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Gene Review

PWAR1  -  Prader Willi/Angelman region RNA 1

Homo sapiens

Synonyms: D15S227E, PAR-1, PAR1
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Disease relevance of PAR1

  • In vivo, treatment of rats with established gastric ulcers with a PAR1 antagonist each day for 1 wk resulted in a significant retardation of healing [1].
  • Here we show that at the relatively high concentration of agonist most likely found at the site of a local thrombus, dual inhibition of the P2Y12 receptor and calcium mobilization result in a complete inhibition of PAR4-induced aggregation, while having no effect on either thrombin or PAR1-mediated platelet aggregation [2].
  • We hypothesized that PAR1 activation contributed to prostate cancer cell progression [3].
  • In this study, we examined 1,074 prostate biopsies by tissue microarray analysis and demonstrated that PAR1 expression is significantly increased in prostate cancer compared to normal prostate epithelial cells and benign prostatic hyperplasia [3].
  • Although the thrombin-mediated regulation of clot formation has been studied extensively over the past decades, the possible role of thrombin in tumor metastasis via PAR1 has only recently received attention and is briefly discussed herein [4].

High impact information on PAR1

  • PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells [5].
  • 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 [5].
  • We therefore developed screening and selection methods to characterize sperm conversions in two meiotic crossover hot spots in the major histocompatibility complex (MHC) and one in the sex chromosomal pseudoautosomal pairing region PAR1 (ref. 9). All three hot spots are active in gene conversion and crossover [6].
  • To determine whether at high resolution this autosomal pattern also applies to PAR1, we have examined linkage disequilibrium over an interval of 43 kb around the gene SHOX [7].
  • An obligatory exchange occurs in PAR1, an Xp/Yp pseudoautosomal region of 2.6 Mb, which creates a male-specific recombination 'hot domain' with a recombination rate that is about 20 times higher than the genome average [7].

Chemical compound and disease context of PAR1


Biological context of PAR1

  • We identified submicroscopic PAR1 deletions encompassing the recently described short stature homeobox-containing gene SHOX (refs 7,8) segregating with the LWD phenotype in 5 families [13].
  • In a six-generation pedigree with LWD, we established linkage to the marker DXYS6814 in the pseudoautosomal region (PAR1) of the X and Y chromosomes (Z max=6.28; theta=0) [13].
  • A selective PAR1 agonist (TFLLR-NH(2)) induced platelet aggregation and VEGF release but suppressed endostatin release [1].
  • Human platelets express two thrombin receptors, PAR1 and PAR4, both of which signal platelet activation [2].
  • Stimulation of platelets with a PAR1-activating peptide (SFLLRN), PAR4-activating peptide (AYPGKF), and thrombin resulted in Thr308 and Ser473 phosphorylation of Akt, which results in its activation [14].

Anatomical context of PAR1

  • Compared with wild-type cells, Par1-/- endothelial cells showed markedly decreased responses to low concentrations of thrombin, and cells that lacked both PAR1 and PAR4 showed no responses to even high concentrations of thrombin [15].
  • We aimed to determine the cleavage site(s) responsive for the proteolytic inactivation of PAR1 in human umbilical vein endothelial cells [16].
  • On the cellular level, TFLLRN and thrombin prompted HT-29 cell migration and matrix adhesion by a PKCepsilon-dependent mechanism as concluded because of the inhibition of PAR1-mediated effects by the PKC inhibitor bisindolylmaleimide I and the PKCepsilon translocation inhibitory peptide EAVSLKPT but not by the PKC inhibitor Gö 6976 [17].
  • Activation of endothelial PAR1 and PAR2 causes nitric oxide-mediated arterial smooth muscle relaxation in a number of species and PAR4 activation causes similar responses in isolated rat aorta [18].
  • Contracted human pulmonary artery ring segments suspended for isometric tension measurement relaxed in a concentration- and endothelium-dependent manner to thrombin (0.001-0.1 U/ml), trypsin (0.01-1 U/ml), and the PAR1-activating peptide, SFLLRN (0.1-10 microM) [18].

Associations of PAR1 with chemical compounds

  • Because adenosine diphosphate and thromboxane A(2) have been shown to cause platelet aggregation by concomitant signaling through G(q) and G(i) pathways, we investigated whether coactivation of G(q) and G(i) signaling pathways is the general mechanism by which PAR1 and PAR4 agonists also activate platelet fibrinogen receptor (alphaIIbbeta3) [19].
  • Thrombin activates platelets mainly through protease-activated receptor 1 (PAR1), PAR4, and glycoprotein Ib [19].
  • P2Y12 receptor inhibitors clinically in use such as clopidogrel are postulated to decrease platelet aggregation through partial inhibition of PAR1 signaling [2].
  • We demonstrated that stimulation of PAR1 by thrombin or thrombin receptor activating peptide (TRAP6), in androgen-independent DU145 and PC-3 cells resulted in increased DNA binding activity of the NFkappaB p65 subunit [3].
  • Several new target genes previously documented to influence bone formation were up-regulated by DHEA such as Notch 2, insulin receptor, thrombin receptor (PAR1) [20].

