β-Arrestin–mediated β1-adrenergic receptor transactivation of the EGFR confers cardioprotection
Takahisa Noma, … , Robert J. Lefkowitz, Howard A. Rockman
Takahisa Noma, … , Robert J. Lefkowitz, Howard A. Rockman
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2445-2458. https://doi.org/10.1172/JCI31901.
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Research Article

β-Arrestin–mediated β1-adrenergic receptor transactivation of the EGFR confers cardioprotection

Abstract

Deleterious effects on the heart from chronic stimulation of β-adrenergic receptors (βARs), members of the 7 transmembrane receptor family, have classically been shown to result from Gs-dependent adenylyl cyclase activation. Here, we identify a new signaling mechanism using both in vitro and in vivo systems whereby β-arrestins mediate β1AR signaling to the EGFR. This β-arrestin–dependent transactivation of the EGFR, which is independent of G protein activation, requires the G protein–coupled receptor kinases 5 and 6. In mice undergoing chronic sympathetic stimulation, this novel signaling pathway is shown to promote activation of cardioprotective pathways that counteract the effects of catecholamine toxicity. These findings suggest that drugs that act as classical antagonists for G protein signaling, but also stimulate signaling via β-arrestin–mediated cytoprotective pathways, would represent a novel class of agents that could be developed for multiple members of the 7 transmembrane receptor family.

Authors

Takahisa Noma, Anthony Lemaire, Sathyamangla V. Naga Prasad, Liza Barki-Harrington, Douglas G. Tilley, Juhsien Chen, Philippe Le Corvoisier, Jonathan D. Violin, Huijun Wei, Robert J. Lefkowitz, Howard A. Rockman

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Figure 2

β-Arrestin is required for β1AR-mediated EGFR transactivation.

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β-Arrestin is required for β1AR-mediated EGFR transactivation. ...
(A) HEK293 cells stably expressing WT β1AR, PKA– β1AR, or GRK– β1AR were transfected with GFP–β-arrestin. In the absence of agonist, GFP–β-arrestin (green) had a cytosolic distribution (i–iii). Ten minutes of agonist stimulation (Dob) resulted in redistribution of GFP–β-arrestin to the membrane in cells expressing WT β1AR and PKA– β1AR (iv and v, arrowheads), whereas no redistribution was observed in cells expressing GRK– β1AR (vi, arrows). Original magnification, ×100. (B) HEK293 cells stably expressing PKA– β1AR were transfected with FLAG-EGFR alone (Mock) or with siRNAs targeting β-arrestin1 (si-βarr1), β-arrestin2, β-arrestin1/2, or scrambled siRNA (si-control). Reduced Dob-stimulated phospho-EGFR and phospho-ERK1/2 were observed in cells transfected with siRNA targeting β-arrestin. (C) HEK293 cells stably expressing WT β1AR were transfected with EGFR-GFP and si-control or si-βarr1/2 to knock down expression (right panel). In the absence of agonist, EGFR-GFP was located at the membrane (i and v, arrows), while EGF stimulation induced EGFR-GFP redistribution into aggregates (iv and viii). Treatment of si-control–transfected cells with Dob or ISO also resulted in redistribution of EGFR into aggregates (ii and iii, arrowheads), an effect that was diminished in si-βarr1/2–transfected cells, where EGFR-GFP remained at the membrane (vi and vii, arrows). Original magnification, ×150.