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The Activation Mechanism of F2R
F2R, also known as the thrombin receptor, is a G protein-coupled receptor. The thrombin binds to the nitrogen end of the thrombin receptor on the surface of the platelet and is hydrolyzed to produce a new nitrogen terminus. The new nitrogen terminus binds to the thrombin receptor itself through the intramolecular reaction, thereby activating the thrombin receptor, triggering the transmission of intracellular signals and ultimately leading to the aggregation of blood microplates. Therefore, thrombin receptor is also called protease activated receptor-1 (PAR-1). Subsequently, protease activated receptor 2, 3, 4 subtypes were found successively. In addition, the first six amino acid peptide of the new terminus(serine-phenylalanine-leucine-leucine-arginine-asparagine, SFLLRN) can also activate thrombin receptor, which is called thrombin receptor activation peptide (TRAP), commonly used for thrombin receptor activation in vitro and in vivo.
Figure1. Mechanism of thrombin receptor activation. (From J Clin Invest).
F2R and Melanoma
Melanoma remains the deadliest form of skin cancer with limited and inefficient treatment options for patients with metastatic disease. PAR-1 is considered to play an important role in the progression of human melanoma. PAR-1 is known to activate adhesive, invasive and angiogenic factors to promote melanoma metastasis.
The activation of thrombin can be seen in a variety of cancers leading to the production of the PAR-1 signal. Melanoma triggers the up-regulation of the thrombin cascade of tissue factors (TF), which leads to the activation of coagulation factor X and the expression of thrombin. In addition, many studies have shown that the expression of TF constitutive type in melanoma cells can activate thrombin through independent coagulation, leading to the activation of the PAR-1 receptor and promoting the metastasis of melanoma. By silencing PAR-1, gene expression in melanoma cells can be suppressed. So, PAR-1 may be used as a new target for the treatment of human melanoma. Moreover, PAR-1 regulates many of the genes necessary for melanoma growth and metastasis, such as CX-43 and maspin, which can also be new targets for melanoma treatment.
F2R and Atherosclerotic Thrombosis
In spite of the current standard treatment including dual antiplatelet therapy, the recurrence rates of ischemic events remain high for high-risk patients with atherosclerotic disease. This may be in part attributed to the fact that other key platelet activation pathways remain uninhibited and can thus continue to trigger platelet activation and lead to thrombotic complications. Thrombin is a powerful inducer of platelet activation and mediates its effects directly on platelets through protease activator receptors (PARs), particularly the PAR-1 subtype, making PAR-1 inhibition an attractive approach for reducing atherothrombotic events. These observations have led to the development of several PAR-1 antagonists. Vorapaxar is a direct inhibitor of PAR-1 and is the only agent approved for the prevention of recurrent ischemic events in patients with prior myocardial infarction or peripheral artery disease.