Regulatory relationships of PAR1


Other interactions of PAR1

  • RESULTS: One PWS subject with maternal disomy 15 showed weak but detectable expression of PAR1, whereas SNRPN expression was detected in two PWS subjects [one with the 15q11-q13 deletion and one with a t(15;15) karyotype and maternal disomy 15], and the remaining typical PWS subjects showed no expression of the imprinted genes or transcripts [24].
  • Twelve patients with different features of Turner syndrome, and with Xp and Yp rearrangements involving the pseudoautosomal region (PAR1) are described [25].
  • Thus PAR4 signaling is shut off less rapidly than PAR1, probably due to differences in receptor phosphorylation [22].
  • We have isolated a novel gene, ASMTL (acetylserotonin methytransferase-like ), in the pseudoautosomal region (PAR1) on the human sex chromosomes [26].
  • GYG2 is outside the pseudoautosomal region PAR1 but still in a region of X-Y shared genes [27].

Analytical, diagnostic and therapeutic context of PAR1

  • Fura-2 fluorometry revealed that the preceding stimulation with trypsin abolished the subsequent [Ca(2+)](i) response to thrombin, while the responses to PAR1-activating peptides remained intact [16].
  • Furthermore, TUNEL assay showed that activation of PAR1 attenuated docetaxel induced apoptosis through the upregulation of the Bcl-2 family protein Bcl-xL [3].
  • Therefore, PAR1 seems to be the responsible receptor for thrombin-induced migration and adhesion of human colon carcinoma cells including PKCepsilon as an essential signal transducer [17].
  • This co-immunoprecipitation failed to occur in cells containing the truncated form of PAR1 that lacked the entire cytoplasmic portion of the receptor [28].
  • METHODS: HEL cells exposed to phorbol 12-myristate 13-acetate (PMA) to induce megakaryocyte differentiation were examined by light microscopy and flow cytometry (DNA ploidy, surface expression of PAR1, PAR3, GPIIb-IIIa) [29].


