Abstract
Beta-arrestin mediates desensitization and internalization of beta-adrenergic receptors (betaARs), but also acts as a scaffold protein in extracellular signal-regulated kinase (ERK) cascade. Thus, we have examined the role of beta-arrestin2 in the betaAR-mediated ERK signaling pathways. Isoproterenol stimulation equally activated cytoplasmic and nuclear ERK in COS-7 cells expressing beta1AR or beta2AR. However, the activity of nuclear ERK was enhanced by co-expression of beta-arrestin2 in beta2AR-but not beta1AR-expressing cells. Pertussis toxin treatment and blockade of Gbetagamma action inhibited beta-arrestin2-enhanced nuclear activation of ERK, suggesting that beta-arrestin2 promotes nuclear ERK localization in a Gbetagamma dependent mechanism upon receptor stimulation. beta2AR containing the carboxyl terminal region of beta1AR lost the beta-arrestin2-promoted nuclear translocation. As the carboxyl terminal region is important for beta-arrestin binding, these results demonstrate that recruitment of beta-arrestin2 to carboxyl terminal region of beta2AR is important for ERK localization to the nucleus.
MeSH terms
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Animals
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Arrestins / genetics
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Arrestins / metabolism
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Arrestins / physiology*
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COS Cells
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Cell Nucleus / metabolism*
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Chlorocebus aethiops
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Cyclic AMP-Dependent Protein Kinases / genetics
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Cytoplasm / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Heterotrimeric GTP-Binding Proteins / antagonists & inhibitors
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Humans
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Isoproterenol / pharmacology
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Microscopy, Fluorescence
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Phosphorylation / drug effects
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Protein Binding
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Protein Kinase Inhibitors / pharmacology
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Protein Transport
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Pyrimidines / pharmacology
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Receptors, Adrenergic, beta-1 / genetics
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Receptors, Adrenergic, beta-1 / metabolism
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Receptors, Adrenergic, beta-2 / genetics
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Receptors, Adrenergic, beta-2 / metabolism
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Receptors, Adrenergic, beta-2 / physiology*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Transfection
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beta-Adrenergic Receptor Kinases
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beta-Arrestins
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src-Family Kinases / antagonists & inhibitors
Substances
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AG 1879
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Arrestins
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Protein Kinase Inhibitors
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Pyrimidines
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Receptors, Adrenergic, beta-1
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Receptors, Adrenergic, beta-2
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Recombinant Fusion Proteins
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beta-Arrestins
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src-Family Kinases
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Cyclic AMP-Dependent Protein Kinases
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beta-Adrenergic Receptor Kinases
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Heterotrimeric GTP-Binding Proteins
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Isoproterenol