Genomes and Genes
par 1 receptor
Summary: A thrombin receptor subtype that couples to HETEROTRIMERIC GTP-BINDING PROTEINS resulting in the activation of a variety of signaling mechanisms including decreased intracellular CYCLIC AMP, increased TYPE C PHOSPHOLIPASES and increased PHOSPHOLIPASE A2.
- Arora P, Cuevas B, Russo A, Johnson G, Trejo J. Persistent transactivation of EGFR and ErbB2/HER2 by protease-activated receptor-1 promotes breast carcinoma cell invasion. Oncogene. 2008;27:4434-45 pubmed publisher..These studies reveal a critical role for PAR1, a receptor activated by tumor-generated proteases, in hyperactivation of ErbB signaling that promotes breast carcinoma cell invasion. ..
- McLaughlin J, Patterson M, Malik A. Protease-activated receptor-3 (PAR3) regulates PAR1 signaling by receptor dimerization. Proc Natl Acad Sci U S A. 2007;104:5662-7 pubmed..Because PAR3 is a critical determinant of PAR1 function, targeting of PAR3 may mitigate the effects of PAR1 in activating endothelial responses such as vascular inflammation. ..
- Kaneider N, Leger A, Agarwal A, Nguyen N, Perides G, Derian C, et al. 'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage. Nat Immunol. 2007;8:1303-12 pubmed..Unexpectedly, we found that the protective effects of PAR1 required transactivation of PAR2 signaling pathways. Our results suggest therapeutics that selectively activate PAR1-PAR2 complexes may be beneficial in the treatment of sepsis. ..
- Mosnier L, Zlokovic B, Griffin J. The cytoprotective protein C pathway. Blood. 2007;109:3161-72 pubmed
- Liu J, Schuff Werner P, Steiner M. Thrombin/thrombin receptor (PAR-1)-mediated induction of IL-8 and VEGF expression in prostate cancer cells. Biochem Biophys Res Commun. 2006;343:183-9 pubmed..The results suggest that the thrombin/PAR-1 system upregulates cytokines in prostate cancer cells which in turn may contribute to the progression of prostate cancer. ..
- Agarwal A, Covic L, Sevigny L, Kaneider N, Lazarides K, Azabdaftari G, et al. Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer. Mol Cancer Ther. 2008;7:2746-57 pubmed publisher..These data provide an in vivo proof-of-concept that targeting the metalloprotease-PAR1 signaling system may be a novel therapeutic approach in the treatment of ovarian cancer. ..
- Kaushal V, Kohli M, Dennis R, Siegel E, Chiles W, Mukunyadzi P. Thrombin receptor expression is upregulated in prostate cancer. Prostate. 2006;66:273-82 pubmed..Its predominant expression in vascular network suggests that it may play a direct and crucial role in angiogenesis and could be a relevant target for therapeutic interventions to control or to prevent disease progression. ..
- Howell D, Johns R, Lasky J, Shan B, Scotton C, Laurent G, et al. Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis. Am J Pathol. 2005;166:1353-65 pubmed
- McLaughlin J, Shen L, Holinstat M, Brooks J, Dibenedetto E, Hamm H. Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1. J Biol Chem. 2005;280:25048-59 pubmed..This model provides an estimate that peptide activation alters receptor/G protein binding to favor Galpha(q) activation over Galpha(12/13) by approximately 800-fold. ..
- Paing M, Temple B, Trejo J. A tyrosine-based sorting signal regulates intracellular trafficking of protease-activated receptor-1: multiple regulatory mechanisms for agonist-induced G protein-coupled receptor internalization. J Biol Chem. 2004;279:21938-47 pubmed..This study is the first to describe a function for a tyrosine-based motif, YXX, in GPCR internalization and reveal novel complexities in the regulation of GPCR trafficking. ..
- Gullapalli A, Wolfe B, Griffin C, Magnuson T, Trejo J. An essential role for SNX1 in lysosomal sorting of protease-activated receptor-1: evidence for retromer-, Hrs-, and Tsg101-independent functions of sorting nexins. Mol Biol Cell. 2006;17:1228-38 pubmed..Together, our findings establish an essential role for endogenous SNX1 in sorting activated PAR1 to a distinct lysosomal degradative pathway that is independent of retromer, Hrs, and Tsg101. ..
