Genomes and Genes
Gene Symbol: PAR-2
Description: F2R like trypsin receptor 1
Alias: GPR11, PAR2, proteinase-activated receptor 2, G-protein coupled receptor 11, coagulation factor II (thrombin) receptor-like 1, protease-activated receptor 2, thrombin receptor-like 1
- Steinhoff M, Neisius U, Ikoma A, Fartasch M, Heyer G, Skov P, et al. Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci. 2003;23:6176-80 pubmed..PAR-2 therefore represents a promising therapeutic target for the treatment of cutaneous neurogenic inflammation and pruritus. ..
- Colognato R, Slupsky J, Jendrach M, Burysek L, Syrovets T, Simmet T. Differential expression and regulation of protease-activated receptors in human peripheral monocytes and monocyte-derived antigen-presenting cells. Blood. 2003;102:2645-52 pubmed..factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) elicits enhanced expression of PAR1, PAR2, and PAR3...
- Trian T, Girodet P, Ousova O, Marthan R, Tunon de Lara J, Berger P. RNA interference decreases PAR-2 expression and function in human airway smooth muscle cells. Am J Respir Cell Mol Biol. 2006;34:49-55 pubmed..and hyperresponsiveness that involves mast cell tryptase and potentially its specific receptor protease activated receptor 2 (PAR-2)...
- Hasdemir B, Bunnett N, Cottrell G. Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) mediates post-endocytic trafficking of protease-activated receptor 2 and calcitonin receptor-like receptor. J Biol Chem. 2007;282:29646-57 pubmed..The ultimate sorting decision to degradative or recycling pathways appears to occur downstream from HRS. ..
- Koo B, Chung K, Hwang K, Kim D. Factor Xa induces mitogenesis of coronary artery smooth muscle cell via activation of PAR-2. FEBS Lett. 2002;523:85-9 pubmed..Several lines of experimental evidence indicate that factor Xa-induced mitogenesis of CASMC is a cellular process mediated by PAR-2 activation. ..
- Luo W, Wang Y, Reiser G. p24A, a type I transmembrane protein, controls ARF1-dependent resensitization of protease-activated receptor-2 by influence on receptor trafficking. J Biol Chem. 2007;282:30246-55 pubmed..These findings identify a new function of p24A as a regulator of signal-dependent trafficking that regulates the life cycle of PAR-2, Thus, we reveal a new molecular mechanism underlying resensitization of PAR-2. ..
- Lin K, Park J, Crews A, Li Y, Adler K. Protease-activated receptor-2 (PAR-2) is a weak enhancer of mucin secretion by human bronchial epithelial cells in vitro. Int J Biochem Cell Biol. 2008;40:1379-88 pubmed..The results suggest that, since PAR-2 activation only weakly increases mucin secretion by human airway epithelial cells in vitro, PAR-2 probably is not a significant contributor to mucin hypersecretion in inflamed airways. ..
- Goon Goh F, Sloss C, Cunningham M, Nilsson M, Cadalbert L, Plevin R. G-protein-dependent and -independent pathways regulate proteinase-activated receptor-2 mediated p65 NFkappaB serine 536 phosphorylation in human keratinocytes. Cell Signal. 2008;20:1267-74 pubmed publisher..Overall these novel data demonstrate an IKK2-dependent, predominantly G-protein-independent pathway involved in PAR-2 regulation of NFkappaB phosphorylation in keratinocytes. ..
- Steinhoff M, Corvera C, Thoma M, Kong W, McAlpine B, Caughey G, et al. Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase. Exp Dermatol. 1999;8:282-94 pubmed..Tryptase may activate PAR-2 on keratinocytes and endothelial cells during inflammation. ..
- Ahmad S, Ahmad A, Rancourt R, Neeves K, Loader J, Hendry Hofer T, et al. Tissue factor signals airway epithelial basal cell survival via coagulation and protease-activated receptor isoforms 1 and 2. Am J Respir Cell Mol Biol. 2013;48:94-104 pubmed publisher..TF also participates in protease-activated receptor (PAR)1 and PAR2 activation. Human epithelial basal cells were previously purified on the basis of TF expression...