  1. Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets. Ma, L., Perini, R., McKnight, W., Dicay, M., Klein, A., Hollenberg, M.D., Wallace, J.L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. PAR4, but not PAR1, signals human platelet aggregation via Ca2+ mobilization and synergistic P2Y12 receptor activation. Holinstat, M., Voss, B., Bilodeau, M.L., McLaughlin, J.N., Cleator, J., Hamm, H.E. J. Biol. Chem. (2006) [Pubmed]
  3. PAR1-mediated NFkappaB activation promotes survival of prostate cancer cells through a Bcl-xL-dependent mechanism. Tantivejkul, K., Loberg, R.D., Mawocha, S.C., Day, L.L., John, L.S., Pienta, B.A., Rubin, M.A., Pienta, K.J. J. Cell. Biochem. (2005) [Pubmed]
  4. Protease-activated receptor 1: a role in prostate cancer metastasis. Yuan, T.C., Lin, M.F. Clinical prostate cancer. (2004) [Pubmed]
  5. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Boire, A., Covic, L., Agarwal, A., Jacques, S., Sherifi, S., Kuliopulos, A. Cell (2005) [Pubmed]
  6. Intense and highly localized gene conversion activity in human meiotic crossover hot spots. Jeffreys, A.J., May, C.A. Nat. Genet. (2004) [Pubmed]
  7. Crossover clustering and rapid decay of linkage disequilibrium in the Xp/Yp pseudoautosomal gene SHOX. May, C.A., Shone, A.C., Kalaydjieva, L., Sajantila, A., Jeffreys, A.J. Nat. Genet. (2002) [Pubmed]
  8. Ligation of protease-activated receptor 1 enhances alpha(v)beta6 integrin-dependent TGF-beta activation and promotes acute lung injury. Jenkins, R.G., Su, X., Su, G., Scotton, C.J., Camerer, E., Laurent, G.J., Davis, G.E., Chambers, R.C., Matthay, M.A., Sheppard, D. J. Clin. Invest. (2006) [Pubmed]
  9. Injury-related factors and conditions down-regulate the thrombin receptor (PAR-1) in a human neuronal cell line. Weinstein, J.R., Lau, A.L., Brass, L.F., Cunningham, D.D. J. Neurochem. (1998) [Pubmed]
  10. A novel PAR-1-type thrombin receptor signaling pathway: cyclic AMP-independent activation of PKA in SNB-19 glioblastoma cells. Zieger, M., Tausch, S., Henklein, P., Nowak, G., Kaufmann, R. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  11. Thalidomide protects endothelial cells from doxorubicin-induced apoptosis but alters cell morphology. Kaushal, V., Kaushal, G.P., Melkaveri, S.N., Mehta, P. J. Thromb. Haemost. (2004) [Pubmed]
  12. Protease-activated receptor-1 in human brain: localization and functional expression in astrocytes. Junge, C.E., Lee, C.J., Hubbard, K.B., Zhang, Z., Olson, J.J., Hepler, J.R., Brat, D.J., Traynelis, S.F. Exp. Neurol. (2004) [Pubmed]
  13. Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Shears, D.J., Vassal, H.J., Goodman, F.R., Palmer, R.W., Reardon, W., Superti-Furga, A., Scambler, P.J., Winter, R.M. Nat. Genet. (1998) [Pubmed]
  14. Akt activation in platelets depends on Gi signaling pathways. Kim, S., Jin, J., Kunapuli, S.P. J. Biol. Chem. (2004) [Pubmed]
  15. Protease-activated receptors 1 and 4 mediate thrombin signaling in endothelial cells. Kataoka, H., Hamilton, J.R., McKemy, D.D., Camerer, E., Zheng, Y.W., Cheng, A., Griffin, C., Coughlin, S.R. Blood (2003) [Pubmed]
  16. Inactivation of protease-activated receptor-1 by proteolytic removal of the ligand region in vascular endothelial cells. Nakayama, T., Hirano, K., Hirano, M., Nishimura, J., Kuga, H., Nakamura, K., Takahashi, S., Kanaide, H. Biochem. Pharmacol. (2004) [Pubmed]
  17. PAR1-type thrombin receptor stimulates migration and matrix adhesion of human colon carcinoma cells by a PKCepsilon-dependent mechanism. Heider, I., Schulze, B., Oswald, E., Henklein, P., Scheele, J., Kaufmann, R. Oncol. Res. (2004) [Pubmed]
  18. Protease-activated receptor (PAR) 1 but not PAR2 or PAR4 mediates endothelium-dependent relaxation to thrombin and trypsin in human pulmonary arteries. Hamilton, J.R., Moffatt, J.D., Frauman, A.G., Cocks, T.M. J. Cardiovasc. Pharmacol. (2001) [Pubmed]
  19. Protease-activated receptors 1 and 4 do not stimulate G(i) signaling pathways in the absence of secreted ADP and cause human platelet aggregation independently of G(i) signaling. Kim, S., Foster, C., Lecchi, A., Quinton, T.M., Prosser, D.M., Jin, J., Cattaneo, M., Kunapuli, S.P. Blood (2002) [Pubmed]
  20. The effects of dexamethasone and dehydroepiandrosterone (DHEA) on cytokines and receptor expression in a human osteoblastic cell line: Potential steroid-sparing role for DHEA. Harding, G., Mak, Y.T., Evans, B., Cheung, J., Macdonald, D., Hampson, G. Cytokine (2006) [Pubmed]
  21. Inhibition of thrombin-induced vascular endothelial growth factor production in human neuroblastoma (NB-1) cells by argatroban. Sarker, K.P., Biswas, K.K., Yamaji, K., Yamakuchi, M., Hashiguchi, T., Lee, K.Y., Maruyama, I. Pathophysiol. Haemost. Thromb. (2005) [Pubmed]
  22. Protease-activated receptors 1 and 4 are shut off with distinct kinetics after activation by thrombin. Shapiro, M.J., Weiss, E.J., Faruqi, T.R., Coughlin, S.R. J. Biol. Chem. (2000) [Pubmed]
  23. Protease-activated receptor-1 down-regulation: a mutant HeLa cell line suggests novel requirements for PAR1 phosphorylation and recruitment to clathrin-coated pits. Trejo, J., Altschuler, Y., Fu, H.W., Mostov, K.E., Coughlin, S.R. J. Biol. Chem. (2000) [Pubmed]
  24. Analysis of imprinted genes in subjects with Prader-Willi syndrome and chromosome 15 abnormalities. Muralidhar, B., Marney, A., Butler, M.G. Genet. Med. (1999) [Pubmed]
  25. Short arm rearrangements of sex chromosomes with haploinsufficiency of the SHOX gene are associated with Leri-Weill dyschondrosteosis. Palka, G., Stuppia, L., Guanciali Franchi, P., Chiarelli, F., Fischetto, R., Borrelli, P., Giannotti, A., Fioretti, G., Rinaldi, M.M., Mingarelli, R., Rappold, G.A., Calabrese, G. Clin. Genet. (2000) [Pubmed]
  26. Gene duplications as a recurrent theme in the evolution of the human pseudoautosomal region 1: isolation of the gene ASMTL. Ried, K., Rao, E., Schiebel, K., Rappold, G.A. Hum. Mol. Genet. (1998) [Pubmed]
  27. Structure and chromosomal localization of the human glycogenin-2 gene GYG2. Zhai, L., Mu, J., Zong, H., DePaoli-Roach, A.A., Roach, P.J. Gene (2000) [Pubmed]
  28. Tumor cell invasion is promoted by activation of protease activated receptor-1 in cooperation with the alpha vbeta 5 integrin. Even-Ram, S.C., Maoz, M., Pokroy, E., Reich, R., Katz, B.Z., Gutwein, P., Altevogt, P., Bar-Shavit, R. J. Biol. Chem. (2001) [Pubmed]
  29. Expression of protease activated receptor 3 (PAR3) is upregulated by induction of megakaryocyte phenotype in human erythroleukemia (HEL) cells. Cupit, L.D., Schmidt, V.A., Gnatenko, D.V., Bahou, W.F. Exp. Hematol. (2004) [Pubmed]
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