J. Jin, Y. Mao, D. Thomas, S. Kim, J. Daniel, S. Kunapuli
Biochemical Pharmacology. 2009, 77, 835-844
Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling
A. Sveshnikova, A. Balatskiy, A. Demianova, T. Shepelyuk, S. Shakhidzhanov, M. Balatskaya, A. Pichugin, F. Ataullakhanov, M. Panteleev
Journal of Thrombosis and Haemostasis. 2016, 14, 2045-2057
It is known that thrombin can cause the decrease of the concentration of cAMP in platelets via inhibition of adenylate cyclase (which catalyzes the conversion of ATP to cAMP) through the Gi protein associated with the thrombin receptor, or indirectly, via promoting the release of ADP, and an increase in the activity of phosphodiesterases (enzymes that catalyze the hydrolysis of cAMP in AMP). However, it is assumed that this effect is mediated by the P2Y12 receptor activation by secreted ADP
Platelet Secretion. In: Michelson AD, editor. Platelets (Fourth Edition)
Flaumenhaft R, Sharda A
Academic Press. 2019, None, 349-70
Platelet Signal Transduction. In: Michelson AD, editor. Platelets (Fourth Edition)
Lee RH, Stefanini L, Bergmeier W.
Academic Press. 2019, None, 329-48
In addition to PAR receptors, thrombin can bind GPIb-V-IX. It is assumed that binding to GPIb enhances thrombin affinity to PAR receptors, dramatically accelerating their proteolysis, thereby accelerating PAR-dependent platelet activation
Primary haemostasis: newer insights
M. Berndt, P. Metharom, R. Andrews
Haemophilia. 2014, 20, 15-22
Thrombin is one of the most potent platelet activators and leads to platelet aggregation, the release of ADP and ATP, synthesis of thromboxane A2 (TxA2), and, like collagen, can lead to the strongest degree of platelet activation - procoagulant activity. These signaling paths will be described later.
АDP-induced platelet activation
ADP is contained in dense platelet granules, which are secreted upon platelet activation
New Fundamentals in Hemostasis
H. Versteeg, J. Heemskerk, M. Levi, P. Reitsma
Physiological Reviews. 2013, 93, 327-358
Adenosine diphosphate (ADP)–induced thromboxane A2generation in human platelets requires coordinated signaling through integrin αIIbβ3 and ADP receptors
J. Jin, T. Quinton, J. Zhang, S. Rittenhouse, S. Kunapuli
Blood. 2002, 99, 193-198
Mechanisms of platelet activation: Need for new strategies to protect against platelet-mediated atherothrombosis
L. Jennings
Thrombosis and Haemostasis. 2009, 102, 248-257
Platelet adhesion, shape change, and aggregation: rapid initiation and signal transduction events
A. Gear
Canadian Journal of Physiology and Pharmacology. 1994, 72, 285-294
There are two types of ADP receptors on the platelet surface, P2Y1, and P2Y12, both of which are GPCRs
Defective platelet activation in Gαq-deficient mice
S. Offermanns, C. Toombs, Y. Hu, M. Simon
Nature. 1997, 389, 183-186
The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways
J. Burkhart, M. Vaudel, S. Gambaryan, S. Radau, U. Walter, L. Martens, J. Geiger, A. Sickmann, R. Zahedi
Blood. 2012, 120, e73-e82
Platelet Secretion. In: Michelson AD, editor. Platelets (Fourth Edition)
Flaumenhaft R, Sharda A
Academic Press. 2019, None, 349-70
The P2Y1 receptor transmits a signal via the Gq protein, which leads to the same platelet signaling as thrombin, yet significantly less strong
Heterogeneity of Integrin αIIbβ3 Function in Pediatric Immune Thrombocytopenia Revealed by Continuous Flow Cytometry Analysis
A. Martyanov, D. Morozova, M. Sorokina, A. Filkova, D. Fedorova, S. Uzueva, E. Suntsova, G. Novichkova, P. Zharkov, M. Panteleev, A. Sveshnikova
International Journal of Molecular Sciences. 2020, 21, 3035
Platelet signaling
Stalker TJ, Newman DK, Ma P, Wannemacher KM, Brass LF
Handbook of Experimental Pharmacology. 2012, None, 59-85
Platelet signaling
Stalker TJ, Newman DK, Ma P, Wannemacher KM, Brass LF
Handbook of Experimental Pharmacology. 2012, None, 59-85
Considering ADP as a platelet activator, it should be noted that in plasma, ADP is hydrolyzed to AMP with a half-life of 10-15 minutes, which affects the number of platelets that it can activate. Hydrolysis of ADP in plasma occurs under the action of ADPase, which is produced by lymphocytes and endothelial cells
Metabolism of adenine nucleotides in human blood.
