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Abstract
Protease-Activated Receptor-2 (PAR2) has been implicated through genetic knockout mice with cytokine regulation and arthritis development. Many studies have associated PAR2 with inflammatory conditions (arthritis, airways inflammation, IBD) and key events in tumor progression (angiogenesis, metastasis), but they have relied heavily on the use of single agonists to identify physiological roles for PAR2. However such probes are now known not to be highly selective for PAR2, and thus precisely what PAR2 does and what mechanisms of downstream regulation are truly affected remain obscure. Effects of PAR2 activation on gene expression in Human Embryonic Kidney cells (HEK293), a commonly studied cell line in PAR2 research, were investigated here by comparing 19,000 human genes for intersecting up- or down-regulation by both trypsin (an endogenous protease that activates PAR2) and a PAR2 activating hexapeptide (2f-LIGRLO-NH2). Among 2,500 human genes regulated similarly by both agonists, there were clear associations between PAR2 activation and cellular metabolism (1,000 genes), the cell cycle, the MAPK pathway, HDAC and sirtuin enzymes, inflammatory cytokines, and anti-complement function. PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. This is the first widespread profiling of specific activation of PAR2 and provides a valuable platform for better understanding key mechanistic roles of PAR2 in human physiology. Results clearly support the development of both antagonists and agonists of human PAR2 as potential disease modifying therapeutic agents.
Highlights
900 human G protein-coupled receptors (GPCRs) are annotated, forming a diverse family of membrane-spanning cell-surface proteins that may account for .2% of the human genome [1,2]
Genes regulated by trypsin and peptide agonists To identify candidate genes that might be differentially expressed as a result of Protease-Activated Receptor-2 (PAR2) activation in human embryonic kidney cells (HEK293), cDNA microarray analyses were performed using a human Compugen array of,19,000 different human genes
It is clear from this study that PAR2 activation is selfsustaining and strongly implicated in cell metabolism, proliferation and inflammation
Summary
900 human G protein-coupled receptors (GPCRs) are annotated, forming a diverse family of membrane-spanning cell-surface proteins that may account for .2% of the human genome [1,2]. GPCRs are single polypeptide chains containing seven membrane-localized helices connected by three extracellular and three intracellular loops, with extracellular amino and intracellular carboxyl termini. Both extracellular and intracellular domains vary substantially in size, the former having evolved to selectively recognize many types of GPCR-activating extracellular ligands, while the latter mediate signal transduction through coupling to combinations of G proteins resulting in extensive functional diversity [3]. Protease activated receptors (PARs) are unusual GPCRs [4] with as yet no known endogenous extracellular ligands. Short synthetic peptides corresponding to the new N-terminus can trigger PAR activation, but only at much higher concentrations than proteases [4]. PAR2 is activated by mainly serine proteases (e.g. trypsin, tryptase, cathepsin G) but not thrombin and may be linked to inflammatory and proliferative disorders [4]
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