Abstract
Protease-activated receptors (PARs) belong to the G protein-coupled receptor (GPCR) family. Compared to other GPCRs, the specificity of the four PARs is the lack of physiologically soluble ligands able to induce their activation. Indeed, PARs are physiologically activated after proteolytic cleavage of their N-terminal domain by proteases. The resulting N-terminal end becomes a tethered activation ligand that interact with the extracellular loop 2 domain and thus induce PAR signal. PARs expression is ubiquitous and these receptors have been largely described in chronic inflammatory diseases and cancer. In this review, after describing their discovery, structure, mechanisms of activation, we then focus on the roles of PARs in the intestine and the two main diseases affecting the organ, namely inflammatory bowel diseases and cancer.
Highlights
Protease-activated receptors (PARs) belong to the family of G-protein coupled receptors (GPCRs)
Each receptor can be stimulated by an activator ligand—TFLLR for PAR1, SLIGKV for PAR2, TFRGAP for PAR3, and GYPGQV for PAR4—followed by an amino acid sequence involved in the inhibition of its self-activation [21]
The authors demonstrated that MMP1 activates PAR1 via an activator ligand located two amino acids upstream of the one generated by thrombin (PRSFLLR ligand), but resulting in the same signaling as the one induced by thrombin
Summary
Protease-activated receptors (PARs) belong to the G protein-coupled receptor (GPCR) family. Compared to other GPCRs, the specificity of the four PARs is the lack of physiologically soluble ligands able to induce their activation. PARs are physiologically activated after proteolytic cleavage of their N-terminal domain by proteases. The resulting N-terminal end becomes a tethered activation ligand that interact with the extracellular loop 2 domain and induce PAR signal. PARs expression is ubiquitous and these receptors have been largely described in chronic inflammatory diseases and cancer. After describing their discovery, structure, mechanisms of activation, we focus on the roles of PARs in the intestine and the two main diseases affecting the organ, namely inflammatory bowel diseases and cancer
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