- Ramachandran R, Mihara K, Chung H, Renaux B, Lau C, Muruve D, et al. Neutrophil elastase acts as a biased agonist for proteinase-activated receptor-2 (PAR2). J Biol Chem. 2011;286:24638-48 pubmed publisher..Our data illustrate a new mode of PAR regulation that involves biased PAR(2) signaling by neutrophil elastase and a disarming/silencing effect of cathepsin-G and proteinase-3. ..
- Nystedt S, Emilsson K, Wahlestedt C, Sundelin J. Molecular cloning of a potential proteinase activated receptor. Proc Natl Acad Sci U S A. 1994;91:9208-12 pubmed..Because this, to our knowledge, is the second example, besides the thrombin receptor, of a proteolytically activated seven-transmembrane G-protein-coupled receptor, we have provisionally named it proteinase activated receptor 2.
- Botham A, Guo X, Xiao Y, Morice A, Compton S, Sadofsky L. Palmitoylation of human proteinase-activated receptor-2 differentially regulates receptor-triggered ERK1/2 activation, calcium signalling and endocytosis. Biochem J. 2011;438:359-67 pubmed publisher..In conclusion, palmitoylation plays an important role in the regulation of PAR(2) expression, agonist sensitivity, desensitization and internalization. ..
- Santulli R, Derian C, Darrow A, Tomko K, Eckardt A, Seiberg M, et al. Evidence for the presence of a protease-activated receptor distinct from the thrombin receptor in human keratinocytes. Proc Natl Acad Sci U S A. 1995;92:9151-5 pubmed..Levels of thrombin receptor message were equivalent in the two cell types. Our results indicate that human keratinocytes possess PAR-2, suggesting a potential role for this receptor in tissue repair and/or skin-related disorders. ..
- Rallabhandi P, Nhu Q, Toshchakov V, Piao W, Medvedev A, Hollenberg M, et al. Analysis of proteinase-activated receptor 2 and TLR4 signal transduction: a novel paradigm for receptor cooperativity. J Biol Chem. 2008;283:24314-25 pubmed publisherProteinase-activated receptor 2 (PAR2), a seven-transmembrane G protein-coupled receptor, is activated at inflammatory sites by proteolytic cleavage of its extracellular N terminus by trypsin-like enzymes, exposing a tethered, receptor-..
- Buddenkotte J, Stroh C, Engels I, Moormann C, Shpacovitch V, Seeliger S, et al. Agonists of proteinase-activated receptor-2 stimulate upregulation of intercellular cell adhesion molecule-1 in primary human keratinocytes via activation of NF-kappa B. J Invest Dermatol. 2005;124:38-45 pubmedProteinase-activated receptor-2 (PAR2) belongs to a new G protein-coupled receptor subfamily that is activated by various serine proteases. Recent knowledge indicates that PAR2 is involved in cutaneous inflammation and immune response...
- Shetty P, Tang H, Tayo B, Morrison A, Hanis C, Rao D, et al. Variants in CXADR and F2RL1 are associated with blood pressure and obesity in African-Americans in regions identified through admixture mapping. J Hypertens. 2012;30:1970-6 pubmed..This study suggests that CXADR and F2RL1 likely play important roles in BP and obesity variation, respectively; and these findings are consistent with those of other studies, so replication and functional analyses are necessary. ..
- Kanke T, Macfarlane S, Seatter M, Davenport E, Paul A, McKenzie R, et al. Proteinase-activated receptor-2-mediated activation of stress-activated protein kinases and inhibitory kappa B kinases in NCTC 2544 keratinocytes. J Biol Chem. 2001;276:31657-66 pubmed..This study shows for the first time proteinase-activated receptor-2-mediated stimulation of both SAP kinase and IKK signaling and differing roles for PKC isoforms in the regulation of each pathway. ..
