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J. Biol. Chem., Vol. 281, Issue 42, 31399-31407, October 20, 2006

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Insulin-like Growth Factors Mediate Heterotrimeric G Protein-dependent ERK1/2 Activation by Transactivating Sphingosine 1-Phosphate Receptors^*

From the Departments of Medicine and Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425 and the Research Service of the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401

Although several studies have shown that a subset of insulin-like growth factor (IGF) signals require the activation of heterotrimeric G proteins, the molecular mechanisms underlying IGF-stimulated G protein signaling remain poorly understood. Here, we have studied the mechanism by which endogenous IGF receptors activate the ERK1/2 mitogen-activated protein kinase cascade in HEK293 cells. In these cells, treatment with pertussis toxin and expression of a G_q/11-(305–359) peptide that inhibits G_q/11 signaling additively inhibited IGF-stimulated ERK1/2 activation, indicating that the signal was almost completely G protein-dependent. Treatment with IGF-1 or IGF-2 promoted translocation of green fluorescent protein (GFP)-tagged sphingosine kinase (SK) 1 from the cytosol to the plasma membrane, increased endogenous SK activity within 30 s of stimulation, and caused a statistically significant increase in intracellular and extracellular sphingosine 1-phosphate (S1P) concentration. Using a GFP-tagged S1P₁ receptor as a biological sensor for the generation of physiologically relevant S1P levels, we found that IGF-1 and IGF-2 induced GFP-S1P receptor internalization and that the effect was blocked by pretreatment with the SK inhibitor, dimethylsphingosine. Treating cells with dimethylsphingosine, silencing SK1 expression by RNA interference, and blocking endogenous S1P receptors with the competitive antagonist VPC23019 all significantly inhibited IGF-stimulated ERK1/2 activation, suggesting that IGFs elicit G protein-dependent ERK1/2 activation by stimulating SK1-dependent transactivation of S1P receptors. Given the ubiquity of SK and S1P receptor expression, S1P receptor transactivation may represent a general mechanism for G protein-dependent signaling by non-G protein-coupled receptors.

Received for publication, June 5, 2006 , and in revised form, July 24, 2006.

^* This work was supported by National Institutes of Health Grants DK58283 (to L. M. L.) and GM62887 (to L. M. O.) and the Research Service of the Department of Veterans Affairs. 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: Division of Endocrinology, Diabetes & Medical Genetics, Dept. of Medicine, Medical University of South Carolina, 96 Jonathan Lucas St., 816 CSB, P. O. Box 250624, Charleston, SC 29425. Tel.: 843-792-2529; Fax: 843-792-4114; E-mail: luttrell{at}musc.edu.

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