Molecular Mechanisms of Growth Hormone Action

Growth hormone (GH) has long been known as a regulator of body growth and metabolism, both in humans and in domestic animals, yet the molecular basis for these responses to GH has remained elusive. Our laboratory has recently identified the tyrosine kinase JAK2 as an early signaling molecule for GH. Growth hormone rapidly promotes the association of GH receptor with JAK2, activates JAK2, and promotes the phosphorylation of both GH receptor and JAK2 on tyrosines. A number of signaling proteins that lie downstream of JAK2 have been identified based on their ability to bind to these phosphorylated tyrosines in GH receptor/JAK2 complexes and(or) be phosphorylated on tyrosines in response to GH (presumably by JAK2). These proteins include 1) the signal transducers and activators of transcription (Stat) 1, 3, and 5, which have been implicated as regulators of transcription of a variety of genes; 2) the insulin receptor substrate (IRS) 1, which may mediate some of the metabolic effects of GH; and 3) Shc proteins, which lie upstream of Ras and the mitogen-activated protein (MAP) kinases designated ERKs 1 and 2, proteins implicated in the regulation of cellular growth and(or) differentiation. These signaling molecules are thought to work in concert with each other and with other signaling molecules to elicit the diverse effects of GH. Growth hormone is now recognized as being one of a group of hormones and growth factors that regulate JAK kinases. To gain insight into how the extracellular influences might selectively regulate one particular JAK-coupled receptor, we examined the effect of a potent synthetic glucocorticoid, dexamethasone, on signaling by GH and other JAK2-coupled receptors. Dexamethasone was found to selectively decrease JAK2 phosphorylation in response to GH. This decrease was accompanied by a decrease in the number of GH receptors in the plasma membrane but not in the intact cell, suggesting dexamethasone causes a redistribution of GH receptors away from the plasma membrane. Using truncated and mutated GH receptors expressed in CHO cells, two regions of the receptor were implicated in the inhibitory effect of dexamethasone. Interestingly, these regions differed from the regions implicated in GH-induced internalization and phorbol ester-induced decreases in GH binding. The insight gained into GH signal transduction as a result of recognizing that JAK2 activation is an early, and most likely initiating, signaling molecule for GH has greatly advanced our understanding of the molecular basis for GH action during the past 3 yr. Further insight gained in the next few years into the actions of GH and the interactions of GH with other hormones, growth factors, and cytokines should enable us to understand better the molecular basis for the diverse actions of GH on body growth and metabolism.