TY - JOUR T1 - Thrombin-Mediated Direct Activation of Proteinase-Activated Receptor-2: Another Target for Thrombin Signaling JF - Molecular Pharmacology JO - Mol Pharmacol SP - 606 LP - 614 DO - 10.1124/mol.115.102723 VL - 89 IS - 5 AU - Koichiro Mihara AU - Rithwik Ramachandran AU - Mahmoud Saifeddine AU - Kristina K. Hansen AU - Bernard Renaux AU - Danny Polley AU - Stacy Gibson AU - Christina Vanderboor AU - Morley D. Hollenberg Y1 - 2016/05/01 UR - http://molpharm.aspetjournals.org/content/89/5/606.abstract N2 - 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. ER -