MOLECULAR BASIS OF GROWTH HORMONE ACTION

The intracellular pathways by which binding of GH to its receptor elicits its diverse effects on growth, differentiation and metabolism have eluded investigators for many years. We have hypothesized that activation by GH of a GH receptor (GHR)-associated tyrosine kinase is an important early, and perhaps, initiating step in signal transduction by GH. This was suggested by initial studies showing that GH stimulates the tyrosyl phosphorylation of the GHR and that highly purified GH-GHR complexes have tyrosine kinase activity. These findings were consistent with GHR itself being a ligand-activated tyrosine kinase like the receptors for many growth factors. However, more recent studies using cells transfected with the cloned liver GHR cDNA lead to the hypothesis that the GHR forms a complex with a non-receptor tyrosine kinase, the amount of which may vary with cell type. Experiments using truncated GHRs expressed in Chinese hamster ovary (CHO) and rat insulinoma (RIN) cells indicate that the kinase is likely to be a -120-kDa protein. The physiological importance of the GHR-associated kinase is attested to by experiments using anti-phosphotyrosine antibodies, tyrosine kinase inhibitors, and/or truncated and mutated GHRs. The results of these experiments indicate that the GHR-associated tyrosine kinase: 1) is stimulated very rapidly following binding of GH to its receptor (<30 sec); 2) is stimulated by very low GH concentrations (0.5 ng/ml); and 3) is likely to play a role in stimulation by GH of a variety of cellular responses, including MAP (mitogen activated protein) kinase activity and C-/fos gene expression. Furthermore, phosphorylation of specific tyrosyl residues in GHR appears to be necessary for some responses to GH, including stimulation of MAP kinase activity. These results suggest that the GHR-associated lyrosine kinase has at least two roles. The first is to phosphorylate and thereby activate other proteins. The second is to phosphorylate tyrosyl residues in itself and the GHR. These phosphorylated tyrosines may serve as docking sites for proteins in other signalling pathways. This new vision of how GH functions should lead to the identification of new cellular actions for GH and thereby increase our understanding of how GH regulates growth, differentiation and metabolism.