- Yuan T, Lin M. Protease-activated receptor 1: a role in prostate cancer metastasis. Clin Prostate Cancer. 2004;3:189-91 pubmed
- Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell. 2005;120:303-13 pubmed..These results demonstrate that MMP-1 in the stromal-tumor microenvironment can alter the behavior of cancer cells through PAR1 to promote cell migration and invasion. ..
- Rickard A, Portell C, Kell P, Vinson S, McHowat J. Protease-activated receptor stimulation activates a Ca2+-independent phospholipase A2 in bladder microvascular endothelial cells. Am J Physiol Renal Physiol. 2005;288:F714-21 pubmed
- Turcotte S, Desrosiers R, Brand G, Beliveau R. von Hippel-Lindau tumor suppressor protein stimulation by thrombin involves RhoA activation. Int J Cancer. 2004;112:777-86 pubmed..Together, these results demonstrate that thrombin induces both pVHL expression via PAR1/RhoA activation as well as the stimulation of renal cancer cell invasion suggesting a role for thrombin in tumor invasion. ..
- Hansen K, Saifeddine M, Hollenberg M. Tethered ligand-derived peptides of proteinase-activated receptor 3 (PAR3) activate PAR1 and PAR2 in Jurkat T cells. Immunology. 2004;112:183-90 pubmed
- Kouklis P, Konstantoulaki M, Vogel S, Broman M, Malik A. Cdc42 regulates the restoration of endothelial barrier function. Circ Res. 2004;94:159-66 pubmed..The delayed activation of Cdc42 represents a negative-feedback mechanism that signals AJ reassembly after the increase in endothelial permeability induced by inflammatory mediators such as thrombin. ..
- Feistritzer C, Riewald M. Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood. 2005;105:3178-84 pubmed
- Booden M, Eckert L, Der C, Trejo J. Persistent signaling by dysregulated thrombin receptor trafficking promotes breast carcinoma cell invasion. Mol Cell Biol. 2004;24:1990-9 pubmed..Thus, our results reveal that a novel alteration in trafficking of activated PAR1 causes persistent signaling and, in addition to other processes and proteins, contributes to breast carcinoma cell invasion. ..
- Ludeman M, Zheng Y, Ishii K, Coughlin S. Regulated shedding of PAR1 N-terminal exodomain from endothelial cells. J Biol Chem. 2004;279:18592-9 pubmed..Nonetheless, regulated shedding of G protein-coupled receptors represents a new mechanism by which signaling by this important class of receptors might be modulated. ..
- Shi X, Gangadharan B, Brass L, Ruf W, Mueller B. Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis. Mol Cancer Res. 2004;2:395-402 pubmed..Together, these data confirm a role for PAR1 in migration and metastasis and demonstrate an unexpected role for PAR2 in thrombin-dependent tumor cell migration and in metastasis. ..
- Morris D, Ding Y, Ricks T, Gullapalli A, Wolfe B, Trejo J. Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration, and invasion of breast cancer cells. Cancer Res. 2006;66:307-14 pubmed
- Swift S, Leger A, Talavera J, Zhang L, Bohm A, Kuliopulos A. Role of the PAR1 receptor 8th helix in signaling: the 7-8-1 receptor activation mechanism. J Biol Chem. 2006;281:4109-16 pubmed..This "7-8-1" interaction network was found to be prevalent in G protein-coupled receptors involved in endothelial signaling and angiogenesis. ..
- Ludeman M, Kataoka H, Srinivasan Y, Esmon N, Esmon C, Coughlin S. PAR1 cleavage and signaling in response to activated protein C and thrombin. J Biol Chem. 2005;280:13122-8 pubmed..Although consistent with reports that sufficiently high concentrations of APC can cleave and activate PAR1 in culture, our data suggest that a significant physiological role for PAR1 activation by APC is unlikely. ..
- Chen C, Paing M, Trejo J. Termination of protease-activated receptor-1 signaling by beta-arrestins is independent of receptor phosphorylation. J Biol Chem. 2004;279:10020-31 pubmed..These findings reveal a new level of complexity in the regulation of protease-activated GPCR signaling. ..
