M. Molino | Semantic Scholar

Tryptase is the first protease other than trypsin that has been shown to activate human PAR-2, and in contrast, although tryptase clearly activates thrombin receptors in COS-1 cells, it does not appear to cleave endogenous throm bin receptors in platelets or CHRF-288 cells.

PAR1 is the predominant thrombin receptor expressed in HUVEC and cleavage of PAR1 is required for endothelial cell responses to throm bin; although PAR3 may be expressed, there is still no evidence that it mediatesThrombin responses; and transactivation of PAR2 by cleaved PAR1 can contribute to endothelialcell responses to Thrombin, particularly when signaling through PAR1 has been blocked.

The results suggest that the expression of both thrombin receptors and PAR-2 on endothelial cells serves more to extend the range of proteases to which the cells can respond than it does to extendThe range of potential responses.

This review focuses on recent information about the manner in which signaling through these receptors is initiated and terminated, including evidence for inter- as well as intramolecular modes of activation, and continuing efforts to identify additional, biologically-relevant proteases that can activate PAR family members.

PAR1 is the predominant thrombin receptor expressed in HUVEC and cleavage of PAR1 is required for endothelial cell responses toThrombin, and transactivation of PAR2 by cleaved PAR1 can contribute to endothelial cells responses to throm bin, particularly when signaling through PAR2 is blocked.

Exposure to cathepsin G disables signaling through human PAR3, and prevents murine PAR3 from serving its normal role, which is to facilitate PAR4 cleavage at low thrombin concentrations, extend the range of possible interactions between PAR family members and proteases, and provide further support for species-specific differences in the interaction of these receptors with proteases other than throm bin.

The ability of cathepsin G to inhibit responses to thrombin, but not SFLLRN, is suggested to be due to cleavage of the receptor at Phe55-Trp56, deleting the tethered ligand domain, and shows that cathePSin G can activateThrombin receptors, but only if the cleavage site at P he55- Trp56 is mutated or otherwise protected.

Results demonstrate that following receptor cleavage a fragment containing the original N-terminus of the receptor is released from the platelet surface, and demonstrate that based upon epitope mapping, this fragment is at least 15-20 residues long and it is possible to quantitate the receptor fragment in the supemates of cells exposed to thrombin.

Current information about the thrombin receptor and PAR-2 is summarized and their roles in platelet and endothelial cell biology, their interactions with proteases, and the known mechanisms for receptor redistribution and replacement are considered.