Protease-Activated Receptors in the Intestine: Focus on Inflammation and Cancer

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.

Serine proteases at the cutting edge of IBD: Focus on gastrointestinal inflammation

“…The uncontrolled exposure of colonic mucosa to such high trypsin levels was likely to cleave PAR‐2, a membrane‐spanning cell surface receptor that is believed to localize throughout the GI tract. PAR‐2 activation increased intestinal permeability thus promoting bacterial translocation from the gut lumen with a subsequent immune activation 65,66 . Coupling PAR‐2 processing (in response to trypsin or PAR‐2 agonists) with TJ rearrangements was then proposed to impair the barrier function and induce inflammation 67 .…”

Trefoil Factor Family Member 2 (TFF2) as an Inflammatory-Induced and Anti-Inflammatory Tissue Repair Factor

“…Indeed, TFF2-deficient mice have an increased gastric ulceration degree compared to wild-type mice following indomethacin administration [3]. Since there is numerous inflammatory diseases [4,[15][16][17] that develop in the digestive and respiratory systems, we would like to summarize hypothetic links between the TFF2 and selected inflammatory-related processes [2,[18][19][20].…”

Shared and disease-specific host gene-microbiome interactions across human diseases

“…The host pathways enriched for CRC-specific interactions are known to modulate tumor growth, progression and metastasis in CRC, such as Interleukin-10 signaling, signaling by NOTCH1 in cancer, and regulation of MECP2 expression and activity 63–66 . The host pathways we identified as enriched for IBD-specific interactions are known to be responsible for maintenance of gastric mucosa integrity, inflammatory response, and host defence against invading pathogens, such as thrombin signalling through proteinase activated receptors (PARs), and glucagon type ligand receptors 67,68 . For IBS-specific interactions, the enriched host pathways identified here have been shown to regulate homeostasis of intestinal tissue and proinflammatory mechanisms in IBS, such as sumoylation of DNA damage response and repair proteins, and arachidonic acid metabolism 69–71 .…”