- Wilson S, Gallagher S, Warpeha K, Hawthorne S. Amplification of MMP-2 and MMP-9 production by prostate cancer cell lines via activation of protease-activated receptors. Prostate. 2004;60:168-74 pubmed..Preliminary studies show the activation of PAR-1 or PAR-2 produced increased levels of MMP-2 and MMP-9 activity in prostate cancer cell lines, indicating their potential role in the metastasis of prostate cancer cells. ..
- Grisaru Granovsky S, Salah Z, Maoz M, Pruss D, Beller U, Bar Shavit R. Differential expression of protease activated receptor 1 (Par1) and pY397FAK in benign and malignant human ovarian tissue samples. Int J Cancer. 2005;113:372-8 pubmed..Altogether our data suggest that hPar1 and FAK cooperate to promote ovarian cancer malignancy. ..
- Tang H, Low B, Rutherford S, Hao Q. Thrombin induces endocytosis of endoglin and type-II TGF-beta receptor and down-regulation of TGF-beta signaling in endothelial cells. Blood. 2005;105:1977-85 pubmed..Since TGF-beta plays a crucial role in the resolution phase of angiogenesis, the down-regulation of TGF-beta signaling by thrombin-PAR1 pathway may provide a new insight into the mechanism of the proangiogenic effect of thrombin. ..
- James C, Collison D, Duncan G. Characterization and functional activity of thrombin receptors in the human lens. Invest Ophthalmol Vis Sci. 2005;46:925-32 pubmed..PAR3 mRNA was also detected, but the receptor itself, if present, was not coupled to the above signaling elements. ..
- Massi D, Naldini A, Ardinghi C, Carraro F, Franchi A, Paglierani M, et al. Expression of protease-activated receptors 1 and 2 in melanocytic nevi and malignant melanoma. Hum Pathol. 2005;36:676-85 pubmed..Conversely, the significance of PAR-2 up-regulation in both benign and malignant melanocytic lesions requires further research. ..
- Saban R, D Andrea M, Andrade Gordon P, Derian C, Dozmorov I, Ihnat M, et al. Mandatory role of proteinase-activated receptor 1 in experimental bladder inflammation. BMC Physiol. 2007;7:4 pubmed..It remains to be determined whether or not mechanisms targeting PAR1 gene silencing or PAR1 blockade will ameliorate the clinical manifestations of cystitis. ..
- Trivedi V, Boire A, Tchernychev B, Kaneider N, Leger A, O Callaghan K, et al. Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site. Cell. 2009;137:332-43 pubmed publisher..These studies provide a link between matrix-dependent activation of metalloproteases and platelet-G protein signaling and identify MMP1-PAR1 as a potential target for the prevention of arterial thrombosis. ..
- Naito Y, Uchiyama K, Kuroda M, Takagi T, Kokura S, Yoshida N, et al. Role of pancreatic trypsin in chronic esophagitis induced by gastroduodenal reflux in rats. J Gastroenterol. 2006;41:198-208 pubmed
- Ramstrom S, Oberg K, Akerström F, Enström C, Lindahl T. Platelet PAR1 receptor density--correlation to platelet activation response and changes in exposure after platelet activation. Thromb Res. 2008;121:681-8 pubmed..We found a significant reduction in PAR1 surface exposure after adding PAR1-AP, while activation with ADP, PAR4-AP or CRP increased the exposure. ..
- Ketabchi S, Massi D, Ficarra G, Rubino I, Franchi A, Paglierani M, et al. Expression of protease-activated receptor-1 and -2 in orofacial granulomatosis. Oral Dis. 2007;13:419-25 pubmed..Simultaneous overexpression of PARs, MMPs and COXs suggests synergism among these proinflammatory receptors and enzymes. ..
- Brueckmann M, Hoffmann U, Engelhardt C, Lang S, Fukudome K, Haase K, et al. Prognostic value of platelet-derived growth factor in patients with severe sepsis. Growth Factors. 2007;25:15-24 pubmed..PDGF-BB may serve as useful laboratory marker to predict survival in patients presenting with severe sepsis. ..
