Disease relevance of F2RL2

• Expression of protease activated receptor 3 (PAR3) is upregulated by induction of megakaryocyte phenotype in human erythroleukemia (HEL) cells [1].
• Likewise, high expression levels of PAR1 and PAR3 were observed in the cytotrophoblast cells of complete hydatidiform mole as compared to minimal levels in normal age-matched placenta [2].
• In this study, we report coexpression of proteinase-activated receptor (PAR)-1- and PAR-3-type thrombin receptors in primary cultures obtained from surgically resected specimens of renal cell carcinomas (RCCs) [3].
• We now report that Par3(-/-) mice were protected against ferric chloride-induced thrombosis of mesenteric arterioles and against thromboplastin-induced pulmonary embolism [4].
• In contrast to the exclusively neuronal staining in the brain parenchyma of naïve animals, PAR1 and PAR3 occurred in addition on microglial cells in the penumbra after transient and after permanent focal ischemia [5].

High impact information on F2RL2

• PAR3 is a cofactor for PAR4 activation by thrombin [6].
• PAR4 messenger RNA was detected in mouse megakaryocytes and a PAR4-activating peptide caused secretion and aggregation of PAR3-deficient mouse platelets [7].
• Furthermore, pVHL interacts with the Par3-Par6-atypical PKC complex, suggesting a mechanism for linking polarity pathways to microtubule capture and ciliogenesis [8].
• However, the function of the apparently nonsignaling receptor PAR3 also expressed in endothelial cells is unknown [9].
• Using bioluminescent resonance energy transfer-2, we showed that PAR1 had comparable dimerization affinity for PAR3 as for itself [9].

Biological context of F2RL2

• The ORF codes for a seven transmembrane domain protein of 385 amino acids with 33% amino acid sequence identity with PAR1, PAR2, and PAR3 [10].
• We report here the structure of the mouse and human PAR3 genes as well as the organization of a PAR gene cluster encompassing the genes encoding PARs 1, 2, and 3 [11].
• Together these results support a role for PAR1, and potentially PAR2 and PAR3 in the invasive phase of human placentation [12].
• Differential genomic blotting using a yeast artificial chromosome known to contain the PAR-1 and PAR-2 genes identified the PAR-3 gene within a PAR gene cluster spanning approximately 100 kilobases at 5q13 [13].
• Notably, this inhibition occurred without loss of the binding sites for two monoclonal antibodies that flank the tethered ligand on human PAR3 [14].

Anatomical context of F2RL2

• Human monocytes express mainly PAR1 and less PAR3 [15].
• The human proteinase-activated receptor-3 (PAR-3) gene. Identification within a Par gene cluster and characterization in vascular endothelial cells and platelets [13].
• PAR1, PAR2, and PAR3 are expressed in cultured 8- to 13-week-old EVTs, and in situ in 18- to 20-week-old placental syncytiotrophoblasts and invasive trophoblasts [12].
• Elastase had no effect on thrombin responses in mouse platelets, but when added to COS cells expressing human PAR3, both cathepsin G and elastase prevented activation of phospholipase C by thrombin [14].
• Neutrophil proteases can inactivate human PAR3 and abolish the co-receptor function of PAR3 on murine platelets [14].

Associations of F2RL2 with chemical compounds

• PAR3 antisense oligonucleotides substantially inhibit thrombin-stimulated [3H]thymidine incorporation and PtdIns(3,4,5)P3 generation but had no effect on thrombin-induced phosphoinositide hydrolysis [16].
• In comparison, thrombin has low affinity and slow cleavage rates for peptides that have a P(3) proline as occurs in human PAR3 [17].

Regulatory relationships of F2RL2

• The epithelial cells strongly express protease-activated receptor (PAR)-1 and PAR-2 mRNA and weakly express PAR-3 mRNA [18].
• The agonist of the protease-activated receptor-1 (PAR) but not PAR3 mimics thrombin-induced vascular endothelial growth factor release in human smooth muscle cells [19].
• We propose that PAR-3 is able to signal autonomously to induce IL-8 release mediated by ERK1/2 phosphorylation, which contributes actively to inflammatory responses [20].

Other interactions of F2RL2

• In contrast, thrombin, an activator for PAR1, PAR3, and PAR4, showed minimal effects [21].
• Thus, although PAR-3 is postulated to represent a second thrombin receptor, its modest endothelial cell and platelet expression suggest that PAR-3 activation by alpha-thrombin is less relevant for physiological responses in these mature cells [13].
• It was found that HDFs express PAR-1 and PAR-3, and thrombin induces approximately 7.4-fold increase in IL-8 secretion from HDFs [22].
• In contrast, the agonist of PAR3, TFR- GAP, did not affect VEGF release or expression [19].
• When nasal epithelial cells were activated with fungi, PAR2 and PAR3 mRNAs were more strongly expressed than in nonactivated cells [23].

Analytical, diagnostic and therapeutic context of F2RL2

• 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 [24].
• Northern blots detected both of those receptors and, to a lesser extent, PAR3, but PAR4 message was undetectable and there was no response to PAR4 agonist peptides [25].
• Northern blot analysis (approximately 10-fold) and quantitative RT-PCR (approximately threefold) confirmed the upregulation of PAR3 mRNA expression (by 24 hours) in cells exposed to PMA [1].
• PMA-stimulated HEL cells showed enhanced PAR3 cell-surface expression (approximately threefold increase by day 2) by flow cytometry [1].
• The expression of PAR-1 and PAR-3 on protein level was investigated with confocal laser fluorescence and freeze-fracture electron microscopy [3].

References