title: Beta-arrestin-dependent regulation of the cofilin pathway downstream of protease-activated receptor-2.
abstract: Beta-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 Galpha(q/11)-coupled receptor, which has been proposed as a therapeutic target for inflammation and cancer, requires the scaffolding function of beta-arrestins for chemotaxis. We hypothesized that PAR-2 can trigger specific responses by differential activation of two pathways, one through classic Galpha(q)/Ca(2+) signaling and one through beta-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 beta-arrestin-dependent dephosphorylation and activation of the actin filament-severing protein (cofilin) independently of Galpha(q)/Ca(2+) 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) Beta-arrestins can interact with cofilin, LIMK, and chronophin and colocalize with them in membrane protrusions, suggesting that beta-arrestins may spatially regulate their activities. These findings identify cofilin as a novel target of beta-arrestin-dependent scaffolding and suggest that many PAR-2-induced processes may be independent of Galpha(q/11) protein coupling.
authors.affiliation: Cell, Molecular, and Developmental Biology Program and Biomedical Sciences Division, University of California-Riverside, B605 Statistics Road, Riverside, CA 92521, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Zoudilova
authors.forename: Puneet
authors.initials: P
authors.lastname: Kumar
authors.forename: Lan
authors.initials: L
authors.lastname: Ge
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Gary M
authors.initials: GM
authors.lastname: Bokoch
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: DeFea
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019390:Arrestins / Q000172:deficiency / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D054461:Lim Kinases; D051379:Mice; D018345:Mice, Knockout; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism*; D000071557:beta-Arrestins
chemical_list: D051339:Actin Depolymerizing Factors; D019390:Arrestins; D044464:Receptor, PAR-2; D000071557:beta-Arrestins; D011494:Protein Kinases; D054461:Lim Kinases; C515893:Limk1 protein, mouse; D010749:Phosphoprotein Phosphatases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11