Evaluation of the F2R IVS-14A/T PAR1 polymorphism with subsequent cardiovascular events and bleeding in patients who have undergone percutaneous coronary intervention

Friedman, Eitan A.; Texeira, Luisa; Delaney, Jessica; Weeke, Peter; Lynch, D. C.; Kasasbeh, Ehab; Song, Yanna; Harrell, Frank E.; Denny, Joshua C.; Hamm, Heidi E.; Roden, Dan M.; Cleator, John H.

doi:10.1007/s11239-015-1285-4

Cited by 7 publications

(3 citation statements)

References 39 publications

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“…103 However, in a clinical study with 660 patients who underwent percutaneous coronary intervention, there was no evidence of increased major adverse cardiovascular events or bleeding risk correlated with the polymorphism. 107 The recently described difference in reactivity between PAR4 sequence variants provides the most compelling evidence that single nucleotide polymorphisms can influence a physiological response downstream of PARs. 104,105 Edelstein and colleagues identified 2 single nucleotide polymorphisms (rs773902 and rs2227346) that result in sequence variants at positions 120 (Ala/Thr) in transmembrane helix 2 (TM2) and 296 (Phe/Val) in TM6, respectively ( Figure 4A).…”

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confidence: 99%

Protease-activated receptors in hemostasis

Nieman

2016

Blood

114

123

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Protease signaling in cells elicits multiple physiologically important responses via protease-activated receptors (PARs). There are 4 members of this family of G-protein–coupled receptors (PAR1-4). PARs are activated by proteolysis of the N terminus to reveal a tethered ligand. The rate-limiting step of PAR signaling is determined by the efficiency of proteolysis of the N terminus, which is regulated by allosteric binding sites, cofactors, membrane localization, and receptor dimerization. This ultimately controls the initiation of PAR signaling. In addition, these factors also control the cellular response by directing signaling toward G-protein or β-arrestin pathways. PAR1 signaling on endothelial cells is controlled by the activating protease and heterodimerization with PAR2 or PAR3. As a consequence, the genetic and epigenetic control of PARs and their cofactors in physiologic and pathophysiologic conditions have the potential to influence cellular behavior. Recent studies have uncovered polymorphisms that result in PAR4 sequence variants with altered reactivity that interact to influence platelet response. This further demonstrates how interactions within the plasma membrane can control the physiological output. Understanding the structural rearrangement following PAR activation and how PARs are allosterically controlled within the plasma membrane will determine how best to target this family of receptors therapeutically. The purpose of this article is to review how signaling from PARs is influenced by alternative cleavage sites and the physical interactions within the membrane. Going forward, it will be important to relate the altered signaling to the molecular arrangement of PARs in the cell membrane and to determine how these may be influenced genetically.

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confidence: 99%

Protease-activated receptors in hemostasis

Nieman

2016

Blood

114

123

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“…function and has been shown to influence cardiovascular disease outcomes and cancer prognosis (79)(80)(81). Specifically, the AA genotype increases the risk of ischemic events in ST-elevation myocardial infarction patients (82) and is associated with an increased metastatic risk in renal carcinoma (83,84).…”

Section: Wwwannualreviewsorg • Diversity In Par Drug Development 359mentioning

confidence: 99%

Challenges and Opportunities in Protease-Activated Receptor Drug Development

Hamilton

Trejo

2017

Annu. Rev. Pharmacol. Toxicol.

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Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors (GPCRs) that transduce cellular responses to extracellular proteases. PARs have important functions in the vasculature, inflammation, and cancer and are important drug targets. A unique feature of PARs is their irreversible proteolytic mechanism of activation that results in the generation of a tethered ligand that cannot diffuse away. Despite the fact that GPCRs have proved to be the most successful class of druggable targets, the development of agents that target PARs specifically has been challenging. As a consequence, researchers have taken a remarkable diversity of approaches to develop pharmacological entities that modulate PAR function. Here, we present an overview of the diversity of therapeutic agents that have been developed against PARs. We further discuss PAR biased signaling and the influence of receptor compartmentalization, posttranslational modifications, and dimerization, which are important considerations for drug development.

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“…It is involved the progression and metastasis of various types of tumors, including sarcoma, melanoma, breast cancer, lung cancer, prostate cancer and pancreatic cancer [17][18][19][20]. F2r also plays an important role in coagulation and inflammation in response to injury [18,[21][22][23]. However, the effects of F2r in osteoclasts are still not clear.…”

Section: Introductionmentioning

confidence: 99%

F2r negatively regulates osteoclastogenesis through inhibiting the Akt and NFκB signaling pathways

Zhang¹,

Wang²,

Zhu³

et al. 2020

Int. J. Biol. Sci.

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G-protein-coupled receptors (GPCRs) are pivotal drug targets for many diseases. Coagulation Factor II Thrombin Receptor (F2R) is an important member of GPCR family that is highly expressed in osteoclasts. However, the role of F2r in osteoclasts is still unclear. Here, to examine the functions of F2r on osteoclast formation, differentiation, activation, survival, and acidification, we employed loss-of-function and gain-of-function approaches to study F2r using F2r-targeted short hairpin RNA (sh-F2r) lentivirus and overexpression plasmid pLX304-F2r lentivirus respectively, in mouse bone marrow cells (MBMs) induced osteoclasts. We used three shRNAs targeting F2r which had the ability to efficiently and consistently knock down the expression of F2r at different levels. Notably, F2r knockdown trigged a significant increase in osteoclast activity, number, and size, as well as promoted bone resorption and F-actin ring formation with increased osteoclast marker gene expression. Moreover, F2r overexpression blocked osteoclast formation, maturation, and acidification, indicating that F2r negatively regulates osteoclast formation and function. Furthermore, we investigated the mechanism(s) underlying the role of F2r in osteoclasts. We detected RANKL-induced signaling pathways related protein changes F2r knockdown cells and found significantly increased pAkt levels in sh-F2r infected cells, as well as significantly enhanced phosphorylation of p65 and IKBα in early stages of RANKL stimulation. These data demonstrated that F2r responds to RANKL stimulation to attenuate osteoclastogenesis through inhibiting the both F2r-Akt and F2r-NFκB signaling pathways, which lead a reduction in the expression of osteoclast genes. Our study suggests that targeting F2r may be a novel therapeutic approach for bone diseases, such as osteoporosis.

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Evaluation of the F2R IVS-14A/T PAR1 polymorphism with subsequent cardiovascular events and bleeding in patients who have undergone percutaneous coronary intervention

Cited by 7 publications

References 39 publications

Protease-activated receptors in hemostasis

Protease-activated receptors in hemostasis

Challenges and Opportunities in Protease-Activated Receptor Drug Development

F2r negatively regulates osteoclastogenesis through inhibiting the Akt and NFκB signaling pathways

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