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The growth hormone receptor: mechanism of activation and clinical implications

Nature Reviews Endocrinology volume 6, pages 515–525 (2010)Cite this article

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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.

Key Points

  • 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)

  • Receptor loss-of-function, predominantly owing to mutations in the extracellular domain, results in growth hormone insensitivity or Laron syndrome

  • Receptor gain-of-function mutations are not known, but excessive receptor stimulation by growth hormone leads to gigantism, adult acromegaly and cancer (if autocrine growth hormone signaling is involved)

  • The hormone–receptor complex is well-defined at a molecular level for the extracellular domain

  • The growth hormone receptor exists as a constitutive dimer, and activation involves rearrangement of the receptor subunits to align the tyrosine-protein kinases JAK2 and Src bound below the cell membrane for activation

  • JAK2 and the Src family of proto-oncogene tyrosine-protein kinases initiate signaling, the former involving the key transcription factor signal transducer and activator of transcription 5b

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Figure 1: Major physiological actions of growth hormone and insulin-like growth factor 1 action.
Figure 2: Locations of known point mutations in the extracellular domain of the human growth hormone receptor associated with impaired postnatal growth.
Figure 3: Signaling pathways of growth hormone.
Figure 4: Model for the activation of the growth hormone receptor by growth hormone.

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Acknowledgements

M. J. Waters is supported by grants from the Australian National Health and Medical Research Council.

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  1. The University of Queensland, Institute for Molecular Bioscience, St Lucia, 4072, Qld, Australia

    Andrew J. Brooks & Michael J. Waters

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A. J. Brooks and M. J. Waters researched the data for the article and both provided a substantial contribution to discussions of the content. A. J. Brooks and M. J. Waters contributed equally to writing the article and reviewed and/or edited the manuscript before submission.

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Brooks, A., Waters, M. The growth hormone receptor: mechanism of activation and clinical implications. Nat Rev Endocrinol 6, 515–525 (2010). https://doi.org/10.1038/nrendo.2010.123

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