Overview of PAR1 signaling. The proteolytic cleavage of the amino-terminus of PAR1 exposes a specific tethered ligand that can bind to an extracellular binding pocket and activate the receptor, leading to signaling via intracellular G proteins and β-arrestin. The amino acid sequence of the protease-sensitive region of PAR1 and the cleavage sites of representative proteases are shown. The different intracellular signaling pathways and the effects on cells triggered by PAR1 via coupling to different G proteins and β-arrestin are indicated. Direct coupling of PAR1 via Gαi is not fully established and may depend on the interaction of PAR1 with coreceptors, for example, EPCR and sphingosine 1-phosphate receptor 1 (S1P1).69,70 EC, endothelial cells; MMP1 and MMP13, matrix metalloproteinase-1 and -13; PR3, proteinase 3.