S. Coade, J. Pearson
Circulation Research. 1989, 65, 531-537
Demonstration of a novel ecto-enzyme on human erythrocytes, capable of degrading ADP and of inhibiting ADP-induced platelet aggregation
J. LUTHJE, A. SCHOMBURG, A. OGILVIE
European Journal of Biochemistry. 1988, 175, 285-289
Platelet activation by TxA2, serotonin, and adrenaline
TxA2 is also a weak platelet activator and is considered an even weaker activator than ADP. Upon addition of TxA2 (or its stable analog U46619), platelets in vitro exhibit all functional responses except for the procoagulant
Mechanisms of platelet activation: Need for new strategies to protect against platelet-mediated atherothrombosis
L. Jennings
Thrombosis and Haemostasis. 2009, 102, 248-257
Platelet signaling
Stalker TJ, Newman DK, Ma P, Wannemacher KM, Brass LF
Handbook of Experimental Pharmacology. 2012, None, 59-85
The evolution of megakaryocytes to platelets
P. Nurden, C. Poujol, A. Nurden
Baillière's Clinical Haematology. 1997, 10, 1-27
In TP-/- mice, prolonged bleeding time was observed. Their platelets were unable to aggregate in response to TxA2 administration, and their aggregation time in response to collagen was increased. In vitro, in the presence of aspirin (inhibitor of TxA2 synthesis), platelet responses to ADP or collagen are impaired. The defect in response to thrombin looks like a shift in the concentration/aggregation curve, which indicates that TxA2 synthesis only supports platelet activation from thrombin but is not required for this process
Platelet signaling
Stalker TJ, Newman DK, Ma P, Wannemacher KM, Brass LF
Handbook of Experimental Pharmacology. 2012, None, 59-85
Platelet activation by TxA2 does not cause synthesis and release of TxA2
Possible involvement of cytoskeleton in collagen-stimulated activation of phospholipases in human platelets
Nakano T, Hanasaki K, Arita H.
Journal of Biological Chemistry. 1989, 264, 5400-6
Detection of local ATP release from activated platelets using cell surface-attached firefly luciferase
R. Beigi, E. Kobatake, M. Aizawa, G. Dubyak
American Journal of Physiology-Cell Physiology. 1999, 276, C267-C278
Persistence of thromboxane A2-like material and platelet release-inducing activity in plasma.
J. Smith, C. Ingerman, M. Silver
Journal of Clinical Investigation. 1976, 58, 1119-1122
Currently, the TxA2 signaling cascade in platelets is not completely understood. It is not clear why TxA2 synthesis is not initiated upon platelet activation by TxA2, although intracellular events, in this case, are completely identical to the case of platelet activation by ADP. It is possible that the short-lived TxA2 plays the role of a weak initiator of the platelet activation process, while the longer-lived ADP enhances this process and expands the platelet activation area.
Adrenaline and serotonin may also play a significant role in platelet activation
Signaling During Platelet Adhesion and Activation
Z. Li, M. Delaney, K. O'Brien, X. Du
Arteriosclerosis, Thrombosis, and Vascular Biology. 2010, 30, 2341-2349
Molecular Mechanisms of SERT in Platelets: Regulation of Plasma Serotonin Levels
C. Mercado, F. Kilic
Molecular Interventions. 2010, 10, 231-241
Signaling During Platelet Adhesion and Activation
Z. Li, M. Delaney, K. O'Brien, X. Du
Arteriosclerosis, Thrombosis, and Vascular Biology. 2010, 30, 2341-2349
Epinephrine restores platelet functions inhibited by ticagrelor: A mechanistic approach
A. Martin, D. Zlotnik, G. Bonete, E. Baron, B. Decouture, T. Belleville-Rolland, B. Le Bonniec, S. Poirault-Chassac, M. Alessi, P. Gaussem, A. Godier, C. Bachelot-Loza
European Journal of Pharmacology. 2020, 866, 172798
