Proteinase-activated receptors (PARs) – focus on receptor-receptor-interactions and their physiological and pathophysiological impact

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.

Proteinase-activated receptors (PARs) as targets for antiplatelet therapy

“…Classical heterotrimeric guanine nucleotide-binding protein (G protein) dependent pathways downstream of PAR activation have been well characterized for each PAR subtype [24]. PAR1 and PAR2 functionally couple to multiple G proteins including the Gαq/11, Gαi/o and Gα12/13 subfamilies [25][26][27].…”

Proteinase-activated Receptor 2 Promotes Cancer Cell Migration through RNA Methylation-mediated Repression of miR-125b

“…Because of the complexity of microenvironment, the molecular mechanisms by which proteinases promote metastasis have not been fully understood. Notably, all these proteinases can selectively activate protease-activated receptor 2 (PAR 2 ) 2 through proteolysis of the receptor (4). PAR 2 belongs to the PAR family of G-protein-coupled receptors (GPCRs).…”

Coagulation and non‐coagulation effects of thrombin

“…The intracellular domains of PARs tightly bind Ga and Gbc subunits; activation of the receptor stimulates the exchange of GTP for GDP, resulting in phosphorylation of the intracellular Ga subunit, which induces the release of the Ga subunit from its tight binding to the Gbc subunit [9]. Depending on several factors, such as the duration of activation, the concentration of the ligand, and the location and presence of coreceptors of PARs, activation of the receptor stimulates the phosphorylation of one of the intracellular Ga subunit families: Ga 12/13, Ga i/o , or Ga q .…”