Abstract
Proteinase-activated receptors (PARs) are a subfamily of G protein-coupled receptors (GPCRs) with four members, PAR1, PAR2, PAR3 and PAR4, playing critical functions in hemostasis, thrombosis, embryonic development, wound healing, inflammation and cancer progression. PARs are characterized by a unique activation mechanism involving receptor cleavage by different proteinases at specific sites within the extracellular amino-terminus and the exposure of amino-terminal “tethered ligand“ domains that bind to and activate the cleaved receptors. After activation, the PAR family members are able to stimulate complex intracellular signalling networks via classical G protein-mediated pathways and beta-arrestin signalling. In addition, different receptor crosstalk mechanisms critically contribute to a high diversity of PAR signal transduction and receptor-trafficking processes that result in multiple physiological effects.In this review, we summarize current information about PAR-initiated physical and functional receptor interactions and their physiological and pathological roles. We focus especially on PAR homo- and heterodimerization, transactivation of receptor tyrosine kinases (RTKs) and receptor serine/threonine kinases (RSTKs), communication with other GPCRs, toll-like receptors and NOD-like receptors, ion channel receptors, and on PAR association with cargo receptors. In addition, we discuss the suitability of these receptor interaction mechanisms as targets for modulating PAR signalling in disease.
Highlights
Proteinase-activated receptors (PARs) are a subfamily of G protein-coupled receptors (GPCRs) with four members, PAR1, PAR2, PAR3 and PAR4, playing critical functions in hemostasis, thrombosis, embryonic development, wound healing, inflammation and cancer progression
PARs exhibit an unusual activation mechanism the PAR family members share basic structural features of all GPCRs, including a central core domain composed of seven transmembrane helices (TM-I through TM-VII) connected by three intracellular and three extracellular loops [8], they exhibit a unique mechanism of proteolytic activation
While most GPCRs are activated reversibly by small hydrophilic molecules to elicit cellular responses [9], PAR activation by endogenous proteinases involves the unmasking of an N-terminal ‘tethered ligand’ (TL) that remains attached to the receptor and cannot diffuse away [1,2,3,4,5,6,7]
Summary
Protease-activated receptors in hemostasis, thrombosis and vascular biology. Rahman A, True AL, Anwar KN, Ye RD, Voyno-Yasenetskaya TA, Malik AB: Galpha(q) and Gbetagamma regulate PAR-1 signaling of thrombin-induced NF-kappaB activation and ICAM-1 transcription in endothelial cells. Ramachandran R, Mihara K, Mathur M, Rochdi MD, Bouvier M, Defea K, Hollenberg MD: Agonist-biased signaling via proteinase activated receptor-2: differential activation of calcium and mitogen-activated protein kinase pathways.
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