Molecular Mechanisms of SERT in Platelets: Regulation of Plasma Serotonin Levels
C. Mercado, F. Kilic
Molecular Interventions. 2010, 10, 231-241
Signaling During Platelet Adhesion and Activation
Z. Li, M. Delaney, K. O'Brien, X. Du
Arteriosclerosis, Thrombosis, and Vascular Biology. 2010, 30, 2341-2349
Receptors that cause tyrosine-kinase signaling
The second important signaling branch in platelets is tyrosine kinase signaling. Tyrosine kinase signaling in platelets is built around a cascade of tyrosine kinases, which phosphorylate both each other and the surrounding effector proteins
Platelet ITAM signaling
W. Bergmeier, L. Stefanini
Current Opinion in Hematology. 2013, 20, 445-450
Src family kinases: at the forefront of platelet activation
Y. Senis, A. Mazharian, J. Mori
Blood. 2014, 124, 2013-2024
The Src, Syk, and Tec family kinases: Distinct types of molecular switches
J. Bradshaw
Cellular Signalling. 2010, 22, 1175-1184
Src family kinases: at the forefront of platelet activation
Y. Senis, A. Mazharian, J. Mori
Blood. 2014, 124, 2013-2024
Src family kinases: at the forefront of platelet activation
Y. Senis, A. Mazharian, J. Mori
Blood. 2014, 124, 2013-2024
Dominant Role of the Protein-Tyrosine Phosphatase CD148 in Regulating Platelet Activation Relative to Protein-Tyrosine Phosphatase-1B
J. Mori, Y. Wang, S. Ellison, S. Heising, B. Neel, M. Tremblay, S. Watson, Y. Senis
Arteriosclerosis, Thrombosis, and Vascular Biology. 2012, 32, 2956-2965
The Src, Syk, and Tec family kinases: Distinct types of molecular switches
J. Bradshaw
Cellular Signalling. 2010, 22, 1175-1184
The Src, Syk, and Tec family kinases: Distinct types of molecular switches
J. Bradshaw
Cellular Signalling. 2010, 22, 1175-1184
Mechanisms of receptor tyrosine kinase activation in cancer
Z. Du, C. Lovly
Molecular Cancer. 2018, 17, None
The key kinases required for the initiation of tyrosine kinase signaling in platelets are the tyrosine kinases of the SFK family, as well as the kinases Syk and Btk. Tyrosine kinases of the SFK family, which include Src, Fyn, and Lyn in platelets
Src family kinases: at the forefront of platelet activation
Y. Senis, A. Mazharian, J. Mori
Blood. 2014, 124, 2013-2024
The Src, Syk, and Tec family kinases: Distinct types of molecular switches
J. Bradshaw
Cellular Signalling. 2010, 22, 1175-1184
Src family kinases: at the forefront of platelet activation
Y. Senis, A. Mazharian, J. Mori
Blood. 2014, 124, 2013-2024
SH2 domains: modulators of nonreceptor tyrosine kinase activity
P. Filippakopoulos, S. Müller, S. Knapp
Current Opinion in Structural Biology. 2009, 19, 643-649
SH3 domain ligand binding: What's the consensus and where's the specificity?
K. Saksela, P. Permi
FEBS Letters. 2012, 586, 2609-2614
Molecular priming of Lyn by GPVI enables an immune receptor to adopt a hemostatic role
A. Schmaier, Z. Zou, A. Kazlauskas, L. Emert-Sedlak, K. Fong, K. Neeves, S. Maloney, S. Diamond, S. Kunapuli, J. Ware, L. Brass, T. Smithgall, K. Saksela, M. Kahn
Proceedings of the National Academy of Sciences. 2009, 106, 21167-21172
Src family kinases: at the forefront of platelet activation
Y. Senis, A. Mazharian, J. Mori
Blood. 2014, 124, 2013-2024
The Src, Syk, and Tec family kinases: Distinct types of molecular switches
J. Bradshaw
Cellular Signalling. 2010, 22, 1175-1184
Src family kinases: at the forefront of platelet activation
Y. Senis, A. Mazharian, J. Mori
Blood. 2014, 124, 2013-2024
The Src, Syk, and Tec family kinases: Distinct types of molecular switches
J. Bradshaw
Cellular Signalling. 2010, 22, 1175-1184
The Src, Syk, and Tec family kinases: Distinct types of molecular switches
J. Bradshaw
Cellular Signalling. 2010, 22, 1175-1184
