Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection.
Abstract
Deleterious effects on the heart from chronic stimulation of beta-adrenergic receptors
(betaARs), 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 beta-arrestins mediate beta1AR
signaling to the EGFR. This beta-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
beta-arrestin-mediated cytoprotective pathways, would represent a novel class of agents
that could be developed for multiple members of the 7 transmembrane receptor family.
Type
Journal articleSubject
AnimalsArrestins
Cell Line
Heart
Humans
Mice
Mice, Transgenic
Mutation
Myocardium
Phosphorylation
Protein Binding
Protein-Serine-Threonine Kinases
Receptor, Epidermal Growth Factor
Receptors, Adrenergic, beta-1
Signal Transduction
Transcriptional Activation
beta-Arrestins
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http://hdl.handle.net/10161/5925Published Version (Please cite this version)
10.1172/JCI31901Publication Info
Barki-Harrington, L; Chen, J; Le Corvoisier, P; Lefkowitz, Robert J; Lemaire, A; Naga Prasad, SV; ... Wei, H (2007). Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J Clin Invest, 117(9). pp. 2445-2458. 10.1172/JCI31901. Retrieved from http://hdl.handle.net/10161/5925.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Robert J. Lefkowitz
James B. Duke Professor of Medicine
The focus of work in this laboratory is on the elucidation of the molecular properties
and regulatory mechanisms controlling the function of G protein-coupled receptors.
As model systems we utilize the so called adrenergic receptors for adrenaline and
related molecules. The goal is to learn the general principles of signal transduction
from the outside to the inside of the cell which are involved in systems as diverse
as sensory perception, neuro- transmitter and hormonal signaling. Stud
Howard Allan Rockman
Edward S. Orgain Professor of Cardiology, in the School of Medicine
Rockman Lab: Molecular Mechanisms of Hypertrophy and Heart Failure Overall Research
Direction: The major focus of this laboratory is to understand the molecular mechanisms
of hypertrophy and heart failure. My laboratory uses a strategy that combines state
of the art molecular techniques to generate transgenic and gene targeted mouse models,
combined with sophisticated physiologic measures of in vivo cardiac function. In
this manner, candidate molecules are either selectively
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