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Violin, Jonathan D.; Ren, Xiu-Rong; Lefkowitz, Robert J.
Journal of biological chemistry/The Journal of biological chemistry, 07/2006, Letnik: 281, Številka: 29Journal Article
The small family of G-protein-coupled receptor kinases (GRKs) regulate cell signaling by phosphorylating heptahelical receptors, thereby promoting receptor interaction with β-arrestins. This switches a receptor from G-protein activation to G-protein desensitization, receptor internalization, and β-arrestin-dependent signal activation. However, the specificity of GRKs for recruiting β-arrestins to specific receptors has not been elucidated. Here we use the β2-adrenergic receptor (β2AR), the archetypal nonvisual heptahelical receptor, as a model to test functional GRK specificity. We monitor endogenous GRK activity with a fluorescence resonance energy transfer assay in live cells by measuring kinetics of the interaction between the β2AR and β-arrestins. We show that β2AR phosphorylation is required for high affinity β-arrestin binding, and we use small interfering RNA silencing to show that HEK-293 and U2-OS cells use different subsets of their expressed GRKs to promote β-arrestin recruitment, with significant GRK redundancy evident in both cell types. Surprisingly, the GRK specificity for β-arrestin recruitment does not correlate with that for bulk receptor phosphorylation, indicating that β-arrestin recruitment is specific for a subset of receptor phosphorylations on specific sites. Moreover, multiple members of the GRK family are able to phosphorylate the β2AR and induce β-arrestin recruitment, with their relative contributions largely determined by their relative expression levels. Because GRK isoforms vary in their regulation, this partially redundant system ensures β-arrestin recruitment while providing the opportunity for tissue-specific regulation of the rate of β-arrestin recruitment.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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