Syk tyrosine kinases are OR switches - they can be activated by activating one of the two regulatory sites. The structure of Syk kinases is less complex than the structure of SFK kinases: Syk consists of three domains: one catalytic and two SH2 domains
Molecular Mechanism of the Syk Activation Switch
E. Tsang, A. Giannetti, D. Shaw, M. Dinh, J. Tse, S. Gandhi, H. Ho, S. Wang, E. Papp, J. Bradshaw
Journal of Biological Chemistry. 2008, 283, 32650-32659
The Src, Syk, and Tec family kinases: Distinct types of molecular switches
J. Bradshaw
Cellular Signalling. 2010, 22, 1175-1184
Molecular Mechanism of the Syk Activation Switch
E. Tsang, A. Giannetti, D. Shaw, M. Dinh, J. Tse, S. Gandhi, H. Ho, S. Wang, E. Papp, J. Bradshaw
Journal of Biological Chemistry. 2008, 283, 32650-32659
Molecular Mechanism of the Syk Activation Switch
E. Tsang, A. Giannetti, D. Shaw, M. Dinh, J. Tse, S. Gandhi, H. Ho, S. Wang, E. Papp, J. Bradshaw
Journal of Biological Chemistry. 2008, 283, 32650-32659
The N-terminal SH2 domain of Syk is required for (hem)ITAM, but not integrin, signaling in mouse platelets
C. Hughes, B. Finney, F. Koentgen, K. Lowe, S. Watson
Blood. 2015, 125, 144-154
Tyrosine kinases Btk and Tec
The Src, Syk, and Tec family kinases: Distinct types of molecular switches
J. Bradshaw
Cellular Signalling. 2010, 22, 1175-1184
The Src, Syk, and Tec family kinases: Distinct types of molecular switches
J. Bradshaw
Cellular Signalling. 2010, 22, 1175-1184
The Src, Syk, and Tec family kinases: Distinct types of molecular switches
J. Bradshaw
Cellular Signalling. 2010, 22, 1175-1184
Platelet Signal Transduction. In: Michelson AD, editor. Platelets (Fourth Edition)
Lee RH, Stefanini L, Bergmeier W.
Academic Press. 2019, None, 329-48
Impact of the PI3-kinase/Akt pathway on ITAM and hemITAM receptors: Haemostasis, platelet activation and antithrombotic therapy
A. Moroi, S. Watson
Biochemical Pharmacology. 2015, 94, 186-194
The Src, Syk, and Tec family kinases: Distinct types of molecular switches
J. Bradshaw
Cellular Signalling. 2010, 22, 1175-1184
Src family kinases: at the forefront of platelet activation
Y. Senis, A. Mazharian, J. Mori
Blood. 2014, 124, 2013-2024
Dynamics of the Tec-family tyrosine kinase SH3 domains
J. Roberts, S. Tarafdar, R. Joseph, A. Andreotti, T. Smithgall, J. Engen, T. Wales
Protein Science. 2016, 25, 852-864
Impact of the PI3-kinase/Akt pathway on ITAM and hemITAM receptors: Haemostasis, platelet activation and antithrombotic therapy
A. Moroi, S. Watson
Biochemical Pharmacology. 2015, 94, 186-194
Platelet ITAM signaling
W. Bergmeier, L. Stefanini
Current Opinion in Hematology. 2013, 20, 445-450
Ibrutinib-associated bleeding: pathogenesis, management and risk reduction strategies
J. Shatzel, S. Olson, D. Tao, O. McCarty, A. Danilov, T. DeLoughery
Journal of Thrombosis and Haemostasis. 2017, 15, 835-847
The activation of tyrosine kinases is the first step in initiating the assembly of signalosomes — large protein complexes — centcentersintracellular signal propagation
The transmembrane adapter LAT plays a central role in immune receptor signalling
P. Wonerow, S. Watson
Oncogene. 2001, 20, 6273-6283
Control of Platelet CLEC-2-Mediated Activation by Receptor Clustering and Tyrosine Kinase Signaling
A. Martyanov, F. Balabin, J. Dunster, M. Panteleev, J. Gibbins, A. Sveshnikova
Biophysical Journal. 2020, 118, 2641-2655
Impact of the PI3-kinase/Akt pathway on ITAM and hemITAM receptors: Haemostasis, platelet activation and antithrombotic therapy
A. Moroi, S. Watson
Biochemical Pharmacology. 2015, 94, 186-194
Platelet Signal Transduction. In: Michelson AD, editor. Platelets (Fourth Edition)
Lee RH, Stefanini L, Bergmeier W.
