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.

Figure 1

Model for activation of PAR_1. The scheme illustrates activation of the intact receptor by distinct mechanisms involving either proteolysis (left) or a synthetic PAR₁-activating peptide (right): (A) proteolysis unmasks a tethered receptor-activating ligand (TL) sequence. The classical ‘canonical’ PAR₁ TL sequence generated by thrombin is: SFLLRN--- [10]. Distinct ‘non-canonical’ receptor-activating TL sequences are also generated by neutrophil proteinase-3 (PR3: TLDPR---) [11], matrix metalloproteinase-1 (MMP1: PRSFLL---) [12,13], neutrophil elastase (NE: RNPNDK---) [11], and activated protein-C (APC: NPNDK---) [14,15]. The different proteinase-revealed TLs can drive very distinct signal pathways (distinct coloured arrows for PAR₁ response at the bottom). (B) synthetic peptides with sequences that mimic the tethered ligand (e.g. TFLLRN-NH₂ for PAR₁) can activate PAR signalling without the need for receptor proteolysis. Peptides derived from the different enzyme-revealed tethered ligand sequences can stimulate ‘biased signaling’. (Illustration modified with permission from Hollenberg & Compton, Ref. [2]).

Figure 2

PAR receptor crosstalk. Scheme illustrating the interaction of PARs and their crosstalk with other receptors [GPCRs: G protein-coupled receptors (AT1: angiotensin receptor subtype 1, B2 receptor: bradykinin B2 receptor, EP: prostaglandin receptor, 5HT2 receptor: serotonin receptor subtype 2; P2Y12: purinergic ADP receptor; SP1PR1: sphingosine-1-phosphate receptor 1); PAR: proteinase-activated receptor; RTKs: receptor tyrosine kinases (EGFR: epidermal growth factor receptor; FGFR: fibroblast growth factor receptor; IGFR: insulin-like growth factor receptor; Met: hepatocyte growth factor (HGF) receptor; PDGFR: platelet derived growth factor receptor; VEGFR: vascular endothelial growth factor receptor); RSTKs: receptor serine/threonine kinases (ALK: activin-like kinase); TLRs: toll-like receptors (NLRs: NOD-like receptors, nucleotide oligomerization domain receptors); NMDA receptor: N-methyl-D-aspartate receptor; P2X1 receptor: ATP-gated cation channel; TRPA1: transient receptor potential ankyrin A1; TRPV: transient receptor potential vanilloid; p23, p24A: transmembrane proteins of the early secretory pathway. PARs can form homomeric interactions (indicated by light red-light red coloured symbols) or heteromeric interactions with other PARs (light red-dark red coloured symbols).

Figure 3

Concepts and mechanisms of PAR receptor crosstalk with other receptors and signal transducers. PAR receptor crosstalk involves (A) transactivation of receptor tyrosine kinases (RTKs) and receptor serine/threonine kinases (RSTKs), (B) PAR-PAR receptor interactions, and (C) PAR interplay with other non-PAR GPCRs and non-PAR signal transducers. (A) PARs can mediate transactivation of RTKs by an immediate matrix metalloproteinase (MMP)-catalysed release of RTK agonists from the cell surface, e.g. heparin-binding EGF, or transforming growth factor (TGF)-α, that in turn stimulates RTK signalling. PARs are also able to mediate transactivation of RSTKs by mechanisms including integrin-mediated activation of latent TGF-β. In addition, PARs can induce RTK transactivation via intracellular mechanisms including activation of Src, generation of reactive oxygen species (ROS), and inhibition of protein tyrosine phosphatases (PTPs). (B) PAR-PAR crosstalk involves PAR homo- and heterodimerization and PAR-PAR trans-signalling. (C) PARs are able to mediate transactivation of other non-GPCRs via extracellular release of GPCR agonists (e.g. the prostaglandin receptor by release of prostaglandins) and by intracellular mechanisms on the signalling (bradykinin B2 receptor, purinergic ADP receptor), gene transcription (angiotensin receptor subtype 1, serotonin receptor subtype 2), and receptor trafficking level. PARs further communicate with non-PAR signal transducers at both the signalling (toll-like receptors, ion channel receptors, NOD-like receptors) and receptor trafficking level (cargo receptors p23 and p24A).