Disease relevance of F2RL1

• Here we investigate the role of PAR-2 in the constitutive migration of a metastatic breast cancer cell line, MDA MB-231, and use small interfering RNA to determine the contribution of each beta-arrestin to this process [1].
• However, the functional consequences of PAR-2 expression in cancer cells, especially in pancreatic cancer cells, are poorly understood [2].
• Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis [3].
• In normal kidneys, PAR-2 gene expression was barely detectable, whereas in IgAN biopsies the mRNA levels for this protease receptor were strikingly increased and directly correlated with the extent of interstitial fibrosis [4].
• Thus, HAT might promote PAR-2-mediated IL-8 production to accumulate inflammatory cells in the epidermal layer of psoriasis [5].

Psychiatry related information on F2RL1

• In this study, we report that PAR-2 was up-regulated on neurons in conjunction with neuroinflammation in brain tissue from patients with HIV-1-associated dementia [6].
• Our data indicate that a pathogen-derived proteinase like EPa can potentially silence the function of PAR2 in the respiratory tract, thereby altering the host innate defense mechanisms and respiratory functions, and thus contributing to pathogenesis in the setting of a disease like CF [7].

High impact information on F2RL1

• Our results indicate that trypsin released from the epithelium can initiate powerful bronchoprotection in the airways by activation of epithelial PAR2 [8].
• As the airway epithelium is morphologically similar and also expresses one of these receptors, PAR2, and is a major source of PGE2, we reasoned that bronchial epithelial PAR2 might also participate in prostanoid-dependent cytoprotection in the airways [8].
• PAR2 expression was increased on astrocytes and infiltrating macrophages in human MS and murine EAE central nervous system (CNS) white matter (P < 0.05) [9].
• PAR2 activation in macrophages resulted in the release of soluble oligodendrocyte cytotoxins (P < 0.01) [9].
• Macrophages and astrocytes from PAR2 wild-type (WT) and knockout (KO) mice exhibited differential immune gene expression with PAR2 KO macrophages showing significantly higher interleukin 10 production after lipopolysaccharide stimulation (P < 0.001) [9].

Chemical compound and disease context of F2RL1

• Reverse transcriptase PCR and Western blot analysis were used to show the expression of both TMPRSS2 and PAR-2 in the androgen-dependent LNCaP prostate cancer cell line [10].
• Like thrombin receptors, activation of PAR-2 caused pertussis toxin-sensitive phospholipase C activation as well as activation of phospholipase A2, leading to the release of PGI2 [11].
• Trypsin and proteinase-activated receptor 2 (PAR-2) act together in an autocrine loop that promotes proliferation, invasion, and metastasis through various mechanisms, of which prostaglandin synthesis is important [12].
• These findings suggest that the neutrophil serine proteinases may play a role in PAR-2-mediated lung inflammation [13].
• PAR-2-mediated intestinal electrolyte secretion by release of mast cell tryptase and potentiation of PAR-2 expression by tumor necrosis factor-alpha may contribute to the hypersecretion observed in inflammatory processes such as chronic inflammatory bowel disease [14].

Biological context of F2RL1

• Protease-activated receptor-2 (PAR-2) is activated by trypsin-like serine proteases and can promote cell migration through an ERK1/2-dependent pathway, involving formation of a scaffolding complex at the leading edge of the cell [1].
• However, unlike PAR-1, the PAR-2-mediated intracellular signal transductions are hardly known [15].
• Here, using yeast two-hybrid screening with a human brain cDNA library, we identified an interacting partner of human PAR-2, the Jun activation domain-binding protein 1 (Jab1) [15].
• Together these results support a role for PAR1, and potentially PAR2 and PAR3 in the invasive phase of human placentation [16].
• Protease-activated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma [17].

Anatomical context of F2RL1

• Our results indicate that human keratinocytes possess PAR-2, suggesting a potential role for this receptor in tissue repair and/or skin-related disorders [18].
• Northern blot analyses detected a transcript of PAR-2 in total RNA from keratinocytes but not fibroblasts [18].
• Further, stimulation of monocytes or macrophages with thrombin or PAR1-AP, but not with PAR2-or PAR4-AP, triggers expression of monocyte chemoattractant protein-1 (MCP-1) both at the mRNA and the protein level [19].
• When added to human endothelial cells, which normally express PAR-2 and thrombin receptors, or keratinocytes, which express only PAR-2, tryptase caused an increase in cytosolic Ca2+ [20].
• The epithelial cells strongly express protease-activated receptor (PAR)-1 and PAR-2 mRNA and weakly express PAR-3 mRNA [21].

