Journal ArticleDOI
The growth hormone receptor: mechanism of activation and clinical implications
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TLDR
A model in which the growth hormone receptor exists as a constitutive dimer is discussed in the light of salient information from closely related class 1 cytokine receptors, such as the erythropoietin, prolactin and thrombopOietin receptors.Abstract:
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 growth hormone and altered availability of exogenous IGF-1. Excessive activation of the growth hormone receptor by circulating growth hormone results in gigantism and acromegaly, whereas cell transformation and cancer can occur in response to autocrine activation of the receptor. Advances in understanding the mechanism of receptor activation have led to a model in which the growth hormone receptor exists as a constitutive dimer. Binding of the hormone realigns the subunits by rotation and closer apposition, resulting in juxtaposition of the catalytic domains of the associated tyrosine-protein kinase JAK2 below the cell membrane. This change results in activation of JAK2 by transphosphorylation, then phosphorylation of receptor tyrosines in the cytoplasmic domain, which enables binding of adaptor proteins, as well as direct phosphorylation of target proteins. This model is discussed in the light of salient information from closely related class 1 cytokine receptors, such as the erythropoietin, prolactin and thrombopoietin receptors.read more
Citations
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Journal ArticleDOI
Mechanism of Activation of Protein Kinase JAK2 by the Growth Hormone Receptor
Andrew J. Brooks,Wei Dai,Megan L. O'Mara,Daniel Abankwa,Yash Chhabra,Rebecca A. Pelekanos,Olivier Gardon,Kathryn A. Tunny,Kristopher M. Blucher,Craig J. Morton,Michael W. Parker,Michael W. Parker,Emma Sierecki,Yann Gambin,Guillermo A. Gomez,Kirill Alexandrov,Ian A. Wilson,Manolis Doxastakis,Alan E. Mark,Michael J. Waters +19 more
TL;DR: 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.
Journal ArticleDOI
Somatotropic Signaling: Trade-Offs Between Growth, Reproductive Development, and Longevity
TL;DR: Results obtained in GH-related mutant mice provide striking examples of mutations of a single gene delaying aging, reducing age-related disease, and extending lifespan in a mammal and providing novel experimental systems for the study of mechanisms of aging.
Journal ArticleDOI
Development of SNAP-tag fluorogenic probes for wash-free fluorescence imaging
Xiaoli Sun,Aihua Zhang,Brenda Baker,Luo Sun,Angela Howard,John Buswell,Damien Maurel,Anastasiya Masharina,Kai Johnsson,Christopher J. Noren,Ming-Qun Xu,Ivan R. Corrêa +11 more
TL;DR: A fast‐labeling variant of SNAP‐tag, termed SNAPf, is characterized, which displays up to a tenfold increase in its reactivity towards benzylguanine substrates and enables highly sensitive spatiotemporal investigation of protein dynamics in living cells.
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BMP signaling in mesenchymal stem cell differentiation and bone formation.
Maureen Beederman,Joseph D. Lamplot,Guoxin Nan,Jinhua Wang,Xing Liu,Liangjun Yin,Ruidong Li,Wei Shui,Hongyu Zhang,Stephanie H. Kim,Wenwen Zhang,Jiye Zhang,Yuhan Kong,Sahitya K. Denduluri,Mary Rose Rogers,Abdullah Pratt,Rex C. Haydon,Hue H. Luu,Jovito Angeles,Lewis L. Shi,Tong-Chuan He +20 more
TL;DR: Current knowledge of BMP-mediated osteogenesis is summarized, with a focus on BMP9, by presenting recently completed work which may help to further elucidate these pathways.
Journal ArticleDOI
Metabolic actions of insulin-like growth factor-I in normal physiology and diabetes.
TL;DR: The administration of IGF-I to patients with extreme insulin resistance results in improvement in glycemic control, and IGF- I is associated with lowering glucose and enhancing insulin sensitivity in Type 1 and Type 2 diabetes.
References
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Journal ArticleDOI
Trafficking of Receptor Tyrosine Kinases to the Nucleus
Graham Carpenter,Hong-Jun Liao +1 more
TL;DR: It is recognized that trafficking to these novel destinations involves new biochemical mechanisms, such as proteolytic processing or interaction with translocons, and that these trafficking events have a function in signal transduction, implicating the receptor itself as a signaling element between the cell surface and the nucleus.
Journal ArticleDOI
Nuclear targeting of the growth hormone receptor results in dysregulation of cell proliferation and tumorigenesis.
Becky L. Conway-Campbell,Jong Wei Wooh,Andrew J. Brooks,David Gordon,Richard J. C. Brown,Agnieszka M. Lichanska,Hong Soon Chin,Chenoa Barton,Glen M. Boyle,Peter G. Parsons,David A. Jans,Michael J. Waters +11 more
TL;DR: 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.
Journal ArticleDOI
Differential effects of growth hormone and insulin-like growth factor I on colony formation of epiphyseal chondrocytes in suspension culture in rats of different ages
TL;DR: The results show that GH as well as IGF-I induced colony formation among epiphyseal chondrocytes in suspension culture, although the effects of GH and IGF-i are different in terms of distribution of cloning efficiency.
Journal ArticleDOI
The role of the WSXWS equivalent motif in growth hormone receptor function.
TL;DR: It is shown that Y222A and S226A receptors have structural perturbations, which result in decreased signal transduction, and the crystal structure of the ligand-occupied extracellular domain of growth hormone receptor indicates that Tyr222 and Ser226 have important interactions within the second beta-barrel domain, providing a structural basis for results.
Journal ArticleDOI
Growth hormone receptor is expressed in human breast cancer.
TL;DR: Analysis of human breast carcinomas revealed that growth hormone receptor (GHR) is expressed in human breast cancer and appears to be up-regulated compared to adjacent normal breast tissue, suggesting that GHR-mediated signaling pathways are involved in the development ofhuman breast cancer, possibly via autocrine or paracrine mechanisms.
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