Proteinase-activated Receptor 2: Springboard of Tumors

Abstract

Proteinase-activated receptors (PARs) were discovered more than 25 years ago and since then, their role in cancer has been under investigation. Research has primarily focused on the receptors located on the membrane of cancer cells and their impact on metabolism, intracellular signalling, and proliferation. Regarding the host response to cancer, studies have predominantly examined the relationship of thrombin receptors with blood clotting in distant metastatic spread. However, limited studies have examined the role of PARs, especially PAR-2, in the host anti-tumor immunity. This review article provides insights into the role of PAR-2 on cancer cells and immune competent cells involved in cancer development and progression. It also discussed the current knowledge of the importance of PAR-2 activation at various stages of cancer progression and its association with cancer-related pain.PARs, identified in the early 1990s, are ubiquitous surface molecules participating in many biological processes. They belong to a family of G protein-coupled receptors with seven membrane-spanning domains that are activated by tethered ligand sequences within their amino terminal, which are made accessible by site-specific proteolysis. Enzymes, such as thrombin and trypsin, site-specifically cleave the N-terminal end of PARs and thus enable their activation. This new N-terminal tethered ligand sequence in the extracellular domains of the receptor activates signalling through the associated G-protein. PARs participate in tissue growth, differentiation, regeneration, repair, inflammatory response regulation, and also in malignant transformation (1). There are four different PARs responding to activation by specific proteinases: PAR-1 activated by thrombin, complex of coagulation factors TF-VIIa-Xa or Xa, plasmin, activated protein C, MMP-1 or granzyme. PAR-2 activated by trypsin, tryptase, complex of coagulation factors TF-Va, TF-VIIa-Xa and TF-VIIa, matriptase, bacterial, fungal, or parasitic frass proteinases. PAR-3 activated by thrombin. PAR-4 activated by thrombin, trypsin, complex of coagulation factors TF-VIIa-Xa, plasmin, cathepsin G, certain bacterial proteinases, kalikreins or matriptase. Soluble synthesized amino acid sequence of the tethered ligand can also activate the PAR: SFLLRN-NH 2 for human PAR-1 and murine PAR-1), SLIGKV-NH 2 for human PAR-2 (SLIGRL-NH 2 for murine PAR-2) and AYPGKF-NH 2 for PAR-4 (Figure 1). After the site-specific proteolysis, intracellular processes including Ca ++ mobilization, PKC and MAP kinase activation accompanied with internalization, intracellular sorting resulting in a shape changes, adhesion, secretion, growth, or motility are induced. Generally, PARs are involved in different physiological and pathological processes including cell differentiation, inflammation, edema formation, fibrosis, coagulation and local or systemic blood circulation, neurodegeneration, and cancer.Whereas PARs -1, -3 and -4 are in large activated by thrombin, this is not the case for PAR-2. In case of PAR-2, the ...