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Submitted on April 25, 2005
Accepted on July 13, 2005
Department of Molecular Medicine, Karolinska Institute. Stockholm. Sweden, The Walter and Eliza Hall Institute of Medical Research, Victoria, Australia. To whom correspondence should be addressed
* To whom correspondence should be addressed. E-mail: Amilcar.Flores{at}cmm.ki.se.
Growth hormone has been of significant scientific interest for decades because its capacity to dramatically change physiological growth parameters. Furthermore, GH interacts with a range of other hormonal pathways and is an established pharmacological agent for which novel therapeutical applications can be foreseen. It is easy to see the requirement for a number of post-receptor mechanisms to regulate and control target tissue sensitivity to this versatile hormone. In recent years, some of the components that take part in the down-regulatory mechanism targeting the activated GH receptor have been defined and the physiological significance of some of these key components has begun to be characterized. Down-regulation of the GH receptor is achieved through a complex mechanism that involves rapid ubiquitin-dependent endocytosis of the receptor, the action of tyrosine phosphatases and the degradation by the proteasome. The SOCS protein family, particularly SOCS2, plays an important role in regulating GH actions. The aim of this review is to summarize collected knowledge, including very recent findings, regarding the intracellular mechanisms responsible for the GH receptor signaling down-regulation. Insights into these mechanisms can be of relevance to several aspects of GH research. It can help to understand growth related disease conditions, to explain GH resistance and may be used to develop pharmaceuticals that enhance some the beneficial actions of endogenously secreted GH in a tissue specific manner.
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