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.
Journal ArticleDOI
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
Endocrine assessment, molecular characterization and treatment of growth hormone insensitivity disorders.
Martin O. Savage,Kenneth M. Attie,Alessia David,Louise A. Metherell,Adrian J. L. Clark,Cecilia Camacho-Hübner +5 more
TL;DR: Treatment with recombinant human insulin-like growth factor 1 in classical cases is summarized and new targets for treatment are discussed, together with therapy using the complex formed between rhIGF1 andrhIGF-binding protein 3.
Journal ArticleDOI
Autocrine human growth hormone promotes tumor angiogenesis in mammary carcinoma.
Severine E. Brunet-Dunand,Cécile M. Vouyovitch,Silvia Araneda,Vijay Pandey,Laurent J.-P. Vidal,Cristin G. Print,Hichem C. Mertani,Peter E. Lobie,Jo K. Perry +8 more
TL;DR: It is demonstrated that autocrine hGH expression in the human mammary carcinoma cell line MCF-7 stimulated the survival, proliferation, migration, and invasion of a human microvascular endothelial cell line (HMEC-1).
Journal ArticleDOI
The Contribution of Growth Hormone to Mammary Neoplasia
Jo K. Perry,Kumarasamypet M. Mohankumar,B. Starling Emerald,Hichem C. Mertani,Peter E. Lobie +4 more
TL;DR: This review will highlight recent evidence linking GH and mammary carcinoma and discuss GH-antagonism as a potential therapeutic approach for treatment of breast cancer.
Journal ArticleDOI
In Vivo Targeting of the Growth Hormone Receptor (GHR) Box1 Sequence Demonstrates that the GHR Does Not Signal Exclusively through JAK2
Johanna L. Barclay,Linda M. Kerr,Leela Arthur,Jennifer E. Rowland,Jennifer E. Rowland,Caroline N. Nelson,Mayumi Ishikawa,Elisabetta M. d’Aniello,Mary White,Peter G. Noakes,Michael J. Waters +10 more
TL;DR: The creation of targeted knock-in mice wherein the Box1 motif required for JAK2 activation by the GH receptor (GHR) has been disabled by four Pro/Ala mutations is reported, emphasizing the key role of Jak2 in postnatal growth and the minimization of obesity in older males.
Journal ArticleDOI
Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors
TL;DR: Results show that Mpl stimulation results in the activation of Lyn kinase, which appears to limit the proliferative response through a signaling cascade that regulates MAPK activity, which suggest that SFKs modify the rate of TPO-induced proliferation and are likely to affect cell cycle regulation during megakaryocytopoiesis.
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