β-Arrestin-2 regulates the development of allergic asthma

Walker, Julia K. L.; Fong, Alan M.; Lawson, Barbara L.; Savov, Jordan D.; Patel, Dhavalkumar D.; Schwartz, David A.; Lefkowitz, Robert J.

doi:10.1172/jci17265

Cited by 109 publications

(153 citation statements)

References 39 publications

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“…In lung epithelial cells, the glucocorticoiddependent repression of β-arrestin-2 also might contribute to the clinical synergism by impairing the proinflammatory effects of β2AR agonists that require receptor coupling to the MAPK pathway through the scaffolding function of β-arrestin-2. Consistent with the beneficial effects of decreased β-arrestin-2 expression in the treatment of obstructive airway disease, genetic deletion of the β-arrestin-2 gene was found to prevent airway hyperresponsiveness in a mouse model of asthma (25).…”

Section: Discussionmentioning

confidence: 59%

Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors

Oakley

Revollo

Cidlowski

2012

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptors (GPCRs) compose the largest family of cell surface receptors and are the most common target of therapeutic drugs. The nonvisual arrestins, β-arrestin-1 and β-arrestin-2, are multifunctional scaffolding proteins that play critical roles in GPCR signaling. On binding of activated GPCRs at the plasma membrane, β-arrestins terminate G protein-dependent responses (desensitization) and stimulate β-arrestin-dependent signaling pathways. Alterations in the cellular complement of β-arrestin-1 and β-arrestin-2 occur in many human diseases, and their genetic ablation in mice has severe consequences. Surprisingly, however, the factors that control β-arrestin gene expression are poorly understood. We demonstrate that glucocorticoids differentially regulate β-arrestin-1 and β-arrestin-2 gene expression in multiple cell types. Glucocorticoids act via the glucocorticoid receptor (GR) to induce the synthesis of β-arrestin-1 and repress the expression of β-arrestin-2. Glucocorticoid-dependent regulation involves the recruitment of ligand-activated glucocorticoid receptors to conserved and functional glucocorticoid response elements in intron-1 of the β-arrestin-1 gene and intron-11 of the β-arrestin-2 gene. In human lung adenocarcinoma cells, the increased expression of β-arrestin-1 after glucocorticoid treatment impairs G protein-dependent activation of inositol phosphate signaling while enhancing β-arrestin-1-dependent stimulation of the MAPK pathway by protease activated receptor 1. These studies demonstrate that glucocorticoids redirect the signaling profile of GPCRs via alterations in β-arrestin gene expression, revealing a paradigm for cross-talk between nuclear and cell surface receptors and a mechanism by which glucocorticoids alter the clinical efficacy of GPCR-based drugs.

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Section: Discussionmentioning

confidence: 59%

Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors

Oakley

Revollo

Cidlowski

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Ϫ/Ϫ and ␤-arrestin2 Ϫ/Ϫ in a C57BL/6 background were provided by Dr. Robert Lefkowitz (18). PAR-2 Ϫ/Ϫ mice were from Dr. Robin Plevin (University of Strathclyde, Glasgow, Scotland), and were developed by KOWA Pharmaceuticals (Tokyo, Japan) (8).…”

Section: Methodsmentioning

confidence: 99%

β-Arrestins Scaffold Cofilin with Chronophin to Direct Localized Actin Filament Severing and Membrane Protrusions Downstream of Protease-activated Receptor-2

Zoudilova

Min

Richards

et al. 2010

Journal of Biological Chemistry

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Protease-activated receptor-2 (PAR-2) mediates pro-inflammatory signals in a number of organs, including enhancing leukocyte recruitment to sites of injury and infection. At the cellular level, PAR-2 promotes activation of the actin filamentsevering protein cofilin, which is crucial for the reorganization of the actin cytoskeleton and chemotaxis. These responses require the scaffolding functions of ␤-arrestins; however, the mechanism by which ␤-arrestins spatially regulate cofilin activity and the role of this pathway in primary cells has not been investigated. Here, using size-exclusion chromatography and co-immunoprecipitation, we demonstrate that PAR-2 promotes the formation of a complex containing ␤-arrestins, cofilin, and chronophin (CIN) in primary leukocytes and cultured cells. Both association of cofilin with CIN and cell migration are inhibited in leukocytes from ␤-arrestin-2 ؊/؊ mice. We show that, in response to PAR-2 activation, ␤-arrestins scaffold cofilin with its upstream activator CIN, to facilitate the localized generation of free actin barbed ends, leading to membrane protrusion. These studies suggest that a major role of ␤-arrestins in chemotaxis is to spatially regulate cofilin activity to facilitate the formation of a leading edge, and that this pathway may be important for PAR-2-stimulated immune cell migration.Protease-activated-receptor-2 (PAR-2) 2 is a G-protein-coupled receptor that signals, through ␤-arrestin-promoted scaffolds, to promote reorganization of the actin cytoskeleton and chemotaxis (1, 2). In vivo, PAR-2 plays an important role in the recruitment of leukocytes to the sites of inflammation, because this is impaired in PAR-2 Ϫ/Ϫ mice and enhanced by administration of PAR-2 agonists (3-8). However, no studies have yet linked ␤-arrestin-dependent scaffolding of actin assembly proteins to PAR-2-stimulated chemotaxis under physiological conditions.␤-Arrestins are multifunctional proteins that mediate receptor desensitization and internalization and serve as signaling scaffolds. A role for ␤-arrestin scaffolds in signaling by PAR-2 and other receptors was first identified for the spatial regulation of ERK1/2 activity (9 -11). They are now known to scaffold numerous other signaling molecules (12-15), many of which are involved in actin reorganization and chemotaxis (1, 13, 16 -19). An attractive hypothesis is that ␤-arrestins exert spatial control over actin assembly events at the leading edge to promote membrane protrusion and cell migration. A recent advance in this field was the discovery that ␤-arrestins are required for PAR-2-dependent activation of the actin filamentsevering protein, cofilin (14), which binds to the sides of actin filaments, destabilizing them and promoting their severing. Filament severing has two functions: the reorganization of existing filaments and the creation of free actin barbed ends for monomer addition (20). Actin is a polar molecule containing a barbed and pointed end; addition of actin monomers to a growing filament occurs at the barbed end. Alt...

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“…Chemokine-meditated CD4 + T cell migration was impaired in these mice and suggests that β-arrestin 2 may play a major role in the development of allergic asthma. 37 Also, splenocytes derived from β-arrestin 2 knockout mice showed decreased CXCL12-induced migration. 38 Our group recently published a novel role for β-arrestin 1 in cellular migration and metastasis.…”

Section: β-Arrestin In Cellular Movementmentioning

confidence: 99%

Emerging Roles of β-Arrestins

Buchanan

DuBois²

2006

Cell Cycle

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Arrestins were originally characterized as structural adaptor proteins which modulate the desensitization and trafficking of seven-membrane-spanning receptors. From these seminal observations a multitude of novel functions for this gene family have arisen. Here we review the recently identified roles for β-arrestin including its nuclear function and roles in development, cellular migration, and metastasis.

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β-Arrestin-2 regulates the development of allergic asthma

Cited by 109 publications

References 39 publications

Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors

Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors

β-Arrestins Scaffold Cofilin with Chronophin to Direct Localized Actin Filament Severing and Membrane Protrusions Downstream of Protease-activated Receptor-2

Emerging Roles of β-Arrestins

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