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J. Biol. Chem., Vol. 280, Issue 2, 1016-1023, January 14, 2005

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Insulin-induced -Arrestin1 Ser-412 Phosphorylation Is a Mechanism for Desensitization of ERK Activation by G_i-coupled Receptors^*

Christopher J. Hupfeld, Jamie L. Resnik, Satoshi Ugi, and Jerrold M. Olefsky¶||**

From the Department of Medicine, Division of Endocrinology and Metabolism and the Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093, the ^¶Veterans Affairs Hospital, Research Service, San Diego, California 92161, and ^||The Whittier Diabetes Institute, La Jolla, California 92037

-Arrestin1 is an adapter/scaffold for many G protein-coupled receptors during mitogen-activated protein kinase signaling. Phosphorylation of -arrestin1 at position Ser-412 is a regulator of -arrestin1 function, and in the present study, we showed that insulin led to a time- and dose-dependent increase in -arrestin1 Ser-412 phosphorylation, which blocked isoproterenol- and lysophosphatidic acid-induced Ser-412 dephosphorylation and impaired ERK signaling by these G protein-coupled receptor ligands. Insulin treatment also led to accumulation of Ser-412-phosphorylated -arrestin1 at the insulin-like growth factor 1 receptor and prevented insulin-like growth factor 1/Src association. Insulin-induced Ser-412 phosphorylation was partially dependent on ERK as treatment with the MEK inhibitor PD98059 inhibited the insulin effect (62% reduction, p = 0.03). Inhibition of phosphatidylinositol 3-kinase by wortmannin did not have a significant effect (9% reduction, p = 0.41). We also found that the protein phosphatase 2A (PP2A) was in a molecular complex with -arrestin1 and that the PP2A inhibitor okadaic acid increased Ser-412 phosphorylation. Concomitant addition of insulin and okadaic acid did not produce an additive effect on Ser-412 phosphorylation, suggesting a common mechanism. Small t antigen specifically inhibited PP2A, and in HIRcB cells expressing small t antigen, -arrestin1 Ser-412 phosphorylation was increased, and insulin had no further effect. Insulin treatment caused increased -arrestin1 Ser-412 phosphorylation, which blocked mitogen-activated protein kinase signaling and internalization by -arrestin1-dependent receptors with no effect on -adrenergic receptor G_s-mediated cAMP production. These findings provide a new mechanism for insulin-induced desensitization of ERK activation by G_i-coupled receptors.

Received for publication, April 2, 2004 , and in revised form, October 12, 2004.

^* This work was supported by National Institutes of Health Grant K08 DK65127-01 (to C. J. H.). 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.

^** To whom correspondence should be addressed: Dept. of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-6073. Tel.: 858-534-6651; Fax: 858-534-6653; E-mail: jolefsky{at}ucsd.edu.

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