The growth hormone receptor: mechanism of activation and clinical implications

@article{Brooks2010TheGH,
  title={The growth hormone receptor: mechanism of activation and clinical implications},
  author={Andrew J. Brooks and Michael J. Waters},
  journal={Nature Reviews Endocrinology},
  year={2010},
  volume={6},
  pages={515-525}
}
  • A. Brooks, M. Waters
  • Published 1 September 2010
  • Biology, Medicine
  • Nature Reviews Endocrinology
Growth hormone is widely used clinically to promote growth and anabolism and for other purposes. Its actions are mediated via the growth hormone receptor, both directly by tyrosine kinase activation and indirectly by induction of insulin-like growth factor 1 (IGF-1). Insensitivity to growth hormone (Laron syndrome) can result from mutations in the growth hormone receptor and can be treated with IGF-1. This treatment is, however, not fully effective owing to the loss of the direct actions of… 
The growth hormone receptor.
  • M. Waters
  • Biology
    Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society
  • 2016
The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects
TLDR
This review covers the molecular mechanisms of GHR activation and signal transduction as well as the physiological consequences of growth hormone signaling, which plays a significant role in cancer development and aging.
Targeting growth hormone function: strategies and therapeutic applications
TLDR
Current and emerging strategies for antagonizing GH function and the potential disease indications are discussed, including strategies that either inhibit GH production, block its systemic receptor, or interrupt its downstream signaling pathways.
Growth Hormone Receptor Signaling Pathways and its Negative Regulation by SOCS2
TLDR
The analysis of molecular mechanisms involved in inactivation of GHR‐dependent signaling pathway is imperative for understanding GH physiol‐ ogy and provides a mechanism for cross‐talking where multiple factors can regulate GHR signaling during somatic development.
Mouse models of growth hormone insensitivity
TLDR
These mouse lines have revealed an intriguing role of GH action in health, disease, and aging and the phenotype of mouse lines with GHI is reviewed.
Differential effects of STAT proteins on growth hormone-mediated IGF-I gene expression.
TLDR
It is found that human STAT5A is nearly identical to STAT5B in its biochemical and functional responses to GH but that STAT1 and STAT3 show a weaker profile of in vitro binding to STAT DNA elements from the IGF-I gene thanSTAT5B, and are less potent inducers of gene transcription through these elements.
JAK2 activation by growth hormone and other cytokines
TLDR
This study describes a model for activation of the tyrosine kinase Janus kinase 2 (JAK2) by the GH receptor homodimer based on biochemical data and molecular dynamics simulations and believes that this model will apply to most if not all members of the class I cytokine receptor family, and will be useful in the design of small antagonists and agonists of therapeutic value.
Mechanism of Activation of Protein Kinase JAK2 by the Growth Hormone Receptor
TLDR
The mechanism provides a molecular basis for understanding the oncogenic JAK2 mutations responsible for polycythemia vera and certain other hematologic disorders and may thus be of value in the design of small-molecule inhibitors of clinical applicability.
IGF-1R modulation of acute GH-induced STAT5 signaling: role of protein tyrosine phosphatase activity.
TLDR
In this study, potential roles for protein tyrosine phosphatase activity in modulating GH-induced signaling are explored and IGF-1R positively regulates acute GH signaling by preventing access of PTP-1B activity to Janus kinase 2 and thereby preventing PTP -1B-mediated suppression of GH- induced STAT5 activation.
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References

SHOWING 1-10 OF 170 REFERENCES
Negative regulation of growth hormone receptor signaling.
TLDR
The aim of this review is to summarize collected knowledge, including very recent findings, regarding the intracellular mechanisms responsible for the GHR signaling down-regulation and insights into these mechanisms can be of relevance to several aspects of GH research.
An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway
TLDR
It is suggested that F'G' loop movement alters the signalling choice between JAK2 and a Src family kinase by regulating TMD realignment, which could explain debilitated ERK but not STAT5 signalling in some GH-resistant dwarfs and suggest pathway-specific cytokine agonists.
Recent advances in growth hormone signaling
TLDR
Recent findings have added vital information to understanding of these downstream signals induced by GH and mechanisms that terminate GH signaling, and identified new GH signaling proteins and pathways.
Defects in growth hormone receptor signaling
Ligand-independent growth hormone receptor dimerization occurs in the endoplasmic reticulum and is required for ubiquitin system-dependent endocytosis
TLDR
It is postulate that dimerization of GHR molecules is required for ubiquitin system-dependent endocytosis, and evidence is provided that the extracellular domain of the GHR is not required to maintain this interaction.
Nuclear targeting of the growth hormone receptor results in dysregulation of cell proliferation and tumorigenesis
TLDR
It is concluded that aberrant nuclear localization of GHR is a marker of high proliferative status and is sufficient to induce tumorigenesis and tumor progression.
Activation of Chimeric and Full-length Growth Hormone Receptors by Growth Hormone Receptor Monoclonal Antibodies
TLDR
It is proposed that in addition to promoting receptor dimerization, mAb 263 may induce specific changes in receptor conformation similar to GH, which are required for the biological response.
Model for growth hormone receptor activation based on subunit rotation within a receptor dimer
TLDR
It is shown that there is no substantial change in the crystal structure of the liganded and unliganded human GHR extracellular domain, and an activation mechanism involving a relative rotation of subunits within a dimeric receptor as a result of asymmetric placement of the receptor-binding sites on the ligand is proposed.
A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone
Growth hormone is used to increase height in short children who are not deficient in growth hormone, but its efficacy varies largely across individuals. The genetic factors responsible for this
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