Beta‐arrestin‐dependent regulation of the cofilin pathway downstream of Protease‐activated receptor‐2

Abstract

β-arrestins are pleiotropic molecules that mediate signal desensitization, G-protein-independent signaling, scaffolding of signaling molecules, and chemotaxis. Protease-activated-receptor-2 (PAR-2), a Gαq-coupled receptor, which has been proposed as a therapeutic target for inflammation and cancer, requires the scaffolding function of β-arrestins for chemotaxis. We have hypothesized that PAR-2 can trigger specific responses by differential activation of two pathways, one through classic Gαq/Ca2+ signalingand one through β-arrestins, and we hypothesized that the latter involved scaffolding of proteins involved in cell migration. Here, we demonstrate that: PAR-2 promotes β-arrestin-dependent dephosphorylation and activation of the actin filament severing protein (cofilin) independent of Gαq/Ca2+ signaling; PAR-2-evoked cofilin dephosphorylation requires both the activity of a recently identified cofilin-specific phosphatase (chronophin) and inhibition of LIMK activity and β-arrestins bind to both LIMK and chronophin and colocalize with them in lamellipodia, suggesting β-arrestins may spatially regulate their activities. These findings identify a novel target of β-arrestin-dependent scaffolding and reveal that many PAR-2-induced processes may be independent of G-protein coupling. This work was supported by R01GM066151 (KAD) and R01GM44428 (GMB).