Protease activated receptors

The protease-activated receptors, PARs for short, are a family of G protein-coupled receptors (GPCK) that are characterized by the fact that they are activated by serine proteases (mainly thrombin, in the epidermis also by kallikreins). In addition to their role in blood coagulation, protease-activated receptors are also involved in inflammatory and digestive processes. Protease-activated receptors are expressed by various cell types, including thrombocytes, endothelial cells, myocytes and neurons.

Keratinocyte proliferation leads to increased expression and activation of PAR2. Inhibition and deletion of PAR2 leads to a significant suppression of inflammation and oxidative stress, which is accompanied by a reduction in IL-6 and IL-1β levels and an increase in MnSOD levels (Bang E et al. 2021).

• PAR1: Protease-activated receptor 1 or F2R
• PAR2: Protease-activated receptor 2 or F2RL1
• PAR3: Protease-activated receptor 3 or F2RL2
• PAR4: Protease-activated receptor 4 or F2RL3

PAR-1 is the primary receptor for the coagulation factors thrombin and activated factor X; PAR-3 and PAR-4 are also activated by thrombin, while PAR-2 is cleaved by trypsin, tryptase and coagulation factor VIIa in addition to factor Xa. According to recent findings, however, PAR-2 can also be activated by supraphysiological thrombin concentrations.

PARs are activated by proteolytic cleavage of the N-terminus. GPCRs are also known as heptahelical receptors, as they are formed from seven domains that cross the membrane. The eponymous G protein is connected to the receptor via the intracellular side. In protease-activated receptors, activation occurs via cleavage of the extracellular N-terminus. As a result, a new N-terminal end is formed, which activates the receptor at its second extracellular loop as an intrinsic ligand (tethered ligand). In contrast to the reversible activation of many classic GPCRs, this type of activation is irreversible

The protease-activated receptors play a key role in metastasis as they regulate processes such as epithelial-mesenchymal transition (EMT), cell migration, invasion and tumor-stroma interactions. In doing so, PARs interact with other receptors and signaling systems, such as the TGF-β signal transduction pathway, and enhance its pro-metastatic effect. PAR2 also plays a role in other pathophysiological processes such as inflammation, obesity, cachexia and thrombosis formation, all of which are either a risk factor for the development of certain types of cancer or can be a consequence of cancer.

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