The thrombin receptor extracellular domain contains sites crucial for peptide ligand-induced activation.

Bahou, WF; Coller, BS; Potter, Cheri L.; Norton, Karin J.; Kutok, JL; Goligorsky, Michael S.

doi:10.1172/jci116344

Cited by 95 publications

(72 citation statements)

References 38 publications

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“…In an attempt to identify additional PARs that potentially may be clustered in this region of the genome, differential genomic blotting was adapted using a series of cDNA probes encompass- 32 P-radiolabeled PAR-3 cDNA (2B1A) as probe followed by high stringency wash and overnight autoradiography. The table (panel B) delineates the restriction fragment sizes when the blot was stripped and sequentially hybridized with the cDNAs for PAR-1 (20) and PAR-2 (6). As demonstrated, all three genes are contained within the identical NotI (ϳ120 kb) or XhoI (ϳ90 kb) fragments.…”

Section: Resultsmentioning

confidence: 95%

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The Human Proteinase-activated Receptor-3 (PAR-3) Gene

Schmidt¹,

Nierman²,

Maglott³

et al. 1998

Journal of Biological Chemistry

112

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Proteolytically activated receptors (PARs) represent an emerging subset of seven transmembrane G proteincoupled receptors that mediate cell activation events by receptor cleavage at distinct scissile bonds located within receptor amino termini. Differential genomic blotting using a yeast artificial chromosome known to contain the PAR-1 and PAR-2 genes identified the PAR-3 gene within a PAR gene cluster spanning ϳ100 kilobases at 5q13. The PAR-3 gene is relatively small (ϳ12 kilobases); and, like the PAR-1 and PAR-2 genes, it displays a two-exon structure, with the majority of the coding sequence and the proteolytic cleavage site contained within the larger second exon. Sequence analysis of the 5-flanking region demonstrates that the promoter is TATA-less, similar to that seen with PAR-1, with the identification of nucleic acid motifs potentially involved in transcriptional gene regulation, including AP-1, GATA, and octameric sequences. PAR-3 transcripts were apparent in human vascular endothelial cells, although at considerably lower levels than those of PAR-1 and not significantly modulated by the endothelial cell stimulus tumor necrosis factor-␣. Likewise, although PAR-3 mRNA was evident in human platelets, receptor cell surface expression was modest (ϳ10%) compared with that of PAR-1. Thus, although PAR-3 is postulated to represent a second thrombin receptor, its modest endothelial cell and platelet expression suggest that PAR-3 activation by ␣-thrombin is less relevant for physiological responses in these mature cells. Rather, given its disparately greater expression in megakaryocytes (and megakaryocyte-like human erythroleukemia cells), a regulatory role in cellular development (by protease activation) could be postulated.

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Section: Resultsmentioning

confidence: 95%

“…Platelet cell surface PAR-1/PAR-3 expression was completed as described previously (20). Briefly, platelet-rich plasma was prepared in 10 mM EDTA from healthy human donors by differential centrifugation and adjusted to 3 ϫ 10 8 platelets/ml TSE (0.1 M Tris, 0.15 M NaCl, 10 mM EDTA, pH 7.4).…”

Section: Figmentioning

confidence: 99%

The Human Proteinase-activated Receptor-3 (PAR-3) Gene

Schmidt¹,

Nierman²,

Maglott³

et al. 1998

Journal of Biological Chemistry

112

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“…HUVEC express abundant amounts of PAR1 and PAR2 on their surface (Nelken et al, 1992;Molino et al, 1997c;D'Andrea et al, 1998;Bahou et al, 1993;Mirza et al, 1996;Nystedt et al, 1996;Ngaiza et al, 1992;Woolkalis et al, 1995a,b) and at least one report suggests that PAR3 is present as well, albeit at lower densities (Schmidt et al, 1998). Responses to thrombin in endothelial cells include an increase in the cytosolic Ca 2+ concentration.…”

Section: Which Receptor(s) Contribute To Thrombin Responses In Any Pamentioning

confidence: 99%

“…The ®rst studies of the PAR1 ligand binding domain used antibodies to inhibit activation of the receptor by thrombin and the peptide agonists, SFLLRN. Two di erent polyclonal antibodies were used, one raised against the entire receptor N-terminus, the other raised against a 20 residue peptide spanning the thrombin cleavage site (Bahou et al, 1993(Bahou et al, , 1994. The latter antibody prevented PAR1 activation by thrombin, but not by SFLLRN.…”

Section: Ligand Binding Domainsmentioning

confidence: 99%

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Protease activated receptors: theme and variations

Molino²,

et al. 2001

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The four PAR family members are G protein coupled receptors that are normally activated by proteolytic exposure of an occult tethered ligand. Three of the family members are thrombin receptors. The fourth (PAR2) is not activated by thrombin, but can be activated by other proteases, including trypsin, tryptase and Factor Xa. This review focuses on recent information about the manner in which signaling through these receptors is initiated and terminated, including evidence for inter-as well as intramolecular modes of activation, and continuing e orts to identify additional, biologicallyrelevant proteases that can activate PAR family members. Oncogene (2001) 20, 1570 ± 1581.

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Platelet‐Activation Mechanisms and Vascular Remodeling

Rubenstein

Yin

2018

Comprehensive Physiology

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This overview article for the Comprehensive Physiology collection is focused on detailing platelets, how platelets respond to various stimuli, how platelets interact with their external biochemical environment, and the role of platelets in physiological and pathological processes. Specifically, we will discuss the four major functions of platelets: activation, adhesion, aggregation, and inflammation. We will extend this discussion to include various mechanisms that can induce these functional changes and a discussion of some of the salient receptors that are responsible for platelets interacting with their external environment. We will finish with a discussion of how platelets interact with their vascular environment, with a special focus on interactions with the extracellular matrix and endothelial cells, and finally how platelets can aid and possibly initiate the progression of various vascular diseases. Throughout this overview, we will highlight both the historical investigations into the role of platelets in health and disease as well as some of the more current work. Overall, the authors aim for the readers to gain an appreciation for the complexity of platelet functions and the multifaceted role of platelets in the vascular system. © 2017 American Physiological Society. Compr Physiol 8:1117-1156, 2018.

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The thrombin receptor extracellular domain contains sites crucial for peptide ligand-induced activation.

Cited by 95 publications

References 38 publications

The Human Proteinase-activated Receptor-3 (PAR-3) Gene

The Human Proteinase-activated Receptor-3 (PAR-3) Gene

Protease activated receptors: theme and variations

Platelet‐Activation Mechanisms and Vascular Remodeling

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