β-Arrestin-dependent Regulation of the Cofilin Pathway Downstream of Protease-activated Receptor-2*

By M. Zoudilova, Puneet Kumar, Lan Ge, Ping Wang, G. Bokoch, K. DeFea. Journal of Biological Chemistry, 2007

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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/11-coupled receptor, which has been proposed as a therapeutic target for inflammation and cancer, requires the scaffolding function of β-arrestins for chemotaxis. We hypothesized that PAR-2 can trigger specific responses by differential activation of two pathways, one through classic Gαq/Ca2+ signaling and one through β-arrestins, and we proposed that the latter involves scaffolding of proteins involved in cell migration and actin assembly. Here we demonstrate the following. (a) PAR-2 promotes β-arrestin-dependent dephosphorylation and activation of the actin filament-severing protein (cofilin) independently of Gαq/Ca2+ signaling. (b) PAR-2-evoked cofilin dephosphorylation requires both the activity of a recently identified cofilin-specific phosphatase (chronophin) and inhibition of LIM kinase (LIMK) activity. (c) β-Arrestins can interact with cofilin, LIMK, and chronophin and colocalize with them in membrane protrusions, suggesting that β-arrestins may spatially regulate their activities. These findings identify cofilin as a novel target of β-arrestin-dependent scaffolding and suggest that many PAR-2-induced processes may be independent of Gαq/11 protein coupling.

Subfields: Cellular and Molecular Neuroscience, Immunology and Allergy, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2018e4f47bf83cedd12349d3e6e06f2428fef0c7