Academic Press. 2019, None, 329-48
The Src, Syk, and Tec family kinases: Distinct types of molecular switches
J. Bradshaw
Cellular Signalling. 2010, 22, 1175-1184
It is important to note that not only kinases but also phosphatases play an important role in the activation of tyrosine kinase signaling. Thus, in addition to CD148, SFK can also be regulated by PTP1B and DUSP3 phosphatases, which are activated during the propagation of the activation signal by phosphorylation
Dominant Role of the Protein-Tyrosine Phosphatase CD148 in Regulating Platelet Activation Relative to Protein-Tyrosine Phosphatase-1B
J. Mori, Y. Wang, S. Ellison, S. Heising, B. Neel, M. Tremblay, S. Watson, Y. Senis
Arteriosclerosis, Thrombosis, and Vascular Biology. 2012, 32, 2956-2965
Dual-Specificity Phosphatase 3 Deficiency or Inhibition Limits Platelet Activation and Arterial Thrombosis
L. Musumeci, M. Kuijpers, K. Gilio, A. Hego, E. Théâtre, L. Maurissen, M. Vandereyken, C. Diogo, C. Lecut, W. Guilmain, E. Bobkova, J. Eble, R. Dahl, P. Drion, J. Rascon, Y. Mostofi, H. Yuan, E. Sergienko, T. Chung, M. Thiry, Y. Senis, M. Moutschen, T. Mustelin, P. Lancellotti, J. Heemskerk, L. Tautz, C. Oury, S. Rahmouni
Circulation. 2015, 131, 656-668
Dominant Role of the Protein-Tyrosine Phosphatase CD148 in Regulating Platelet Activation Relative to Protein-Tyrosine Phosphatase-1B
J. Mori, Y. Wang, S. Ellison, S. Heising, B. Neel, M. Tremblay, S. Watson, Y. Senis
Arteriosclerosis, Thrombosis, and Vascular Biology. 2012, 32, 2956-2965
ITIM receptors: more than just inhibitors of platelet activation
C. Coxon, M. Geer, Y. Senis
Blood. 2017, 129, 3407-3418
Different roles of SHIP1 according to the cell context: The example of blood platelets
M. Gratacap, S. Séverin, G. Chicanne, M. Plantavid, B. Payrastre
Advances in Enzyme Regulation. 2008, 48, 240-252
Receptors that induce or inhibit tyrosine kinase signaling
There are 3 types of receptors on human platelets that trigger the activation of the tyrosine kinase cascade: the collagen GPVI receptor, the podoplanin receptor CLEC-2, and the immunoglobulin G receptor FcgRIIa
Platelet ITAM signaling
W. Bergmeier, L. Stefanini
Current Opinion in Hematology. 2013, 20, 445-450
Platelet Immunoreceptor Tyrosine-Based Activation Motif (ITAM) Signaling and Vascular Integrity
Y. Boulaftali, P. Hess, M. Kahn, W. Bergmeier
Circulation Research. 2014, 114, 1174-1184
Functional significance of the platelet immune receptors GPVI and CLEC-2
J. Rayes, S. Watson, B. Nieswandt
Journal of Clinical Investigation. 2019, 129, 12-23
Platelet ITAM signaling
W. Bergmeier, L. Stefanini
Current Opinion in Hematology. 2013, 20, 445-450
GPVI and CLEC-2 in hemostasis and vascular integrity
S. WATSON, J. HERBERT, A. POLLITT
Journal of Thrombosis and Haemostasis. 2010, 8, 1456-1467
Human platelet IgG Fc receptor FcγRIIA in immunity and thrombosis
M. Arman, K. Krauel
Journal of Thrombosis and Haemostasis. 2015, 13, 893-908
Signaling by ephrinB1 and Eph kinases in platelets promotes Rap1 activation, platelet adhesion, and aggregation via effector pathways that do not require phosphorylation of ephrinB1
N. Prévost, D. Woulfe, M. Tognolini, T. Tanaka, W. Jian, R. Fortna, H. Jiang, L. Brass
Blood. 2004, 103, 1348-1355
Besides activating tyrosine kinase-dependent receptors on the surface of platelets, inhibitory tyrosine kinase receptors are also present, which carry the ITIM and ITSM sequences in their cytoplasmic domains
ITIM receptors: more than just inhibitors of platelet activation
C. Coxon, M. Geer, Y. Senis
Blood. 2017, 129, 3407-3418
SLAM Family Receptors and SAP Adaptors in Immunity
J. Cannons, S. Tangye, P. Schwartzberg
Annual Review of Immunology. 2011, 29, 665-705
ITIM receptors: more than just inhibitors of platelet activation
C. Coxon, M. Geer, Y. Senis
Blood. 2017, 129, 3407-3418
ITIM receptors: more than just inhibitors of platelet activation
C. Coxon, M. Geer, Y. Senis
Blood. 2017, 129, 3407-3418
PECAM-1 is present not only on platelets but also on leukocytes and endotheliocytes
Platelet Inhibitory Receptors. In: Michelson AD, editor. Platelets (Fourth Edition)
Nagy Z, Senis YA
Academic Press. 2019, None, 279-93
