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J Biol Chem, Vol. 274, Issue 49, 34531-34534, December 3, 1999

COMMUNICATION
Feedback Inhibition of G Protein-coupled Receptor Kinase 2 (GRK2) Activity by Extracellular Signal-regulated Kinases

Julie A. Pitcher, John J. G. Tesmer^¶, Jennifer L. R. Freeman, W. Darrell Capel, W. Carl Stone, and Robert J. Lefkowitz

From the  Howard Hughes Medical Institute and Departments of Medicine (Cardiology) and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710 and the ^¶ Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75235

G protein-coupled receptor kinase (GRK)-mediated receptor phosphorylation and -arrestin binding uncouple G protein-coupled receptors (GPCRs) from their respective G proteins and initiates the process of receptor internalization. In the case of the ₂-adrenergic receptor and lysophosphatidic acid receptor, these processes can lead to ERK activation. Here we identify a novel mechanism whereby the activity of GRK2 is regulated by feedback inhibition. GRK2 is demonstrated to be a phosphoprotein in cells. Mass spectrometry and mutational analysis localize the site of phosphorylation on GRK2 to a carboxyl-terminal serine residue (Ser⁶⁷⁰). Phosphorylation at Ser⁶⁷⁰ impairs the ability of GRK2 to phosphorylate both soluble and membrane-incorporated receptor substrates and dramatically attenuates G-mediated activation of this enzyme. Ser⁶⁷⁰ is located in a peptide sequence that conforms to an ERK consensus phosphorylation sequence, and in vitro, in the presence of heparin, ERK1 phosphorylates GRK2. Inhibition of ERK activity in HEK293 cells potentiates GRK2 activity, whereas, conversely, ERK activation inhibits GRK2 activity. The discovery that ERK phosphorylates and inactivates GRK2 suggests that ERK participates in a feedback regulatory loop. By negatively regulating GRK-mediated receptor phosphorylation, -arrestin-mediated processes such as Src recruitment and clathrin-mediated internalization, which are required for GPCR-mediated ERK activation, are inhibited, thus dampening further ERK activation.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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