HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 31, 21594-21606, August 4, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/31/21594    most recent M513612200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xu, J. Articles by Messina, J. L. Search for Related Content PubMed PubMed Citation Articles by Xu, J. Articles by Messina, J. L. Social Bookmarking                      What's this?

Insulin Reverses Growth Hormone-induced Homologous Desensitization^*

From the Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019

Growth hormone (GH) is secreted in a pulsatile pattern to promote body growth and metabolism. GH exerts its function by activating several signaling pathways, including JAK2/STAT and MEK/ERK. ERK1/2 activation by GH plays important roles in gene expression, cell proliferation, and growth. We previously reported that in rat H4IIE hepatoma cells after an initial GH exposure, a second GH exposure induces STAT5 phosphorylation but not ERK1/2 phosphorylation (Ji, S., Frank, S. J., and Messina, J. L. (2002) J. Biol. Chem. 277, 28384–28393). In this study the mechanisms underlying GH-induced homologous desensitization were investigated. A second GH exposure activated the signaling intermediates upstream of MEK/ERK, including JAK2, Ras, and Raf-1. This correlated with recovery of GH receptor levels, but was insufficient for GH-induced phosphorylation of MEK1/2 and ERK1/2. Insulin restored the ability of a second GH exposure to induce phosphorylation of MEK1/2 and ERK1/2 without altering GH receptor levels or GH-induced phosphorylation/activation of JAK2 and Raf-1. GH and insulin synergized in promoting cell proliferation. Further investigation suggested that insulin increased the amount of MEK bound to KSR (kinase suppressor of Ras) and restored GH-induced tyrosine phosphorylation of KSR. Previous GH exposure also induced desensitization of STAT1 and STAT3 phosphorylation, but this desensitization was not reversed by insulin. Thus, insulin-regulated resensitization of GH signaling may be necessary to reset the complete response to GH after a normal, physiologic pulse of GH.

Received for publication, December 21, 2005 , and in revised form, April 28, 2006.

^* This work was supported by National Institutes of Health Grants DK DK40456 and DK62071 (to J. L. M.). 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 at Birmingham, Birmingham, AL 35294-0019. Tel.: 205-934-4921; Fax: 205-975-1126; E-mail: messina{at}path.uab.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				W. Luo, H. Yu, Z. Cao, T. R. Schoeb, M. Marron, and K. Dybvig Association of Mycoplasma arthritidis Mitogen with Lethal Toxicity but Not with Arthritis in Mice Infect. Immun., November 1, 2008; 76(11): 4989 - 4998. [Abstract] [Full Text] [PDF]

				H. Jin, N. J. Lanning, and C. Carter-Su JAK2, But Not Src Family Kinases, Is Required for STAT, ERK, and Akt Signaling in Response to Growth Hormone in Preadipocytes and Hepatoma Cells Mol. Endocrinol., August 1, 2008; 22(8): 1825 - 1841. [Abstract] [Full Text] [PDF]

				L.-Y. Tang, N. Deng, L.-S. Wang, J. Dai, Z.-L. Wang, X.-S. Jiang, S.-J. Li, L. Li, Q.-H. Sheng, D.-Q. Wu, et al. Quantitative Phosphoproteome Profiling of Wnt3a-mediated Signaling Network: Indicating the Involvement of Ribonucleoside-diphosphate Reductase M2 Subunit Phosphorylation at Residue Serine 20 in Canonical Wnt Signal Transduction Mol. Cell. Proteomics, November 1, 2007; 6(11): 1952 - 1967. [Abstract] [Full Text] [PDF]