- Bohm S, Kong W, Bromme D, Smeekens S, Anderson D, Connolly A, et al. Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2. Biochem J. 1996;314 ( Pt 3):1009-16 pubmed..Thus PAR-2 may serve as a trypsin sensor in the gut. Its expression by cells and tissues not normally exposed to pancreatic trypsin suggests that other proteases could serve as physiological activators...
- Ohta T, Shimizu K, Yi S, Takamura H, Amaya K, Kitagawa H, et al. Protease-activated receptor-2 expression and the role of trypsin in cell proliferation in human pancreatic cancers. Int J Oncol. 2003;23:61-6 pubmed..These findings suggest that trypsin plays a role in the growth of PAR-2-positive pancreatic cancer cells and serves as a potent mitogen in vitro, functioning as a growth factor. ..
- Houliston R, Keogh R, Sugden D, Dudhia J, Carter T, Wheeler Jones C. Protease-activated receptors upregulate cyclooxygenase-2 expression in human endothelial cells. Thromb Haemost. 2002;88:321-8 pubmed..These results demonstrate that regulation of COX-2 induction is an important functional response of HUVEC to PAR activation and suggest that PARs promote sustained upregulation of prostanoid production in human endothelium. ..
- Li Z, Bian L, Li Y, Liang Y, Liang H. Expression of protease-activated receptor-2 (PAR-2) in patients with nasopharyngeal carcinoma: correlation with clinicopathological features and prognosis. Pathol Res Pract. 2009;205:542-50 pubmed publisher..026 and 0.006, respectively). PAR-2 is a possible mediator cooperating with LMP-1 and MMP9 to influence the progression of NPC by inducing angiogenesis and promoting lymph node metastasis. ..
- Ramsay A, Dong Y, Hunt M, Linn M, Samaratunga H, Clements J, et al. Kallikrein-related peptidase 4 (KLK4) initiates intracellular signaling via protease-activated receptors (PARs). KLK4 and PAR-2 are co-expressed during prostate cancer progression. J Biol Chem. 2008;283:12293-304 pubmed publisher..These data provide insight into KLK4-mediated cell signaling and suggest that signals induced by this enzyme via PARs may be important in prostate cancer. ..
- Lourbakos A, Potempa J, Travis J, D Andrea M, Andrade Gordon P, Santulli R, et al. Arginine-specific protease from Porphyromonas gingivalis activates protease-activated receptors on human oral epithelial cells and induces interleukin-6 secretion. Infect Immun. 2001;69:5121-30 pubmed..gingivalis might mediate inflammatory events associated with periodontal disease on first contact with a primary barrier of cells. ..
- D Andrea M, Derian C, Leturcq D, Baker S, Brunmark A, Ling P, et al. Characterization of protease-activated receptor-2 immunoreactivity in normal human tissues. J Histochem Cytochem. 1998;46:157-64 pubmed..A role for PAR-2 in the skin was further supported by its immunolocalization in the epidermis. PAR-2C antibody exemplifies an important tool to address the physiological role(s) of PAR-2. ..
- Nystedt S, Emilsson K, Larsson A, Strombeck B, Sundelin J. Molecular cloning and functional expression of the gene encoding the human proteinase-activated receptor 2. Eur J Biochem. 1995;232:84-9 pubmed..By fluorescence in situ hybridization, the human proteinase-activated receptor 2 gene was mapped to chromosomal region 5q13, where, previously, the related thrombin receptor gene has been located. ..
- Hasdemir B, Murphy J, Cottrell G, Bunnett N. Endosomal deubiquitinating enzymes control ubiquitination and down-regulation of protease-activated receptor 2. J Biol Chem. 2009;284:28453-66 pubmed publisher..Thus, AMSH and UBPY are essential for trafficking and down-regulation of PAR(2) but not for regulating PAR(2) dissociation from beta-arrestin2 or PAR(2)-mediated ERK2 activation. ..