Associations of F2RL1 with chemical compounds

• We found that recombinant tryptase, human mast-cell (HMC-1) supernatant, which contains tryptase, and the PAR2-activating peptide SLIGKV exert fibroproliferative actions in human fibroblasts [22].
• Here we report insights into this action, which after activation of PAR2 leads to increased expression of cyclooxygenase 2 (COX2), a key enzyme in the biosynthesis of prostaglandins, and consequently to enhanced prostaglandin synthesis [22].
• The stimulatory effect of trypsin was dependent on its serine protease activity and was blocked 59% by anti-PAR2 Ab [23].
• Treatment with trypsin, an agonist for PAR-2, and a synthetic PAR-2 agonist peptide induced intracellular Ca(2+) mobilization, and rendered cells refractory to subsequent stimulation with PR3 and vice versa [21].
• Activation of protease-activated receptor (PAR)-1, PAR-2, and PAR-4 stimulates IL-6, IL-8, and prostaglandin E2 release from human respiratory epithelial cells [24].

Physical interactions of F2RL1

• Wegener autoantigen interacts with a "gateway" receptor (PAR-2) on iDCs in vitro triggering their maturation and licenses them for a T helper 1 (Th1)-type response potentially favoring granuloma formation in WG [25].

Enzymatic interactions of F2RL1

• PR3 cleaved the peptide corresponding to the N terminus of PAR-2 with exposure of its tethered ligand [21].

Regulatory relationships of F2RL1

• These results suggest that the PAR-2 signal up-regulates IL-8 release from pancreatic cancer cells [2].
• The expression of PAR-2 on the cell surface was promoted by PR3, and inhibited by cytochalasin B, but not by cycloheximide [21].
• RESULTS: Activation of PAR2 stimulated the proliferation of ESC and the secretion of IL-6 and IL-8 from ESC in a dose-dependent manner [26].
• Human airway trypsin-like protease induces PAR-2-mediated IL-8 release in psoriasis vulgaris [5].
• We found that selective activation of PAR-2 using the peptide SLIGKV augmented TNFalpha-induced MMP-9 protein levels and increased ERK phosphorylation [27].

Other interactions of F2RL1

• IL-8 was produced in a dose-dependent fashion when cells were stimulated with a PAR2 agonist such as trypsin or SLIGKV-amide [28].
• Human airway trypsin-like protease (HAT), a serine protease found in the sputum of patients with chronic airway diseases, is an agonist of protease-activated receptor-2 (PAR-2) [29].
• CONCLUSION: MT-SP1/matriptase induces release of proinflammatory cytokines in endothelial cells through activation of PAR-2 [30].
• The production of cytokine induced by PR3 and the PAR-2 agonist peptide was completely abolished by a phospholipase C inhibitor [21].
• Since our data indicated that keratinocytes possess a trypsin-sensitive receptor, we addressed the possibility that these cells express the human homologue of the newly described murine protease-activated receptor, PAR-2 [Nystedt, S., Emilsson, K., Wahlestedt, C. & Sundelin, J. (1994) Proc. Natl. Acad. Sci. USA 91, 9208-9212] [18].

Analytical, diagnostic and therapeutic context of F2RL1

• Southern blot analysis showed that they were in a cluster on a 560-kb Asc I fragment, in the order PAR-2, PAR-1, and PAR-3 [31].
• Because it has been reported that PAR-1, PAR-2, and PAR-3 may also be involved in the processes of inflammation, we used immunohistochemistry to characterize the expression of all known PARs in normal, acute, and chronic inflamed mouse bladder [32].
• METHODS: We used RT-PCR and immunocytochemistry with confocal microscopy to determine mRNA and protein expression of PAR-1 and PAR-2 in AMs obtained from healthy smokers, asthmatic patients, and healthy subjects [33].
• Reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis revealed that PAR2 mRNA and protein were constitutively expressed in HEEC without upregulation by the stimulation with tumor necrosis factor alpha or trypsin [28].
• The presence of both PAR-1 and PAR-2 on HUR was confirmed by immunoblotting [34].

References