Recent advances in growth hormone signaling.

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.