Thrombin-Mediated Direct Activation of Proteinase-Activated Receptor-2: Another Target for Thrombin Signaling

• Published in: Molecular pharmacology Vol. 89; no. 5; p. 606
• Main Authors: Mihara, Koichiro, Ramachandran, Rithwik, Saifeddine, Mahmoud, Hansen, Kristina K, Renaux, Bernard, Polley, Danny, Gibson, Stacy, Vanderboor, Christina, Hollenberg, Morley D
• Format: Journal Article
• Language: English
• Published: United States 01-05-2016
• Subjects: Amino Acid Substitution; Animals; Aorta; Arrestins - metabolism; beta-Arrestins; Calcium Signaling - drug effects; Cell Line; Endothelium, Vascular - physiology; Humans; In Vitro Techniques; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; MAP Kinase Signaling System - drug effects; Mice; Mutation; Oligopeptides - pharmacology; Peptide Fragments - agonists; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Protein Transport - drug effects; Proteolysis; Rabbits; Receptor, PAR-2 - agonists; Receptor, PAR-2 - chemistry; Receptor, PAR-2 - metabolism; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; Thrombin - metabolism; Vasodilation - drug effects
• ISSN: 1521-0111
• DOI: 10.1124/mol.115.102723

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 triggeringβ-arrestin recruitment. Thus, PAR2 can be added alongside PAR1 and PAR4 to the targets, whereby thrombin can affect tissue function.