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Originally published In Press as doi:10.1074/jbc.M009130200 on January 22, 2001

J. Biol. Chem., Vol. 276, Issue 18, 15192-15199, May 4, 2001
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Regulation of Membrane Targeting of the G Protein-coupled Receptor Kinase 2 by Protein Kinase A and Its Anchoring Protein AKAP79*

Mei Cong, Stephen J. Perry, Fang-Tsyr Lin, Iain D. FraserDagger §, Liaoyuan A. Hu, Wei Chen, Julie A. Pitcher, John D. ScottDagger ||, and Robert J. Lefkowitz||**

From the Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710 and the Dagger  Howard Hughes Medical Institute, Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201

The beta 2 adrenergic receptor (beta 2AR) undergoes desensitization by a process involving its phosphorylation by both protein kinase A (PKA) and G protein-coupled receptor kinases (GRKs). The protein kinase A-anchoring protein AKAP79 influences beta 2AR phosphorylation by complexing PKA with the receptor at the membrane. Here we show that AKAP79 also regulates the ability of GRK2 to phosphorylate agonist-occupied receptors. In human embryonic kidney 293 cells, overexpression of AKAP79 enhances agonist-induced phosphorylation of both the beta 2AR and a mutant of the receptor that cannot be phosphorylated by PKA (beta 2AR/PKA-). Mutants of AKAP79 that do not bind PKA or target to the beta 2AR markedly inhibit phosphorylation of beta 2AR/PKA-. We show that PKA directly phosphorylates GRK2 on serine 685. This modification increases Gbeta gamma subunit binding to GRK2 and thus enhances the ability of the kinase to translocate to the membrane and phosphorylate the receptor. Abrogation of the phosphorylation of serine 685 on GRK2 by mutagenesis (S685A) or by expression of a dominant negative AKAP79 mutant reduces GRK2-mediated translocation to beta 2AR and phosphorylation of agonist-occupied beta 2AR, thus reducing subsequent receptor internalization. Agonist-stimulated PKA-mediated phosphorylation of GRK2 may represent a mechanism for enhancing receptor phosphorylation and desensitization.

* This work was supported in part by National Institutes of Health Grants HL16037 (to R. J. L) and GM48231 (to J. D. S).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address: Division of Biology, California Inst. of Technology, 12000 E. California Blvd., Pasadena, CA 91125.

Present address: Medical Research Council Laboratory of Molecular Cell Biology, University College London, Gower St., London WC1E 6BT, United Kingdom.

|| Investigators of the Howard Hughes Medical Institute

** To whom correspondence should be addressed: Howard Hughes Medical Inst., Box 3821, Duke University Medical Center, Durham, NC 27710. Tel.: 919-684-2974; Fax: 919-684-8875; E-mail: lefko001@receptor-biol.duke.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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