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J. Biol. Chem., Vol. 277, Issue 32, 28384-28393, August 9, 2002
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From the Secretion of growth hormone (GH) in adult
male rats is characterized by high peak and undetectable trough levels,
both of which are required for male-specific pattern of liver gene
expression and GH-induced phosphorylation of STAT5. The present study
suggests that regulation of GH receptor (GHR) levels in rat hepatoma
cells by repeated GH stimulation determines GH responsiveness via the JAK2/STAT5 pathway. A short exposure to GH rapidly reduced GHR levels
which resulted in an equal desensitization of the JAK2/STAT5 pathway.
Recovery of GH-induced STAT5 phosphorylation correlated with the
time-dependent recovery of GHR levels during incubation in
the absence of GH. Acute GH also induced phosphorylation of ERK1/2 and
Akt, and this induction was also inhibited by prior exposure to GH.
However, unlike the JAK2/STAT5 pathway, the effect of GH to activate
the MEK/ERK and phosphatidylinositol 3-kinase/Akt pathways did not
recover following prolonged incubation in the absence of GH. Thus, GH
administration desensitizes the JAK2/STAT5 pathway, possibly because of
down-regulation of GHR, whereas an additional post-receptor mechanism
is required for the prolonged refractoriness of the MEK/ERK and
phosphatidylinositol 3-kinase/Akt pathways toward a second GH
stimulation. Our study suggests that both receptor and post-receptor
mechanisms are important in GH-induced homologous desensitization.
Growth Hormone-induced Differential Desensitization of STAT5,
ERK, and Akt Phosphorylation*
,
, and**
Department of Pathology, Division of
Molecular and Cellular Pathology, the § Department of
Medicine, Division of Endocrinology and Metabolism, and the
¶ Department of Cell Biology, University of Alabama at Birmingham,
and the Birmingham Veterans Affairs Medical Center,
Birmingham, Alabama 35294
*
This work was supported by National Institutes of Health
Grant DK40456 and a grant from the American Diabetes Association (both
to J. L. M.) and by National Institutes of Health Grants DK46395 and DK58259 and a Department of Veterans Affairs merit review
award (all to S. J. F.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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