Reactome | Platelet activation, signaling and aggregation

Platelet activation, signaling and aggregation

Stable Identifier

R-HSA-76002

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Platelet activation, signaling and aggregation

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Platelet activation begins with the initial binding of adhesive ligands and of the excitatory platelet agonists (released or generated at the sites of vascular trauma) to cognate receptors on the platelet membrane (Ruggeri 2002). Intracellular signaling reactions then enhance the adhesive and procoagulant properties of tethered platelets or of platelets circulating in the proximity. Once platelets have adhered they degranulate, releasing stored secondary agents such as ADP, ATP, and synthesize thromboxane A2. These amplify the response, activating and recruiting further platelets to the area and promoting platelet aggregation. These amplify the response, activating and recruiting further platelets to the area and promoting platelet aggregation. Adenosine nucleotides signal through P2 purinergic receptors on the platelet membrane. ADP activates P2Y1 and P2Y12, which signal via both the alpha and gamma:beta components of the heterotrimeric G-protein (Hirsch et al. 2001, 2006), while ATP activates the ionotropic P2X1 receptor (Kunapuli et al. 2003). Activation of these receptors initiates a complex signaling cascade that ultimately results in platelet activation, aggregation and thrombus formation (Kahner et al. 2006). Integrin AlphaIIbBeta3 is the most abundant platelet receptor, with 40 000 to 80 000 copies per resting platelet, acting as a major receptor for fibrinogen and other adhesive molecules (Wagner et al. 1996). Activation of AlphaIIbBeta3 enhances adhesion and leads to platelet-platelet interactions, and thus aggregation (Philips et al. 1991). GP VI is the most potent collagen receptor initiating signal generation, an ability derived from its interaction with the FcRI gamma chain. This results in the phosphorylation of the gamma-chain by non-receptor tyrosine kinases of the Src family (1). The phosphotyrosine motif is recognized by the SH2 domains of Syk, a tyrosine kinase. This association activates the Syk enzyme, leading to activation (by tyrosine phosphorylation) of PLC gamma2 (2). Thrombin is an important platelet agonist generated on the membrane of stimulated platelets. Thrombin acts via cell surface Protease Activated Receptors (PARs). PARs are G-protein coupled receptors activated by a proteolytic cleavage in an extracellular loop (Vu, 1991) (3). Activated PARs signal via G alpha q (4) and via the beta:gamma component of the G-protein (5). Both stimulate PLC giving rise to PIP2 hydrolysis and consequent activation of PI3K (6). PLCgamma2 activation also gives rise to IP3 (7) which stimulates the IP3 receptor (8) leading to increased intracellular calcium. Platelet activation further results in the scramblase-mediated transport of negatively-charged phospholipids to the platelet surface. These phospholipids provide a catalytic surface (with the charge provided by phosphatidylserine and phosphatidylethanolamine) for the tenase complex (formed by the activated forms of the blood coagulation factors factor VIII and factor I).

Literature References

PubMed ID	Title	Journal	Year
2018971	GPIIb-IIIa: the responsive integrin Scarborough, RM, Phillips, DR, Charo, IF	Cell	1991
8704248	Analysis of GPIIb/IIIa receptor number by quantification of 7E3 binding to human platelets Neblock, DS, Coller, BS, Jordan, RE, Wagner, CL, Weisman, HF, Mascelli, MA	Blood	1996
12411949	Platelets in atherothrombosis Ruggeri, ZM	Nat Med	2002
1672265	Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation Wheaton, VI, Vu, TK, Coughlin, SR, Hung, DT	Cell	1991
12681240	Platelet purinergic receptors Dorsam, RT, Kunapuli, SP, Quinton, TM, Kim, S	Curr Opin Pharmacol	2003
16543958	Signaling through PI3Kgamma: a common platform for leukocyte, platelet and cardiovascular stress sensing Hirsch, E, Costa, C, Rommel, C, Montrucchio, G, Barberis, L, Lembo, G	Thromb Haemost	2006
11511514	Resistance to thromboembolism in PI3Kgamma-deficient mice Wymann, M, Laffargue, M, Tropel, P, Hirsch, E, Bosco, O, Altruda, F, Montrucchio, G, Calvez, R	FASEB J	2001
17059469	Nucleotide receptor signaling in platelets Kahner, BN, Prasad, GL, Kunapuli, SP, Shankar, H, Murugappan, S	J Thromb Haemost	2006