Insulin reverses growth hormone-induced homologous desensitization

Jie Xu, Zhongyu Liu, Thomas Clemens, Joseph L. Messina

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)21594-21606
Number of pages13
JournalJournal of Biological Chemistry
Volume281
Issue number31
DOIs
StatePublished - Aug 4 2006
Externally publishedYes

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Growth Hormone
Insulin
Phosphorylation
Mitogen-Activated Protein Kinase Kinases
Somatotropin Receptors
Cell proliferation
Chemical activation
Cell Proliferation
Cell growth
Growth
Metabolism
Gene expression
Protein-Tyrosine Kinases
Tyrosine
Rats
Hepatocellular Carcinoma

ASJC Scopus subject areas

  • Biochemistry

Cite this

Insulin reverses growth hormone-induced homologous desensitization. / Xu, Jie; Liu, Zhongyu; Clemens, Thomas; Messina, Joseph L.

In: Journal of Biological Chemistry, Vol. 281, No. 31, 04.08.2006, p. 21594-21606.

Research output: Contribution to journalArticle

Xu, Jie ; Liu, Zhongyu ; Clemens, Thomas ; Messina, Joseph L. / Insulin reverses growth hormone-induced homologous desensitization. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 31. pp. 21594-21606.
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