Recent advances in growth hormone signaling

Abstract

Growth hormone (GH) is a major regulatory factor for overall body growth as evidenced by the height extremes in people with abnormal circulating GH levels or GH receptor (GHR) disruptions. GH also affects metabolism, cardiac and immune function, mental agility and aging. Currently, GH is being used therapeutically for a variety of clinical conditions including promotion of growth in short statured children, treatment of adults with GH deficiency and HIV-associated wasting. To help reveal previous unrecognized functions of GH, better understand the known functions of GH, and avoid adverse consequences that are often associated with exogenous GH administration, careful delineation of the molecular mechanisms whereby GH induces its diverse effects is needed. GH is a peptide hormone that is secreted into the circulation by the anterior pituitary and acts upon various target tissues expressing GHR. GH binding of GHR activates the tyrosine kinase Janus kinase 2 (JAK2), thus initiating a multitude of signaling cascades that result in a variety of biological responses including cellular proliferation, differentiation and migration, prevention of apoptosis, cytoskeletal reorganization and regulation of metabolic pathways. A number of signaling proteins and pathways activated by GH have been identified, including JAKs, signal transducers and activators of transcription (Stats), the mitogen activated protein kinase (MAPK) pathway, and the phosphatidylinositol 3'-kinase (PI3K) pathway. Although these signal transduction pathways have been well characterized, the manner by which GH activates these pathways, the downstream signals induced by these pathways, and the cross-talk with other pathways are not completely understood. Recent findings have added vital information to our understanding of these downstream signals induced by GH and mechanisms that terminate GH signaling, and identified new GH signaling proteins and pathways. This review will highlight some of these findings, many of which are unexpected and some of which challenge previously held beliefs about the mechanisms of GH signaling.

SNPs within the GH-signaling pathway are associated with the early IGF1 response to GH replacement therapy in GHD adults

“…GH also activates the suppressor of cytokine signaling (SOCS) genes, which mediates an inhibitory effect on the GH signaling (16,17), thereby producing an intracellular negative feed-back loop. In addition, some of the metabolic effects of GH are the results of activation of phosphoinositide 3-kinases (PI3Ks) (18), such as phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit beta (PIK3CB), effects which are thought to be independent of the GHR-induced IGF1 generation.…”

Estrogens in the Control of Growth Hormone Actions in Liver

“…The GHR belongs to type I cytokine receptor, a family of receptors without intrinsic kinase activity (Lanning and Carter-Su, 2006). Figure 2 shows the traditional view of the initiation of GH signaling: one molecule of GH binds two GHR monomers and induces their dimerization.…”

Differential effects of GH and GH-releasing peptide-6 on astrocytes

“…Indeed, the GH receptor (GHR) is expressed in diverse areas throughout the CNS (Fraser et al 1990, Le Greves et al 2005 where this hormone has been shown to be involved in numerous cellular activities such as stimulation of mitosis, cell proliferation and differentiation (Frago et al 2002, Ajo et al 2003. Binding of GH to its receptor mediates many of its effects through activation of the JAK/STAT signalling pathway (Lanning & Carter-Su 2006); however, GHR is also able to signal through additional pathways including the MAPK and the phosphatidylinositol 3 0 -kinase (PI3K; Brooks et al 2008) pathways. Release of GH from the anterior pituitary can be stimulated by ghrelin, as well as by its analogues the GH secretagogues (GHSs), which include GH-releasing peptides (GHRP)-1, -2 and -6.…”