Platelet Inhibitory Receptors. In: Michelson AD, editor. Platelets (Fourth Edition)
Nagy Z, Senis YA
Academic Press. 2019, None, 279-93
Minimal regulation of platelet activity by PECAM-1
T. Dhanjal, E. Ross, J. Auger, O. Mccarty, C. Hughes, Y. Senis, S. Watson
Platelets. 2007, 18, 56-67
Collagen, Convulxin, and Thrombin Stimulate Aggregation-independent Tyrosine Phosphorylation of CD31 in Platelets
M. Cicmil, J. Thomas, T. Sage, F. Barry, M. Leduc, C. Bon, J. Gibbins
Journal of Biological Chemistry. 2000, 275, 27339-27347
Collagen, Convulxin, and Thrombin Stimulate Aggregation-independent Tyrosine Phosphorylation of CD31 in Platelets
M. Cicmil, J. Thomas, T. Sage, F. Barry, M. Leduc, C. Bon, J. Gibbins
Journal of Biological Chemistry. 2000, 275, 27339-27347
Thrombin-induced association of SHP-2 with multiple tyrosine-phosphorylated proteins in human platelets
C. Edmead, D. Crosby, M. Southcott, A. Poole
FEBS Letters. 1999, 459, 27-32
Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP and phospholipase C-γ1 with PECAM-1/CD31
N. Pumphrey, V. Taylor, S. Freeman, M. Douglas, P. Bradfield, S. Young, J. Lord, M. Wakelam, I. Bird, M. Salmon, C. Buckley
FEBS Letters. 1999, 450, 77-83
The cytoplasmic domain G6b-B also consists of two ITAM-ISTM motifs. However, unlike PECAM-1, G6b-B is constantly available for phosphorylation by SFK kinases
Maintenance of murine platelet homeostasis by the kinase Csk and phosphatase CD148
J. Mori, Z. Nagy, G. Di Nunzio, C. Smith, M. Geer, R. Al Ghaithi, J. van Geffen, S. Heising, L. Boothman, B. Tullemans, J. Correia, L. Tee, M. Kuijpers, P. Harrison, J. Heemskerk, G. Jarvis, A. Tarakhovsky, A. Weiss, A. Mazharian, Y. Senis
Blood. 2018, 131, 1122-1144
Maintenance of murine platelet homeostasis by the kinase Csk and phosphatase CD148
J. Mori, Z. Nagy, G. Di Nunzio, C. Smith, M. Geer, R. Al Ghaithi, J. van Geffen, S. Heising, L. Boothman, B. Tullemans, J. Correia, L. Tee, M. Kuijpers, P. Harrison, J. Heemskerk, G. Jarvis, A. Tarakhovsky, A. Weiss, A. Mazharian, Y. Senis
Blood. 2018, 131, 1122-1144
An Investigation of Hierachical Protein Recruitment to the Inhibitory Platelet Receptor, G6B-b
C. Coxon, A. Sadler, J. Huo, R. Campbell
PLoS ONE. 2012, 7, e49543
GPVI – key platelet receptor for collagen
GPVI is a membrane glycoprotein that recognizes several glycine-proline-hydroxyproline (GPO) sequences characteristic of collagen
GPVI and CLEC-2 in hemostasis and vascular integrity
S. WATSON, J. HERBERT, A. POLLITT
Journal of Thrombosis and Haemostasis. 2010, 8, 1456-1467
Fibrin and D-dimer bind to monomeric GPVI
M. Onselaer, A. Hardy, C. Wilson, X. Sanchez, A. Babar, J. Miller, C. Watson, S. Watson, A. Bonna, H. Philippou, A. Herr, D. Mezzano, R. Ariëns, S. Watson
Blood Advances. 2017, 1, 1495-1504
Pharmacological Blockade of Glycoprotein VI Promotes Thrombus Disaggregation in the Absence of Thrombin
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GPVI and CLEC-2 in hemostasis and vascular integrity
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Comparison of the GPVI inhibitors losartan and honokiol
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The cytoplasmic domain of GPVI is associated through salt bridges with the ITAM-containing FcgR chain, on which ITAM is present
Platelet ITAM signaling
W. Bergmeier, L. Stefanini
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A. Moroi, S. Watson
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GPVI and CLEC-2 in hemostasis and vascular integrity
S. WATSON, J. HERBERT, A. POLLITT
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J. Bradshaw
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A. Moroi, S. Watson
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Role of PI3K/Akt signaling in memory CD8 T cell differentiation
E. Kim, M. Suresh
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J. Rayes, S. Watson, B. Nieswandt
Journal of Clinical Investigation. 2019, 129, 12-23
CLEC-2 – a receptor that is required for the prevention of blood-lymph mixing
Lymphatic endothelial cells express podoplanin, a glycoprotein capable of activating platelets through their CLEC-2 receptor, on their surface
Functional significance of the platelet immune receptors GPVI and CLEC-2