- Jacob C, Cottrell G, Gehringer D, Schmidlin F, Grady E, Bunnett N. c-Cbl mediates ubiquitination, degradation, and down-regulation of human protease-activated receptor 2. J Biol Chem. 2005;280:16076-87 pubmed..Thus, c-Cbl mediated ubiquitination and lysosomal degradation of PAR(2) to irrevocably terminate signaling by this and perhaps other GPCRs. ..
- Seeliger S, Derian C, Vergnolle N, Bunnett N, Nawroth R, Schmelz M, et al. Proinflammatory role of proteinase-activated receptor-2 in humans and mice during cutaneous inflammation in vivo. FASEB J. 2003;17:1871-85 pubmed..Thus, PAR-2 may be a beneficial therapeutic target for the treatment of inflammatory skin diseases. ..
- Ricks T, Trejo J. Phosphorylation of protease-activated receptor-2 differentially regulates desensitization and internalization. J Biol Chem. 2009;284:34444-57 pubmed publisherProtease-activated receptor 2 (PAR2) is a G protein-coupled receptor irreversibly activated by extracellular proteases...
- Jiang B, Grage Griebenow E, Csernok E, Butherus K, Ehlers S, Gross W, et al. The role of proteinase 3 (PR3) and the protease-activated receptor-2 (PAR-2) pathway in dendritic cell (DC) maturation of human-DC-like monocytes and murine DC. Clin Exp Rheumatol. 2010;28:56-61 pubmed..and healthy controls (HC) and to investigate whether Proteinase 3 (PR3, a serine protease which can activate PAR2) induces maturation of human DC-like monocytes and murine Flt-3 ligand- and GM-CSF-generated DC...
- Banfi C, Brioschi M, Barbieri S, Eligini S, Barcella S, Tremoli E, et al. Mitochondrial reactive oxygen species: a common pathway for PAR1- and PAR2-mediated tissue factor induction in human endothelial cells. J Thromb Haemost. 2009;7:206-16 pubmed publisher..Moreover, PAR1 and PAR2 activation in the endothelium shifts it toward a prothrombotic condition...
- Luo W, Wang Y, Reiser G. Proteinase-activated receptors, nucleotide P2Y receptors, and ?-opioid receptor-1B are under the control of the type I transmembrane proteins p23 and p24A in post-Golgi trafficking. J Neurochem. 2011;117:71-81 pubmed publisher..In summary, we demonstrate that p24A and p23 are specific cargo receptors of GPCRs and differentially control GPCR trafficking in the biosynthetic pathway, and thereby, p24A and p23 regulate GPCR signaling in astrocytes. ..
- Jeong S, Kim H, Youm J, Ahn S, Choi E, Sohn M, et al. Mite and cockroach allergens activate protease-activated receptor 2 and delay epidermal permeability barrier recovery. J Invest Dermatol. 2008;128:1930-9 pubmed publisher..These results suggest that allergens with protease activity can influence the epidermal permeability barrier homeostasis through PAR-2 activation and consequent modulation of the calcium ions in skin...
- Kawabata A. PAR-2: structure, function and relevance to human diseases of the gastric mucosa. Expert Rev Mol Med. 2002;4:1-17 pubmed..Agonists and/or antagonists for PAR-2 might also be applicable to the clinical treatment of patients with inflammatory diseases in other organs. ..
- Compton S, Sandhu S, Wijesuriya S, Hollenberg M. Glycosylation of human proteinase-activated receptor-2 (hPAR2): role in cell surface expression and signalling. Biochem J. 2002;368:495-505 pubmed..We conclude that hPAR(2) N-linked glycosylation and sialylation regulates receptor expression and/or signalling. ..
