beta1-Adrenergic receptor (beta1AR) stimulation confers cardioprotection via beta-arrestin-de pend ent transactivation of epidermal growth factor receptors (EGFRs), however, the precise mechanism for this salutary process is unknown. We tested the hypothesis that the beta1AR and EGFR form a complex that differentially directs intracellular signaling pathways. beta1AR stimulation and EGF ligand can each induce equivalent EGFR phosphorylation, internalization, and downstream activation of ERK1/2, but only EGF ligand causes translocation of activated ERK to the nucleus, whereas beta1AR-stimulated/EGFR-transactivated ERK is restricted to the cytoplasm. beta1AR and EGFR are shown to interact as a receptor complex both in cell culture and endogenously in human heart, an interaction that is selective and undergoes dynamic regulation by ligand stimulation. Although catecholamine stimulation mediates the retention of beta1AR-EGFR interaction throughout receptor internalization, direct EGF ligand stimulation initiates the internalization of EGFR alone. Continued interaction of beta1AR with EGFR following activation is dependent upon C-terminal tail GRK phosphorylation sites of the beta1AR and recruitment of beta-arrestin. These data reveal a new signaling paradigm in which beta-arrestin is required for the maintenance of a beta1AR-EGFR interaction that can direct cytosolic targeting of ERK in response to catecholamine stimulation.
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http://dx.doi.org/10.1074/jbc.M109.005793 | DOI Listing |
Am J Cancer Res
August 2023
Department of Animal Science, National Chiayi University Chiayi, Taiwan.
Colorectal cancer (CRC) is one of the leading causes of malignancy-related deaths worldwide. Radiotherapy is often combined with surgery to treat patients with more advanced CRC. Despite impressive initial clinical responses, radiotherapy resistance is the main reason for most treatment failures in colorectal cancer.
View Article and Find Full Text PDFJ Chromatogr A
August 2022
College of Life Sciences, Northwest University, Xi'an 710069, China. Electronic address:
The discovery of beta1-adrenoceptor (β-AR) ligands is viewed as an enormous demand for fighting ailments mediated by the receptor including cardiovascular diseases. Such pursuit is gravely challenged due to the lack of lead screening methods with high efficiency. This work developed a chromatographic method for pursuing β-AR ligand from the herbal extract by fusing epidermal growth factor receptor (EGFR) as a tag at its C-terminus to stably express the fusion receptor in E.
View Article and Find Full Text PDFBMC Ophthalmol
December 2021
State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, 5 Yan'erdao Road, Qingdao, 266071, China.
Background: Topical application of β-blocker eye drops induces damage to the ocular surface in clinical. However, the mechanism involved remains incompletely understood. The purpose of this study was to investigate the influence and mechanism of β-blocker eye drops on corneal epithelial wound healing.
View Article and Find Full Text PDFMol Pharmacol
December 2021
Departments of Medicine (J.W., B.P, I.G., X.X., A.W.K., H.J., S.A., R.J.L., H.A.R.), Biochemistry (R.J.W.), Howard Hughes Medical Institute (R.J.L.), and Cell Biology (H.A.R.), Duke University Medical Center, Durham, North Carolina
adrenergic receptors ( ARs) are central regulators of cardiac function and a drug target for cardiac disease. As a member of the G protein-coupled receptor family, ARs activate cellular signaling by primarily coupling to Gs proteins to activate adenylyl cyclase, cAMP-dependent pathways, and the multifunctional adaptor-transducer protein -arrestin. Carvedilol, a traditional -blocker widely used in treating high blood pressure and heart failure by blocking adrenergic receptor-mediated G protein activation, can selectively stimulate Gs-independent -arrestin signaling of adrenergic receptors, a process known as -arrestin-biased agonism.
View Article and Find Full Text PDFCell Signal
February 2021
Center for Translational Medicine, Temple University, Philadelphia, PA 19140, USA. Electronic address:
β1-adrenergic receptor (β1AR)-mediated transactivation of epidermal growth factor receptor (EGFR) engages downstream signaling events that impact numerous cellular processes including growth and survival. While association of these receptors has been shown to occur basally and be important for relaying transactivation-specific intracellular events, the mechanism by which they do so is unclear and elucidation of which would aid in understanding the consequence of disrupting their interaction. Using fluorescence resonance energy transfer (FRET) and immunoprecipitation (IP) analyses, we evaluated the impact of C-terminal truncations of EGFR on its ability to associate with β1AR.
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