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J. Biol. Chem., Vol. 281, Issue 2, 982-992, January 13, 2006

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Insulin Enhances Growth Hormone Induction of the MEK/ERK Signaling Pathway^*

Jie Xu, Adam B. Keeton, John L. Franklin, Xin Li, Derwei Y. Venable, Stuart J. Frank¶, and Joseph L. Messina1

From the Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Department of Cell Biology, University of Alabama, Birmingham, Alabama 35294, and the ^¶Endocrinology Section, Medical Service, Veterans Affairs Medical Center, Birmingham, Alabama 35233

Growth hormone (GH) plays an important role in growth and metabolism by signaling via at least three major pathways, including STATs, ERK1/2, and phosphatidylinositol 3-kinase/Akt. Physiological concentrations of insulin promote growth probably by modulating liver GH receptor (GHR) levels in vivo, but the possible effects of insulin on GH-induced post-GHR signaling have yet to be studied. We hypothesized that short-term insulin, similar to the fluctuations that occur following feeding, affects GH-induced post-GHR signaling. Our present studies suggest that, in rat H4IIE hepatoma cells, insulin (4 h or less) selectively enhanced GH-induced phosphorylation of MEK1/2 and ERK1/2, but not GH-induced activation of STAT5 and Akt. Although insulin pretreatment altered GH-induced formation of Shc·Grb2·SOS complex, it did not significantly affect GH-induced activation of other signaling intermediates upstream of MEK/ERK, including JAK2, Ras, and Raf-1. Immunofluorescent staining indicated that insulin pretreatment facilitated GH-induced cell membrane translocation of MEK1/2. Insulin pretreatment also increased the amount of MEK association with its scaffolding protein, KSR. In summary, short-term insulin treatment of cultured, liver-derived cells selectively sensitized GH-induced MEK/ERK phosphorylation independent of JAK2, Ras, and Raf-1, but likely resulted from increased cell membrane translocation of MEK1/2. These findings suggest that insulin may be necessary for sensitization of cells to GH-induced ERK1/2 activation and provides a potential cellular mechanism by which insulin promotes growth.

Received for publication, May 19, 2005 , and in revised form, November 2, 2005.

^* This work was supported by National Institutes of Health Grants DK40456 and DK62071 (to J. L. M.) and DK46395 (to S. J. F.). 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: Dept. of Pathology, Division of Molecular and Cellular Pathology, Volker Hall, G019, 1670 University Blvd., University of Alabama, Birmingham, AL 35294-0019. Tel.: 205-934-4921; Fax: 205-975-1126; E-mail: messina{at}path.uab.edu.

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