- Bushell T. The emergence of proteinase-activated receptor-2 as a novel target for the treatment of inflammation-related CNS disorders. J Physiol. 2007;581:7-16 pubmed
- Kelso E, Ferrell W, Lockhart J, Elias Jones I, Hembrough T, Dunning L, et al. Expression and proinflammatory role of proteinase-activated receptor 2 in rheumatoid synovium: ex vivo studies using a novel proteinase-activated receptor 2 antagonist. Arthritis Rheum. 2007;56:765-71 pubmed..These findings identify PAR-2 as a novel upstream regulator of proinflammatory cytokine production in RA and indicate its potential as a novel therapeutic target in inflammatory arthritis. ..
- Hachem J, Houben E, Crumrine D, Man M, Schurer N, Roelandt T, et al. Serine protease signaling of epidermal permeability barrier homeostasis. J Invest Dermatol. 2006;126:2074-86 pubmed
- Fyfe M, Bergström M, Aspengren S, Peterson A. PAR-2 activation in intestinal epithelial cells potentiates interleukin-1beta-induced chemokine secretion via MAP kinase signaling pathways. Cytokine. 2005;31:358-67 pubmed..Thus, identifying antagonists to the PAR-2 receptor may be beneficial by inhibiting potentiation of a proinflammatory response, through inhibition of p38 and ERK MAP kinases. ..
- Noorbakhsh F, Vergnolle N, McArthur J, Silva C, Vodjgani M, Andrade Gordon P, et al. Proteinase-activated receptor-2 induction by neuroinflammation prevents neuronal death during HIV infection. J Immunol. 2005;174:7320-9 pubmed..001). Thus, neuroinflammation can exert protective effects by which it induces PAR-2 expression with the ensuing abrogation of neuronal death. ..
- Roosterman D, Schmidlin F, Bunnett N. Rab5a and rab11a mediate agonist-induced trafficking of protease-activated receptor 2. Am J Physiol Cell Physiol. 2003;284:C1319-29 pubmedWe evaluated the contribution of rab5a and rab11a to trafficking and signaling of protease-activated receptor 2 (PAR2), a receptor for trypsin and tryptase. Agonists stimulated internalization of PAR2 into early endosomes containing rab5a...
- Stalheim L, Ding Y, Gullapalli A, Paing M, Wolfe B, Morris D, et al. Multiple independent functions of arrestins in the regulation of protease-activated receptor-2 signaling and trafficking. Mol Pharmacol. 2005;67:78-87 pubmedThe irreversible proteolytic nature of protease-activated receptor-2 (PAR2) activation suggests that mechanism(s) responsible for termination of receptor signaling are critical determinants of the magnitude and duration of PAR2-elicited ..
- Molino M, Barnathan E, Numerof R, Clark J, Dreyer M, Cumashi A, et al. Interactions of mast cell tryptase with thrombin receptors and PAR-2. J Biol Chem. 1997;272:4043-9 pubmed..Tryptase is the first protease other than trypsin that has been shown to activate human PAR-2. Its presence within mast cell granules places it in tissues where PAR-2 is expressed but trypsin is unlikely to reach. ..
- Ramachandran R, Eissa A, Mihara K, Oikonomopoulou K, Saifeddine M, Renaux B, et al. Proteinase-activated receptors (PARs): differential signalling by kallikrein-related peptidases KLK8 and KLK14. Biol Chem. 2012;393:421-7 pubmed publisher..Further, we analysed processing by KLK8 vs. KLK14 of synthetic human and rat PAR2-derived sequences representing the cleavage-activation domain of PAR2...
- 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..In contrast, a combination of TFLLRNPNDK and the PAR2 agonist peptide SLIGRL mimics the thrombin effect on migration, whereas PAR2 agonist alone has no effect...
- Rothmeier A, Ruf W. Protease-activated receptor 2 signaling in inflammation. Semin Immunopathol. 2012;34:133-49 pubmed publisher..While coagulation proteases activate PARs to regulate hemostasis, thrombosis, and cardiovascular function, PAR2 is also activated in extravascular locations by a broad array of serine proteases, including trypsin, tissue ..
