β-Arrestin-dependent Regulation of the Cofilin Pathway Downstream of Protease-activated Receptor-2
Journal of Biological Chemistry
␤-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 G␣ q/11 -coupled receptor, which has been proposed as a therapeutic target for inflammation and cancer, requires the scaffolding function of ␤-arrestins for chemotaxis. We hypothesized that PAR-2 can trigger specific responses by differential activation of two pathways, one through classic G␣ q
... ugh classic G␣ q /Ca 2؉ signaling and one through ␤-arrestins, and we proposed that the latter involves scaffolding of proteins involved in cell migration and actin assembly. Here we demonstrate the fol- lowing. (a) PAR-2 promotes ␤-arrestin-dependent dephosphorylation and activation of the actin filament-severing protein (cofilin) independently of G␣ q /Ca 2؉ signaling. (b) PAR-2evoked cofilin dephosphorylation requires both the activity of a recently identified cofilin-specific phosphatase (chronophin) and inhibition of LIM kinase (LIMK) activity. (c) ␤-Arrestins can interact with cofilin, LIMK, and chronophin and colocalize with them in membrane protrusions, suggesting that ␤-arrestins may spatially regulate their activities. These findings identify cofilin as a novel target of ␤-arrestin-dependent scaffolding and suggest that many PAR-2-induced processes may be independent of G␣ q/11 protein coupling.