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J. Biol. Chem. 278 (51): 51334-51339

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

{beta}-Arrestin1 Mediates Insulin-like Growth Factor 1 (IGF-1) Activation of Phosphatidylinositol 3-Kinase (PI3K) and Anti-apoptosis*

Thomas J. Povsic{ddagger}§, Trudy A. Kohout¶, , and Robert J. Lefkowitz||**

{ddagger}Division of Cardiology and the ||Howard Hughes Medical Institute, Department of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710 and Neurocrine Biosciences Incorporated, San Diego, California 92121

Abstract: {beta}-arrestins (1 and 2) are widely expressed cytosolic proteins that play central roles in G protein-coupled receptor signaling. {beta}-arrestin1 is also recruited to the insulin-like growth factor 1 (IGF-1) receptor, a receptor tyrosine kinase, upon agonist binding. Here we report that, in response to IGF-1 stimulation, {beta}-arrestin1 mediates activation of phosphatidylinositol 3-kinase in a pathway that leads to the subsequent activation of Akt and anti-apoptosis. This process is independent of both Gi and ERK activity. The pathway fails in mouse embryo fibroblasts lacking both {beta}-arrestins and is restored by stable transfection of {beta}-arrestin1. Remarkably, this pathway is insensitive to chemical inhibition of IGF-1 receptor tyrosine kinase activity. These results suggest that, in addition to their roles in G protein-coupled receptor signaling, {beta}-arrestins couple the IGF-1 receptor tyrosine kinase to the phosphatidylinositol 3-kinase system and suggest that this mechanism is operative independently of the tyrosine kinase activity of the receptor.

Received for publication September 8, 2003. Revision received October 6, 2003.

* 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.

§ Funded in part by National Institutes of Health Training Grant HL 07101.

** Investigator of the Howard Hughes Medical Center, funded in part by National Institutes of Health Grants HL 16037 and HL 70631, and to whom correspondence should be addressed: Howard Hughes Medical Inst., Dept. of Medicine and Biochemistry, Box 3821, Duke University Medical Center, Durham, NC 27710. Tel.: 919-684-2974; Fax: 919-684-8875; E-mail: lefko001{at}receptor-biol.duke.edu.

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