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http://purl.uniprot.org/citations/16280323http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/16280323http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/16280323http://www.w3.org/2000/01/rdf-schema#comment"Physiological effects of beta adrenergic receptor (beta2AR) stimulation have been classically shown to result from G(s)-dependent adenylyl cyclase activation. Here we demonstrate a novel signaling mechanism wherein beta-arrestins mediate beta2AR signaling to extracellular-signal regulated kinases 1/2 (ERK 1/2) independent of G protein activation. Activation of ERK1/2 by the beta2AR expressed in HEK-293 cells was resolved into two components dependent, respectively, on G(s)-G(i)/protein kinase A (PKA) or beta-arrestins. G protein-dependent activity was rapid, peaking within 2-5 min, was quite transient, was blocked by pertussis toxin (G(i) inhibitor) and H-89 (PKA inhibitor), and was insensitive to depletion of endogenous beta-arrestins by siRNA. beta-Arrestin-dependent activation was slower in onset (peak 5-10 min), less robust, but more sustained and showed little decrement over 30 min. It was insensitive to pertussis toxin and H-89 and sensitive to depletion of either beta-arrestin1 or -2 by small interfering RNA. In G(s) knock-out mouse embryonic fibroblasts, wild-type beta2AR recruited beta-arrestin2-green fluorescent protein and activated pertussis toxin-insensitive ERK1/2. Furthermore, a novel beta2AR mutant (beta2AR(T68F,Y132G,Y219A) or beta2AR(TYY)), rationally designed based on Evolutionary Trace analysis, was incapable of G protein activation but could recruit beta-arrestins, undergo beta-arrestin-dependent internalization, and activate beta-arrestin-dependent ERK. Interestingly, overexpression of GRK5 or -6 increased mutant receptor phosphorylation and beta-arrestin recruitment, led to the formation of stable receptor-beta-arrestin complexes on endosomes, and increased agonist-stimulated phospho-ERK1/2. In contrast, GRK2, membrane translocation of which requires Gbetagamma release upon G protein activation, was ineffective unless it was constitutively targeted to the plasma membrane by a prenylation signal (CAAX). These findings demonstrate that the beta2AR can signal to ERK via a GRK5/6-beta-arrestin-dependent pathway, which is independent of G protein coupling."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.org/dc/terms/identifier"doi:10.1074/jbc.m506576200"xsd:string
http://purl.uniprot.org/citations/16280323http://purl.org/dc/terms/identifier"doi:10.1074/jbc.m506576200"xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Lefkowitz R.J."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Lefkowitz R.J."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Nelson C.D."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Nelson C.D."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Reiter E."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Reiter E."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Premont R.T."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Premont R.T."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Shenoy S.K."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Shenoy S.K."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Xiao K."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Xiao K."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Drake M.T."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Drake M.T."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Houtz D.A."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Houtz D.A."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Lichtarge O."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Lichtarge O."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Madabushi S."xsd:string
http://purl.uniprot.org/citations/16280323http://purl.uniprot.org/core/author"Madabushi S."xsd:string
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