Abstract
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.
Footnotes
- Received December 12, 2015.
- Accepted March 3, 2016.
These studies were supported in large part by an operating grant from the Canadian Institutes of Health Research (MDH), with ancillary funding from Prostate Cancer Canada, The Calgary Prostate Cancer Centre and the Calgary Motorcycle Ride for Dad. Over part of the time frame of these studies, K.K.H. and R.R. were supported in part by postdoctoral fellowships from the Alberta Heritage Foundation for Medical Research (now: Alberta Innovates Heath Solutions).
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics