THE MECHANISM OF ACTION OF GROWTH-HORMONE

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