| Scientific Background: | PAR-1 belongs to a four member family of G protein-coupled receptors (PAR-1 to -4) that are activated as a result of proteolytic cleavage by certain serine proteases, hence their name. In this modality of activation, a specific proteinase cleaves the PAR receptor within a defined sequence in its extracellular N-terminal domain. This cleavage results in the creation of a new N-terminal sequence (tethered ligand), which subsequently binds to a site in the second extracellular loop of the same receptor. This binding results in the coupling of the receptor to G proteins and in the activation of several signal transduction pathways1-3 Different PARs are activated by different proteinases. Hence, PAR-1 is activated by thrombin (and is also known as the thrombin receptor), as are PAR-3 and PAR-4, while PAR-2 is activated by trypsin1-3 PAR-1 can be also cleaved and activated by other proteinases such as plasmin, Factor Xa, and cathepsin G PAR-1 signals through several G proteins including Gαq, Gαi, and Gα12/13, resulting in the activation of several transduction pathways including Ca2+ mobilization, Rho and Rac signaling, and MAPK activation1-3 PAR-1 is expressed in several cell types including platelets, leukocytes, vascular endothelial cells, gastrointestinal epithelial cells, myocytes, and neurons. The best studied physiological function of PAR-1 is its involvement in the coagulation cascade. Thrombin activates the receptor on the surface of platelets inducing platelet aggregation, granular secretion, and procoagulant activity. PAR-1 also plays a role in vascular ontogenesis. PAR-1 also plays important roles in tumor growth and metastasis. PAR-1 is upregulated in several human cancers as are several proteinases such as plasmin and matrix metalloproteases that act as PAR-1 ligands, thereby creating an autocrine loop. PAR-1 activation in cancer cells transmits mitogenic signals through the activation of the erk1/2 pathway and is involved in tumor spread via its pro-angiogenic activity.4 |