- Desai P, Kurian D, Thirumavalavan N, Desai S, Ziu P, Grant M, et al. A randomized clinical trial investigating the relationship between aprotinin and hypercoagulability in off-pump coronary surgery. Anesth Analg. 2009;109:1387-94 pubmed publisher..These results support further investigation of aprotinin and other PAR-1 antagonists in OPCAB surgery. ..
- Ribeiro F, Simao T, Amoedo N, Andreollo N, Lopes L, Acatauassu R, et al. Evidence for increased expression of tissue factor and protease-activated receptor-1 in human esophageal cancer. Oncol Rep. 2009;21:1599-604 pubmed..Altogether our data suggest a possible role for blood clotting proteins in the biology of human esophageal cancer. ..
- Hermann G, Van Meter M, Rood J, Rogers R. Proteinase-activated receptors in the nucleus of the solitary tract: evidence for glial-neural interactions in autonomic control of the stomach. J Neurosci. 2009;29:9292-300 pubmed publisher..g., NST) neurons. These results show, for the first time, that changes in autonomic control can be directly signaled by glial detection of local chemical stimuli. ..
- Elste A, Petersen I. Expression of proteinase-activated receptor 1-4 (PAR 1-4) in human cancer. J Mol Histol. 2010;41:89-99 pubmed publisher..PAR-3 and PAR-4 are less frequently detectable, their expression and potential role in tumorigenesis require further investigation. ..
- Joo S, Won T, Kim J, Yoo Y, Tak E, Park S, et al. Inhibition of coagulation activation and inflammation by a novel Factor Xa inhibitor synthesized from the earthworm Eisenia andrei. Biol Pharm Bull. 2009;32:253-8 pubmed..Our results provide the first evidence that ESP might interrupt coagulation cascades by inhibiting FXa, and thereby may effectively control the bidirectional alternation between coagulation and inflammation. ..
- Kai Y, Maeda Y, Sasaki T, Kanaide H, Hirano K. Basic and translational research on proteinase-activated receptors: the role of thrombin receptor in cerebral vasospasm in subarachnoid hemorrhage. J Pharmacol Sci. 2008;108:426-32 pubmed..PAR(1) antagonists are thus anticipated to be a novel therapeutic strategy for cerebral vasospasm. However, further studies are needed before establishing the clinical usefulness of PAR(1) antagonists. ..
- Moriyuki K, Nagataki M, Sekiguchi F, Nishikawa H, Kawabata A. Signal transduction for formation/release of interleukin-8 caused by a PAR2-activating peptide in human lung epithelial cells. Regul Pept. 2008;145:42-8 pubmed
- Sutherland M, Friedman H, Pryzdial E. Thrombin enhances herpes simplex virus infection of cells involving protease-activated receptor 1. J Thromb Haemost. 2007;5:1055-61 pubmed..These data show that HSV1 and HSV2 initiate thrombin production to increase the susceptibility of cells to infection through a mechanism involving PAR1-mediated cell modulation. ..
- Ramachandran R, Sadofsky L, Xiao Y, Botham A, Cowen M, Morice A, et al. Inflammatory mediators modulate thrombin and cathepsin-G signaling in human bronchial fibroblasts by inducing expression of proteinase-activated receptor-4. Am J Physiol Lung Cell Mol Physiol. 2007;292:L788-98 pubmed..These findings point to an important mechanism, whereby cellular responses to thrombin and cathepsin-G can be modified during an inflammatory response. ..
- Jesmin S, Gando S, Zaedi S, Sakuraya F. Chronological expression of PAR isoforms in acute liver injury and its amelioration by PAR2 blockade in a rat model of sepsis. Thromb Haemost. 2006;96:830-8 pubmed
- Day J, Landis R, Taylor K. Aprotinin and the protease-activated receptor 1 thrombin receptor: antithrombosis, inflammation, and stroke reduction. Semin Cardiothorac Vasc Anesth. 2006;10:132-42 pubmed
- Leger A, Covic L, Kuliopulos A. Protease-activated receptors in cardiovascular diseases. Circulation. 2006;114:1070-7 pubmed..In addition, we discuss a new class of cell-penetrating inhibitors, termed pepducins, that provide insight into previously unidentified roles of PAR1 and PAR4 in protease signaling. ..