REVIEWS The growth hormone receptor: mechanism of activation and clinical implications Andrew J. Brooks and Michael J. Waters 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. Brooks, A. J. & Waters, M. J. Nat. Rev. Endocrinol. 6, 515–525 (2010); published online 27 July 2010; doi:10.1038/nrendo.2010.123 Introduction Growth hormone, also called somatotropin, is a peptide been gained from both animal models and human cases hormone produced in the anterior pituitary gland that of growth hormone excess, for example, the giant mouse, promotes cell division, regeneration and growth. Growth which expresses a bovine growth hormone transgene, hormone mediates its pleiotropic effects through the and human growth hormone excess syndromes, such as growth hormone receptor, both directly, via activation gi gantism in children or acromegaly in adults. of tyrosine kinases, and indirectly, through induction of The discovery that the growth hormone receptor insulin-like growth factor 1 (IGF-1). This Review addresses signals as a class 1 cytokine receptor via STAT51–3 and the the relative roles of growth hormone and IGF-1 in mediat- presence of growth hormone receptors in virtually every ing their biological effects, as well as the clinical outcome cell of the body have led to the realization that growth of inappropriate growth hormone signaling. Furthermore, hormone acts not only through its classical mediator it summarizes novel information provided by transgenic IGF-1 but also through many additional signaling pro- mouse models and mutagenesis studies on the roles and cesses and mediators.4 Moreover, like other cytokines, mechanisms of activation of the growth hormone receptor growth hormone is produced locally in a variety of in the context of related class 1 cytokine receptors. tissues.4 Its IGF-1-independent actions are exemplified by the several hundred transcripts that display altered Physiological roles of growth hormone levels of expression after deletion of the growth hormone In the past two decades, a number of animal models receptor in the murine liver, the hepatocytes of which lack and cases of human growth deficit resulting from loss of IGF-1 receptors in the adult.5,6 One of the manifestations growth hormone and/or IGF-1 function have provided of this deletion is extensive hepatic steatosis in mice fed novel insights into the physiology of growth hormone a normal diet, a phenomenon also apparent in human (Figure 1). These models include rodents with impair- growth hormone deficiency and growth hormone receptor ment of growth hormone secretion; transgenic mice insensitivity owing to the loss of receptor function (Laron overexpressing a growth hormone antagonist; as well as syndrome).7 Other examples of IGF-1-independent The University of Queensland, Institute both mice and humans with loss-of-function of the growth actions mediated through the growth hormone recep- for Molecular hormone receptor, loss of IGF-1 or of the key signaling tor are ovarian preantral follicle development,8 fusion of Bioscience, St Lucia, Qld 4072, Australia mediator of growth hormone, signal transducer and acti- myoblasts with nascent myotubes to increase muscle fiber (A. J. Brooks, vator of transcription 5 (STAT5). Additional insight has size9 and chondrocyte generation at the growth plate.10 M. J. Waters). Activation of chondrocyte stem cells by growth hormone 11 Correspondence to: Competing interests was shown previously by Lindahl et al., and, in a study A. J. Brooks The authors declare no competing interests. by Blackmore et al.,12 the exercise-dependent increase [email protected] NATURE REVIEWS | ENDOCRINOLOGY VOLUME 6 | SEPTEMBER 2010 | 515 © 2010 Macmillan Publishers Limited. All rights reserved nrendo_123_SEP10.indd 515 2/8/10 14:09:41 REVIEWS Key points protects against excessive catabolism of proteins (used to provide amino acids for the maintenance of glucose pro- ■ The growth hormone receptor mediates a wide range of growth-related and metabolic actions, both directly and via insulin-like growth factor 1 (IGF-1) duction by gluconeogenesis) and, con comitantly, conserves glucose for the brain.16 In the fed state, growth hormone ■ Receptor loss-of-function, predominantly owing to mutations in the extracellular domain, results in growth hormone insensitivity or Laron syndrome promotes anabolism by increasing the produc tion of insulin and IGF-1.1 Through an increase in lipo lysis in ■ Receptor gain-of-function mutations are not known, but excessive receptor stimulation by growth hormone leads to gigantism, adult acromegaly and cancer fasting and insulin and IGF-1 production in the fed state, (if autocrine growth hormone signaling is involved) growth hormone is able to increase muscle mass at the ■ The hormone–receptor complex is well-defined at a molecular level for the expense of adipose tissue, an effect that is evident clinical ly 16 extracellular domain in the treatment of growth hormone deficiency. The ready availability of synthetic, recombinant human ■ The growth hormone receptor exists as a constitutive dimer, and activation involves rearrangement of the receptor subunits to align the tyrosine-protein growth hormone has led to its use as a treatment for short kinases JAK2 and Src bound below the cell membrane for activation stature in children, with or without concomitant growth 17–29 ■ JAK2 and the Src family of proto-oncogene tyrosine-protein kinases initiate hormone deficiency (Table 1). Its effects on anabolism signaling, the former involving the key transcription factor signal transducer have also been found beneficial for disorders unrelated to and activator of transcription 5b short stature, for example, in patients undergoing chronic hemodialysis,30 as well as to prevent muscle wasting in adults with acquired immunodeficiency syndrome, – in whom growth hormone is also able to increase pro- 31 IGF-1 GH duction of CD4-positive T cells. Clear evidence shows that treatment with growth hormone improves cardio- + vascular health, exercise capacity and mental outlook in Immune Lipolysis 32–35 function Insulin resistance growth hormone-deficient adults. Moreover, treat- ment of gonadotropin-resistant women under going Skeletal muscle Renal function Chondrocyte Bone, tooth Insulin proliferation synthesis in vitro fertiliza tion with growth hormone improves hypertrophy pregnancy rates.36 Cardiovascular Gastrointestinal Reproduction Neurogenesis Hepatic endothelium metabolism Growth hormone antagonism Pathologic actions of growth hormone are evident clini- Figure 1 | Major physiological actions of growth hormone and insulin-like growth cally in adults with growth hormone excess (that is, acro- factor 1 action. Given that growth hormone uses signal transducer and activator of transcription 5 (STAT5) to induce both IGF-1 and for many of its direct actions, it is megaly owing to tumors arising from somatotrope cells difficult to attribute specific roles to growth hormone or IGF-1 for many biological of the pituitary gland) with its associated increases in effects. However, those actions which involve more direct growth hormone action mortality and morbidity. If untreated, individuals with are placed to the right, whereas those involving induced IGF-1 to the left, acromegaly can die early from cardiovascular and renal acknowledging that these assignments may change. Note that the growth failure, preceded by neuropathy from cartilage overgrowth hormone–IGF-1 system is regulated by the tight negative feedback loop between owing to carpal tunnel syndrome.2,37 Symptoms are allevi- hepatic IGF-1 production and pituitary growth hormone secretion. Abbreviations: ated by surgery, radiotherapy, treatment with analogs of the GH, growth hormone; IGF-1, insulin-like growth factor 1. growth hormone-inhibiting agent somatostatin, the very effective growth hormone receptor antagonist pegvisomant in neural stem cell number, which overcomes their age- or by combinations of these therapeutic approaches.37 In dependent decline, was shown to be absent in mice with patients with