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J. Biol. Chem., Vol. 282, Issue 9, 6597-6608, March 2, 2007

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Src Docks to A-kinase Anchoring Protein Gravin, Regulating ₂-Adrenergic Receptor Resensitization and Recycling^*

Jiangchuan Tao, Hsien-yu Wang, and Craig C. Malbon¹

From the Departments of Pharmacology and Physiology & Biophysics, School of Medicine, Health Sciences Center, State University of New York, Stony Brook, New York 11794-8651

Gravin (AKAP12) is a membrane-associated scaffold that provides docking for protein kinases, phosphatases, and adaptor molecules obligate for resensitization and recycling of ₂-adrenergic receptors. Gravin binds to the cell membrane in a Ca²⁺-sensitive manner and to receptors through well characterized protein-protein interactions. Although the interaction of serine/threonine, cyclic AMP-dependent protein kinase with protein kinase A-anchoring proteins is well described and involves a kinase regulatory subunit binding domain in the C terminus of these proteins, far less is known about tyrosine kinase docking to members of this family of scaffolds. The non-receptor tyrosine kinase Src regulates resensitization of ₂-adrenergic receptors and docks to gravin. Gravin displays nine proline-rich domains distributed throughout the molecule. One class I ligand for Src homology domain 3 docking, found in the N terminus (¹⁰RXPXXP¹⁵) of gravin, is shown to bind Src. Binding of Src to gravin activates the intrinsic tyrosine kinase of Src. Mutagenesis/deletion of the class I ligand (P15A,P16A) on the N terminus of gravin abolishes both the docking of Src to gravin as well as the receptor resensitization and recycling catalyzed by gravin. The Src-binding peptide-(1–51) of gravin behaves as a dominant-negative for AKAP gravin regulation of receptor resensitization/recycling. The tyrosine kinase Src plays an essential role in the AKAP gravin-mediated receptor resensitization and recycling, an essential aspect of receptor biology.

Received for publication, September 19, 2006 , and in revised form, December 21, 2006.

^* This work was supported by United States Public Health Service Grants DK25410 (to C. C. M.) and GM69375 (to H. Y. W.) from the National Institutes of Health and institutional National Research Service Award T32 DK007521 from the NIDDK, National Institutes of Health (to J. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 631-444-7873; Fax: 631-444-7696; E-mail: craig{at}pharm.sunysb.edu.

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