J. Rayes, S. Watson, B. Nieswandt
Journal of Clinical Investigation. 2019, 129, 12-23
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B. Ho-Tin-Noé, Y. Boulaftali, E. Camerer
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The intracellular signaling cascade of the CLEC-2 receptor, with the exception of the initial stages of activation, is similar to the intracellular cascade of GPVI activation
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Blood. 2015, 125, 144-154
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S. WATSON, J. HERBERT, A. POLLITT
Journal of Thrombosis and Haemostasis. 2010, 8, 1456-1467
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C. Hughes, B. Finney, F. Koentgen, K. Lowe, S. Watson
Blood. 2015, 125, 144-154
Syk and Src Family Kinases Regulate C-type Lectin Receptor 2 (CLEC-2)-mediated Clustering of Podoplanin and Platelet Adhesion to Lymphatic Endothelial Cells
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![Scheme of tyrosine kinase signaling in platelets (based on the signal transduction network of CLEC-2 receptor). Upon binding of the receptor to the ligand (podoplanin, rhodocytin, or fucoidan), receptor clustering occurs. At the same time, it is believed that receptors are clustered in the region of lipid rafts (membrane microdomains enriched in cholesterol). GPVI and FcRIIA also cluster after ligand binding. In resting platelets, small amounts of SFK are maintained in an active state by phosphatases CD148. Active SFKs can also support small numbers of active Syk. Upon clustering of receptors that trigger the activation of tyrosine kinases, either Syk (CLEC-2) or SFK (GPVI, FcRIIA) phosphorylate their cytoplasmic domains, which leads to increased activation of Syk. Active Syk phosphorylates the adapter protein LAT, to which PI3K binds, becoming active. PI3K phosphorylates PIP2, producing PIP3, which acts as a docking site for Btk tyrosine kinase. When Btk lands on the membrane, it becomes active and phosphorylates PLC2, which also binds to phosphorylated LAT. Active PLC2 hydrolyzes PIP2, producing a secondary activation messenger IP3, which activates the IP3R receptor on the endoplasmic reticulum. The IP3R releases calcium ions from the intracellular platelet stores, which are returned there due to the activity of the SERCA pumps. Calcium ions can also inhibit IP3R. This leads to the initiation of calcium oscillations in the cytosol of platelets.](https://astore.sbpreports.com/issues/articles/11/figures/fig_2.png?v=ooekl)
Adhesion and immune receptors
One of the primary responses of platelets to the damage to the blood vessel walls is their adhesion in the damaged area. The key receptors for the platelet adhesion are glycoprotein Ib (GPIb) and aIIbb3-integrins. Glycoprotein Ib and aIIbb3-integrins do not directly activate tyrosine kinase signaling in platelets: neither GPIb nor aIIbb3-integrins have tyrosine residues, available for phosphorylation, that could serve as activation sites for initiating tyrosine kinase signaling
Platelet signaling
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F. MU, S. CRANMER, R. ANDREWS, M. BERNDT
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W. Bergmeier, L. Stefanini
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It has been shown that in bacterial sepsis and the generation of an immune response, platelets can surround bacteria that have appeared in the bloodstream, which will lead to the death of bacteria
The platelet Fc receptor, FcγRIIa
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J. Rayes, S. Watson, B. Nieswandt
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Among the receptors that induce platelet activation, a group of receptors that recognize pathogen-associated molecular patterns (PAMP) and molecular patterns associated with damage (DAMP) - Tall-like receptors (TLR) – stands out
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Activation of TLR receptors initiates the assembly of a signaling complex based on the adapter protein MyD88 — the middosome
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Майоров А.С., Шепелюк Т.О., Балабин Ф.А., Мартьянов А.А., Нечипуренко Д.Ю., Свешникова А.Н.
