THE MECHANISM OF ACTION OF GROWTH-HORMONE

Growth hormone (GH) is the major hormone secreted by the pituitary gland and its pattern of secretion is sexually differentiated in many species. It is a pleiotropic hormone which acts as a growth factor in bone and muscle tissues and as a differentiation factor and a metabolic regulator in the liver and in fat and muscle tissues. The first step in GH action consists of a specific interaction between GH and its receptor (GHR) which is a single transmembrane domain protein presenting similarities to the prolactin receptor and, to a lesser extent, to some members of the cytokine receptor family. At least two types of GH signalling pathways appear to coexist in most target cells. The first one involves a phosphorylation cascade initiated by auto-phosphorylation of JAK2, a tyrosine kinase which is tightly associated to GHR. This is followed by or concomitant to the phosphorylation of intracellular proteins such as mitogen-activated kinase(s), an event preceding the activation of other kinases such as the S6 kinase. A second pathway involves lipidic mediators such as phospholipid breakdown products and protein kinase C. Both pathways are likely to transduce the hormonal message to the nucleus and to activate the transcription of a variety of genes coding for transcription factors, hormones, hormone receptors, enzymes, and plasma proteins (e.g., c-FOS, insulin-like growth factor I, prolactin receptor, cytochrome P-450 IIC, serpins, alpha2 U globulin). Two GH-responsive elements have recently been mapped in the promoter of serpin genes but the corresponding transcription factor(s) have not yet been identified. The only transcription factor identified so far as a GH target is the c-fos protooncogene product whose transient expression was shown to be required for GH induction of the lipoprotein-lipase gene. The availability of molecular tools such as the cloned receptor and target genes should now allow some rapid progress leading to a better understanding of growth hormone functions.