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J. Biol. Chem., Vol. 282, Issue 36, 26150-26157, September 7, 2007

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The Insulin-like Growth Factor Type 1 and Insulin-like Growth Factor Type 2/Mannose-6-phosphate Receptors Independently Regulate ERK1/2 Activity in HEK293 Cells^*

Hesham M. El-Shewy, Mi-Hye Lee, Lina M. Obeid, Ayad A. Jaffa, and Louis M. Luttrell¹

From the Departments of Medicine and Biochemistry and 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

Insulin-like growth factor types 1 and 2 (IGF-1; IGF-2) and insulin-like peptides are all members of the insulin superfamily of peptide hormones but bind to several distinct classes of membrane receptor. Like the insulin receptor, the IGF-1 receptor is a heterotetrameric receptor tyrosine kinase, whereas the IGF-2/ mannose 6-phosphate receptor is a single transmembrane domain protein that is thought to function primarily as clearance receptors. We recently reported that IGF-1 and IGF-2 stimulate the ERK1/2 cascade by triggering sphingosine kinasedependent "transactivation" of G protein-coupled sphingosine-1-phosphate receptors. To determine which IGF receptors mediate this effect, we tested seven insulin family peptides, IGF-1, IGF-2, insulin, and insulin-like peptides 3, 4, 6, and 7, for the ability to activate ERK1/2 in HEK293 cells. Only IGF-1 and IGF-2 potently activated ERK1/2. Although IGF-2 was predictably less potent than IGF-1 in activating the IGF-1 receptor, they were equipotent stimulators of ERK1/2. Knockdown of IGF-1 receptor expression by RNA interference reduced the IGF-1 response to a greater extent than the IGF-2 response, suggesting that IGF-2 did not signal exclusively via the IGF-1 receptor. In contrast, IGF-2 receptor knockdown markedly reduced IGF-2-stimulated ERK1/2 phosphorylation, with no effect on the IGF-1 response. As observed previously, both the IGF-1 and the IGF-2 responses were sensitive to pertussis toxin and the sphingosine kinase inhibitor, dimethylsphingosine. These data indicate that endogenous IGF-1 and IGF-2 receptors can independently initiate ERK1/2 signaling and point to a potential physiologic role for IGF-2 receptors in the cellular response to IGF-2.

Received for publication, April 18, 2007 , and in revised form, July 3, 2007.

^* This work was supported by National Institutes of Health Grants DK58283 (to L. M. L.) and GM62887 (to L. M. O.) and Department of Veterans Affairs Merit and Research Enhancement Award Program awards. 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 and 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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