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F. Cognasse
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IκB kinase phosphorylation of SNAP-23 controls platelet secretion
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From the TLR family, the expression of TLR2 receptors on platelets has been unambiguously demonstrated both at the mRNA and at the protein level
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Efficient phagocytosis of periodontopathogens by neutrophils requires plasma factors, platelets and TLR2
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Journal of Thrombosis and Haemostasis. 2011, 9, 799-809
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A. ASSINGER, M. LAKY, G. SCHABBAUER, A. HIRSCHL, E. BUCHBERGER, B. BINDER, I. VOLF
Journal of Thrombosis and Haemostasis. 2011, 9, 799-809
The platelet surface also contains a sufficient amount of the TLR4 receptor, which recognizes the components of the cell wall of gram-negative bacteria - lipopolysaccharides (LPS)
Platelet Toll-like receptor expression and activation induced by lipopolysaccharide and sepsis
T. Claushuis, A. Van Der Veen, J. Horn, M. Schultz, R. Houtkooper, C. Van ’T Veer, T. Van Der Poll
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TLR7 is expressed in platelets both at the protein and mRNA levels
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K. Hally, A. La Flamme, P. Larsen, S. Harding
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The role of platelets in mediating a response to human influenza infection
M. Koupenova, H. Corkrey, O. Vitseva, G. Manni, C. Pang, L. Clancy, C. Yao, J. Rade, D. Levy, J. Wang, R. Finberg, E. Kurt-Jones, J. Freedman
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Engagement of Platelet Toll-Like Receptor 9 by Novel Endogenous Ligands Promotes Platelet Hyperreactivity and Thrombosis
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In addition to PAMP-induced signaling, platelets can also be a source of DAMP, which will be recognized by TLR receptors. Thus, endogenous mitochondrial DAMPs, mitochondrial DNA (mtDNA), and mitochondrial proteins are powerful immunostimulants
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Journal of Thrombosis and Haemostasis. 2008, 6, 2175-2185
Nitric oxide specifically inhibits integrin-mediated platelet adhesion and spreading on collagen
W. ROBERTS, R. RIBA, S. HOMER-VANNIASINKAM, R. FARNDALE, K. NASEEM
Journal of Thrombosis and Haemostasis. 2008, 6, 2175-2185
Conclusions
Platelet functioning is inextricably associated with the need to simultaneously receive and interpret a large number of external signals. Moreover, in some cases, these signals may contradict each other. Thanks to a complex and accurate network of receptors that trigger GPCR or tyrosine kinase signaling, platelets can “cope with such pressure” and adequately respond to arising breaches of the integrity of blood vessels. Moreover, signaling pathways in platelets can synergistically enhance each other (tyrosine kinase and GPCR) or, conversely, suppress (cAMP / cGMP signaling). Interestingly, platelets also contain voltage-gated receptors, such as the Kv1.3 and APMPA channels
The unique contribution of ion channels to platelet and megakaryocyte function
M. MAHAUT-SMITH
Journal of Thrombosis and Haemostasis. 2012, 10, 1722-1732
It is noteworthy that synergistic enhancement of platelet activation pathways can occur both within the same type of signaling and for different types. So, on the one hand, ADP induces calcium signaling and activation of platelet integrins aIIbb3 in a Gq-dependent manner through the P2Y1 receptor. On the other hand, ADP can also reduce the concentration of cAMP in a Gi-dependent manner through the P2Y12 receptor, which greatly enhances platelet activation. On the other hand, the tyrosine kinase signaling branch and GPCR signaling can amplify each other: both of these signaling branches induce the activation of PI3K, which triggers the phosphoinositide signaling branch. Moreover, activation of phosphoinositide signaling during outside-in signaling via platelet integrins aIIbb3 also becomes an important element of synergistic enhancement of platelet activation.
The interplay between the intracellular signaling pathways in platelets also allows them to be activated momentarily: platelets often become the first line of the body's response to pathology. Moreover, platelets are also important participants in immune processes, such as the body's response to a bacterial or viral infection, or to modulate the responses of components of cellular immunity. Secondary messengers that drive all of these platelet responses and provide interactions between activation signals and platelet functional responses will be the subject of the next part of our review series.
Author Contributions
A.A.M. drew the figures, wrote the text, and edited the paper; M.A.P. supervised the project, wrote the text and edited the paper. All authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The authors declare no conflict of interest
Funding
The project was supported by the Russian Presidential Scholarship SP 2675.2019.4
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