New Insights into Growth Hormone Receptor Function and Clinical Implications

Abstract

Although used as a therapeutic for 50 years, it is only recently that the application of molecular techniques has provided a basis for understanding growth hormone’s (GH) clinical actions. This article reviews progress in our current knowledge of the molecular mechanism of growth hormone (GH) receptor activation based on a number of physicochemical techniques, and documents insights gained into the means used by the activated GH receptor to control the expression of genes regulating growth and metabolism. These findings are related to disorders of short stature, and the therapeutic consequences are summarized.

The Growth Hormone Cascade and Its Role in Mammalian Growth

“…However, JAK2 is a potent kinase that associates with the GHR intracellular domain via the receptor’s proline-rich Box 1 [9]. In addition to transphosphorylation of other GHR-associated JAK2 molecules, JAK2 phosphorylates tyrosine residues on the GHR itself, thereby creating a binding site(s) for Src homology 2 (SH2)-containing proteins such as STATs 1, 3, 5a and 5b [13]. Since the JAK family of proteins consists of only four members (JAK1, 2 and 3, and Tyk2), multiple cytokines activate the same JAK.…”

High level of GHR nuclear translocation in skeletal muscle of a hyperplasic transgenic zebrafish

“…The hormone's actions are mediated via the GH receptor (GHR), which is widely expressed by GH target cells. GHR is the key regulator of post-natal growth and holds important actions over metabolic, reproductive, gastrointestinal, cardiovascular, hepatobiliary, and renal systems (Lichanska & Waters 2008). Concerning muscular tissue, GH and insulin-like growth factor 1 (IGF1) seem to regulate hypertrophy and hyperplasia, these processes being influenced by myogenic regulatory factors (MRFs) (Sabourin & Rudnicki 2000, Hawke & Garry 2001.…”

Effects of Growth Hormone (GH) Overexpression in Signaling Cascades Involved in Promotion of Cell Proliferation and Survival

“…Growth hormone binds to the extracellular domain of the GHR dimer via two asymmetrically-placed binding sites on the hormone: high affinity site 1, and lower affinity site 2. Specificity of the dimerization partner is conferred by the extracellular domain of the receptor, while union of the two moieties is attained at the transmembrane level through leucine zipper-like interactions (Lichanska & Waters, 2008a). The current model posits ligand binding to homodimerized inactive receptor induces relative rotation of the intracellular domains, leading to proper alignment of tyrosine kinase JAK2 .…”

“…STAT5 a and b are essential for many GH functions related to metabolism, body growth and sex-dependent liver gene regulation (Lanning & Carter-Su, 2006), indeed, STAT5b is regarded as the most relevant signaling mediator for GH actions, both direct and IGF1-mediated, as it regulates the transcription of the IGF1 gene (Woelfle et al, 2003a(Woelfle et al, , 2003b. While it is not clear if STAT1 and STAT3 require GHR phosphorylation or bind to phosphotyrosine residues on the receptor, STAT5 can bind to several phosphotyrosine residues at the carboxi-terminal part of the intracellular domain of the receptor (Rowland et al, 2005;Lichanska & Waters, 2008a). To date, there is no sufficient evidence relating the PI3K or the MAPK/Erk pathways with GH-induction of IGF1 transcription.…”