- Palygin O, Ilatovskaya D, Staruschenko A. Protease-activated receptors in kidney disease progression. Am J Physiol Renal Physiol. 2016;311:F1140-F1144 pubmed publisher..Four PARs have been identified to date, of which PAR1 and PAR2 are the most abundant receptors, and have been shown to be expressed in the kidney vascular and tubular cells...
- Son G, Son A, Yang Y, Park W, Chang I, Lee J, et al. Airborne allergens induce protease activated receptor-2-mediated production of inflammatory cytokines in human gingival epithelium. Arch Oral Biol. 2016;61:138-43 pubmed publisher..GCE activates PAR-2, which can induce PLC/IP3-dependent Ca(2+) signaling pathway, ultimately triggering inflammation via the production of pro-inflammatory cytokines such as IL-1Î², IL-6, IL-8, and NLRP 3 in HGECs. ..
- Carvalho R, Nilsson G, Harvima I. Increased mast cell expression of PAR-2 in skin inflammatory diseases and release of IL-8 upon PAR-2 activation. Exp Dermatol. 2010;19:117-22 pubmed publisher..These results show that mast cells express increased levels of PAR-2 in chronic skin inflammation. Also, mast cells can be activated by a PAR-2 agonist to secrete IL-8, a chemokine which can contribute to the progress of inflammation. ..
- Hong J, Hong J, Park B, Lee S, Seo J, Kim K, et al. Chitinase activates protease-activated receptor-2 in human airway epithelial cells. Am J Respir Cell Mol Biol. 2008;39:530-5 pubmed publisher..These results indicate that exogenous chitinase is a potent proteolytic activator of PAR-2 that can directly induce PLC/IP(3)-dependent Ca(2+) signaling in human airway epithelial cells. ..
- Ikeda O, Egami H, Ishiko T, Ishikawa S, Kamohara H, Hidaka H, et al. Signal of proteinase-activated receptor-2 contributes to highly malignant potential of human pancreatic cancer by up-regulation of interleukin-8 release. Int J Oncol. 2006;28:939-46 pubmed..Thus, this signal might contribute to tumor progression and characteristic fibrosis in pancreatic cancer. ..
- Bueno L, Fioramonti J. Protease-activated receptor 2 and gut permeability: a review. Neurogastroenterol Motil. 2008;20:580-7 pubmed publisher..Enhanced fecal protease level has been recently reported in both organic (ulcerative colitis) and functional (irritable bowel syndrome) intestinal disorders and may play a role in the pathogenesis of such diseases. ..
- 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 pubmedProteinase-activated receptor-2 (PAR2) plays a dual role in the respiratory system, being pro- and anti-inflammatory...
- Enomoto A, Yoshihisa Y, Yamakoshi T, Ur Rehman M, Norisugi O, Hara H, et al. UV-B radiation induces macrophage migration inhibitory factor-mediated melanogenesis through activation of protease-activated receptor-2 and stem cell factor in keratinocytes. Am J Pathol. 2011;178:679-87 pubmed publisher..Therefore, MIF-mediated melanogenesis occurs mainly through the activation of PAR-2 and SCF expression in keratinocytes after exposure to UV-B radiation. ..
- Yang Y, Serrano M, Sheoran A, Manque P, Buck G, Widmer G. Over-expression and localization of a host protein on the membrane of Cryptosporidium parvum infected epithelial cells. Mol Biochem Parasitol. 2009;168:95-101 pubmed publisher..This observation indicates that the composition of the host cell membrane is affected by the developing trophozoite, a phenomenon which has not been described previously. ..
- Li S, Jiang P, Xiang Y, Wang W, Zhu Y, Feng W, et al. Protease-activated receptor (PAR)1, PAR2 and PAR4 expressions in esophageal squamous cell carcinoma. Dongwuxue Yanjiu. 2014;35:420-5 pubmed publisherHere, we used reverse transcription-PCR (RT-PCR) and western blot to detect protease-activated receptor (PAR) 1, PAR 2 and PAR 4 expression in cancer tissues and cell lines of esophageal squamous cell carcinoma, and investigated the co-..