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Submitted on November 5, 2003
Accepted on March 3, 2004
Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Junín 956 (1113) Buenos Aires, Argentina, and Department of Geriatrics, School of Medicine, Southern Illinois University, Springfield, IL, USA.
* To whom correspondence should be addressed. E-mail: dturyn{at}qb.ffyb.uba.ar.
High continuous growth hormone (GH) levels in vivo produce desensitization of the JAK2/STAT5 pathway of GH signaling in the liver. To evaluate the mechanisms involved in this desensitization, transgenic mice over-expressing bovine GH were used. In these animals, GH receptor and membrane-associated JAK2 kinase are increased 4.5 and 6 fold, respectively. However, JAK2, STAT5a and 5b do not become tyrosine phosphorylated in response to GH stimulus, nor are these STAT proteins recruited to membranes, suggesting that they cannot bind to the receptor. The content of the suppressor CIS, both total and membrane-associated, is markedly increased in the liver of GH transgenic mice. This could account for the inhibition of STAT5 activation, because CIS competes with STAT5 for GHR docking sites. Existence of an alternative mechanism of negative regulation of this signaling pathway by chronically elevated GH levels is suggested by the low level of JAK2 phosphorylation transgenic mice exhibit. While total SHP-2 phosphatase content is the same in both kind of mice, membrane-associated SHP-2 protein levels increase 4.5 fold in GH transgenic animals. This could explain the dramatic inhibition of JAK2 phosphotyrosine level, thus contributing to the suppression of GH signaling observed in these transgenic mice.
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