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      The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects

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          Abstract

          The growth hormone receptor (GHR), although most well known for regulating growth, has many other important biological functions including regulating metabolism and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems. In addition, growth hormone signaling is an important regulator of aging and plays a significant role in cancer development. Growth hormone activates the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling pathway, and recent studies have provided a new understanding of the mechanism of JAK2 activation by growth hormone binding to its receptor. JAK2 activation is required for growth hormone-mediated activation of STAT1, STAT3, and STAT5, and the negative regulation of JAK–STAT signaling comprises an important step in the control of this signaling pathway. The GHR also activates the Src family kinase signaling pathway independent of JAK2. This review covers the molecular mechanisms of GHR activation and signal transduction as well as the physiological consequences of growth hormone signaling.

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          Most cited references288

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          Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.

          Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.
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            Insulin-like growth factors and their binding proteins: biological actions.

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              Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r).

              Newborn mice homozygous for a targeted disruption of insulin-like growth factor gene (Igf-1) exhibit a growth deficiency similar in severity to that previously observed in viable Igf-2 null mutants (60% of normal birthweight). Depending on genetic background, some of the Igf-1(-/-) dwarfs die shortly after birth, while others survive and reach adulthood. In contrast, null mutants for the Igf1r gene die invariably at birth of respiratory failure and exhibit a more severe growth deficiency (45% normal size). In addition to generalized organ hypoplasia in Igf1r(-/-) embryos, including the muscles, and developmental delays in ossification, deviations from normalcy were observed in the central nervous system and epidermis. Igf-1(-/-)/Igf1r(-/-) double mutants did not differ in phenotype from Igf1r(-/-) single mutants, while in Igf-2(-)/Igf1r(-/-) and Igf-1(-/-)/Igf-2(-) double mutants, which are phenotypically identical, the dwarfism was further exacerbated (30% normal size). The roles of the IGFs in mouse embryonic development, as revealed from the phenotypic differences between these mutants, are discussed.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                13 February 2018
                2018
                : 9
                : 35
                Affiliations
                [1] 1The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland , Brisbane, QLD, Australia
                Author notes

                Edited by: Stefan N. Constantinescu, Ludwig Cancer Research, Belgium

                Reviewed by: Sandra Pellegrini, Institut Pasteur, France; Lily Huang, University of Texas Southwestern Medical Center, United States

                *Correspondence: Andrew J. Brooks, a.brooks@ 123456uq.edu.au

                Specialty section: This article was submitted to Molecular and Structural Endocrinology, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2018.00035
                5816795
                29487568
                1c987cf2-8e4e-4cad-bfde-89e306dadfba
                Copyright © 2018 Dehkhoda, Lee, Medina and Brooks.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 24 July 2017
                : 29 January 2018
                Page count
                Figures: 6, Tables: 3, Equations: 0, References: 324, Pages: 23, Words: 20312
                Funding
                Funded by: National Health and Medical Research Council 10.13039/501100000925
                Award ID: APP1084797
                Categories
                Endocrinology
                Review

                Endocrinology & Diabetes
                growth hormone,growth hormone receptor,janus kinase 2,src family kinase,insulin-like growth factor 1,suppressor of cytokine signaling

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