Regulation of Protease-activated Receptor Signaling by Posttranslational Modifications

Protease-activated receptors (PARs) are a unique family of G protein-coupled receptors (GPCRs) that are irreversibly activated following proteolytic cleavage of their extracellular N-terminus. PARs play critical functions in hemostasis, thrombosis, inflammation, embryonic development and cancer progression. Due to the irreversible proteolytic nature of PAR activation, signaling by the receptors is tightly regulated. Three distinct processes including desensitization, internalization and lysosomal degradation, regulate the temporal and spatial aspects of activated PAR signaling. Posttranslational modifications play a critical role in regulating each of these processes and here we review the nature of PAR posttranslational modifications and their importance in signal regulation. The PARs are activated by numerous proteases, and some can elicit distinct cellular responses, how this biased agonism is determined is unknown. Further study of the function of posttranslational modifications of the PARs will lead to a greater understanding of the physiological regulation of baised agonism and how PAR signaling is precisely controlled in different cellular contexts.