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.

Top Publications

  1. Tellez C, Davis D, Prieto V, Gershenwald J, Johnson M, McCarty M, et al. Quantitative analysis of melanocytic tissue array reveals inverse correlation between activator protein-2alpha and protease-activated receptor-1 expression during melanoma progression. J Invest Dermatol. 2007;127:387-93 pubmed
    ..These findings support our hypothesis that loss of AP-2 is a crucial event in the progression of human melanoma and contributes to the acquisition of the metastatic phenotype via upregulation of PAR-1. ..
  2. Salah Z, Maoz M, Pokroy E, Lotem M, Bar Shavit R, Uziely B. Protease-activated receptor-1 (hPar1), a survival factor eliciting tumor progression. Mol Cancer Res. 2007;5:229-40 pubmed
    ..We conclude that whereas PAR1 gene expression correlates with tumor progression, its neutralization effectively initiates an apoptotic pathway leading at least in part to significantly reduced tumor formation. ..
  3. Depasquale I, Thompson W. Prognosis in human melanoma: PAR-1 expression is superior to other coagulation components and VEGF. Histopathology. 2008;52:500-9 pubmed publisher
    ..PAR-1 expression is the best antibody marker of recurrence risk from those studied. It remains to be seen whether this methodology can predict response to novel antiangiogenic therapies currently entering trial. ..
  4. Blackburn J, Brinckerhoff C. Matrix metalloproteinase-1 and thrombin differentially activate gene expression in endothelial cells via PAR-1 and promote angiogenesis. Am J Pathol. 2008;173:1736-46 pubmed publisher
  5. Deng X, Mercer P, Scotton C, Gilchrist A, Chambers R. Thrombin induces fibroblast CCL2/JE production and release via coupling of PAR1 to Galphaq and cooperation between ERK1/2 and Rho kinase signaling pathways. Mol Biol Cell. 2008;19:2520-33 pubmed publisher
  6. Villares G, Zigler M, Wang H, Melnikova V, Wu H, Friedman R, et al. Targeting melanoma growth and metastasis with systemic delivery of liposome-incorporated protease-activated receptor-1 small interfering RNA. Cancer Res. 2008;68:9078-86 pubmed publisher
    ..We propose that siRNA incorporated into DOPC nanoparticles could be delivered systemically and used as a new modality for melanoma treatment. ..
  7. Tauseef M, Kini V, Knezevic N, Brannan M, Ramchandaran R, Fyrst H, et al. Activation of sphingosine kinase-1 reverses the increase in lung vascular permeability through sphingosine-1-phosphate receptor signaling in endothelial cells. Circ Res. 2008;103:1164-72 pubmed publisher
    ..Our results suggest the crucial role of activation of the SPHK1-->S1P-->S1P1 signaling pathway in response to inflammatory mediators in endothelial cells in regulating endothelial barrier homeostasis...
  8. Uzonyi B, Lotzer K, Jahn S, Kramer C, Hildner M, Bretschneider E, et al. Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells. Proc Natl Acad Sci U S A. 2006;103:6326-31 pubmed
    ..These data show that cysLT2-R activation results in a proinflammatory EC phenotype. Because LTD4 and thrombin are likely to be formed concomitantly in vivo, cysLT2-R and PAR-1 may cooperate to augment vascular injury. ..
  9. Paing M, Johnston C, Siderovski D, Trejo J. Clathrin adaptor AP2 regulates thrombin receptor constitutive internalization and endothelial cell resensitization. Mol Cell Biol. 2006;26:3231-42 pubmed
    ..Our findings establish a novel role for AP2 in direct regulation of PAR1 trafficking, a process critically important to the temporal and spatial aspects of thrombin signaling. ..

More Information


  1. 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. ..
  2. Suzuki H, Motley E, Eguchi K, Hinoki A, Shirai H, Watts V, et al. Distinct roles of protease-activated receptors in signal transduction regulation of endothelial nitric oxide synthase. Hypertension. 2009;53:182-8 pubmed publisher
  3. 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. ..
  4. 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. ..
  5. Mosnier L, Zlokovic B, Griffin J. The cytoprotective protein C pathway. Blood. 2007;109:3161-72 pubmed
  6. 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. ..
  7. 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. ..
  8. 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. ..
  9. 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
  10. 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. ..
  11. 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. ..
  12. 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. ..
  13. Yuan T, Lin M. Protease-activated receptor 1: a role in prostate cancer metastasis. Clin Prostate Cancer. 2004;3:189-91 pubmed
  14. 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. ..
  15. 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
  16. 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. ..
  17. 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
  18. 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. ..
  19. 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
  20. 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. ..
  21. 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. ..
  22. 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. ..
  23. 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
  24. 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. ..
  25. 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. ..
  26. 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. ..
  27. 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. ..
  28. 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. ..
  29. 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. ..
  30. 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. ..
  31. 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. ..
  32. 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. ..
  33. 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. ..
  34. 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
  35. Marx A, Nugoor C, Panneerselvam S, Mandelkow E. Structure and function of polarity-inducing kinase family MARK/Par-1 within the branch of AMPK/Snf1-related kinases. FASEB J. 2010;24:1637-48 pubmed publisher
  36. 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. ..
  37. 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. ..
  38. 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. ..
  39. 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. ..
  40. 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. ..
  41. 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. ..
  42. Blackburn J, Liu I, Coon C, Brinckerhoff C. A matrix metalloproteinase-1/protease activated receptor-1 signaling axis promotes melanoma invasion and metastasis. Oncogene. 2009;28:4237-48 pubmed publisher
  43. 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. ..
  44. 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. ..
  45. 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. ..
  46. Chen D, Carpenter A, Abrahams J, Chambers R, Lechler R, McVey J, et al. Protease-activated receptor 1 activation is necessary for monocyte chemoattractant protein 1-dependent leukocyte recruitment in vivo. J Exp Med. 2008;205:1739-46 pubmed publisher
  47. 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
  48. 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. ..
  49. 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. ..
  50. 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
  51. 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
  52. 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. ..