RT Journal Article SR Electronic T1 Thrombin-Mediated Direct Activation of Proteinase-Activated Receptor-2: Another Target for Thrombin Signaling JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 606 OP 614 DO 10.1124/mol.115.102723 VO 89 IS 5 A1 Koichiro Mihara A1 Rithwik Ramachandran A1 Mahmoud Saifeddine A1 Kristina K. Hansen A1 Bernard Renaux A1 Danny Polley A1 Stacy Gibson A1 Christina Vanderboor A1 Morley D. Hollenberg YR 2016 UL http://molpharm.aspetjournals.org/content/89/5/606.abstract AB Thrombin is known to signal to cells by cleaving/activating a G–protein–coupled family of proteinase-activated receptors (PARs). The signaling mechanism involves the proteolytic unmasking of an N-terminal receptor sequence that acts as a tethered receptor-activating ligand. To date, the recognized targets of thrombin cleavage and activation for signaling are PAR1 and PAR4, in which thrombin cleaves at a conserved target arginine to reveal a tethered ligand. PAR2, which like PAR1 is also cleaved at an N-terminal arginine to unmask its tethered ligand, is generally regarded as a target for trypsin but not for thrombin signaling. We now show that thrombin, at concentrations that can be achieved at sites of acute injury or in a tumor microenvironment, can directly activate PAR2 vasorelaxation and signaling, stimulating calcium and mitogen-activated protein kinase responses along with triggering β–arrestin recruitment. Thus, PAR2 can be added alongside PAR1 and PAR4 to the targets, whereby thrombin can affect tissue function.