Opposing effects of β-arrestin1 and β-arrestin2 on activation and degradation of Src induced by protease-activated receptor 1

Protease-activated receptor 1 (PAR1), a G protein-coupled receptor for thrombin, is irreversibly proteolytically activated. β-Arrestin1 and β-arrestin2 have been reported to have different effects on signal desensitization and transduction of PAR1. In this study, we investigated whether β-arrestin1 and β-arrestin2 regulate Src-dependent activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) induced by PAR1 in HEK 293 cells. Our results show that PAR1-mediated activation of Src and ERK1/2 in HEK 293 cells was increased with overexpression of β-arrestin1 or depletion of β-arrestin2. PAR1-mediated activation of Src and ERK1/2 in HEK 293 cells was decreased or eliminated with depletion of β-arrestin1 or overexpression of β-arrestin2. Furthermore, depletion of β-arrestin2 blocked PAR1-induced degradation of Src. Thus, β-arrestin1 and β-arrestin2 have opposing roles in regulating the activation of Src induced by PAR1. β-Arrestin2 also appears to promote PAR1-induced degradation of Src. This degradation of Src provides a possible mechanism for terminating PAR1 signaling.