To further our understanding of the signal transduction mechanism(s) used by cells sensitive to growth hormone (GH) in mediating GH action, the following hypothesis will be evaluated: the rapid activation of tyrosine kinase activity known to be triggered by GH binding to its receptor is crucial for subsequent biological effects of GH. The end points selected for this analysis are the GH-stimulated phosphorylation of the GH receptor isolated from murine 3T3-F442A fibroblasts, and the production of a panel of mRNA's that encode proteins known to be stimulated by GH. Two approaches will be used to determine whether this tyrosine kinase activity is required for biological action: the tyrosine kinase activity will be blocked with tyrphostin, and the concentration of mRNA's measured; and the tyrosine kinase activity will be potentiated with vanadate, and the same end points analyzed. Comparison of GH-stimulated GH receptor tyrosine kinase activity with the induction of GH-sensitive mRNA's under these opposing conditions will allow me to investigate the relevance of this tyrosine kinase activity to the signal transduction of the GH receptor. The appearance of these mRNA species will provide a marker to monitor the biological effect of either inhibition or prolongation of the tyrosine kinase signal. If a single pattern of stimulation and inhibition is seen for all of the monitored events, it would suggest a common pathway for the mRNA species selected for investigation. However, it is plausible that not all of the mRNA's regulated by GH would respond identically. This finding would raise the possibility of multiple intracellular signal transduction pathways, not all of them dependent solely on the presence of tyrosyl-phosphorylated proteins. There is evidence for pathway divergence for insulin action, but similar experiments have not been performed in GH-responsive cells. While GH is known to affect glucose metabolism, and is required for somatic growth, the mechanism of action of growth hormone is poorly understood. Therefore, findings generated from this study may have potential implications in the control of glucose metabolism and human growth.
| Bouley, Richard; Hasler, Udo; Lu, Hua A J et al. (2008) Bypassing vasopressin receptor signaling pathways in nephrogenic diabetes insipidus. Semin Nephrol 28:266-78 |
| Stred, Susan E; Messina, Joseph L (2003) Identification of hemopexin as a GH-regulated gene. Mol Cell Endocrinol 204:101-10 |
| Stred, Susan E; Cote, Deborah; Weinstock, Ruth S et al. (2003) Regulation of hemopexin transcription by calcium ionophores and phorbol ester in hepatoma cells. Mol Cell Endocrinol 204:111-6 |
