Insulin and other growth factors activate a strikingly similar array of intracellular proteins. Despite the similarities in signal transduction machinery utilized, however, only insulin uniquely triggers the translocation of an insulin sensitive glucose transporter isoform (GLUT4) to the plasma membrane. This movement results in a rapid influx of glucose across the cell membrane. Other growth factors, such as epidermal growth factor and platelet derived growth factor, only mildly stimulate GLUT4 translocation. Recent work by Dr. Birnbaum's laboratory suggests that polyoma middle T antigen, a transforming oncogene which a similar group of intracellular proteins, also increases glucose uptake at least in part by targeting GLUT4 to the plasma membrane. This is an exciting observation in the area of insulin signal transduction research. By comparing mechanisms of signal transduction in insulin treated adipocytes with adipocytes expressing polyoma middle T antigen, and contrasting these events with the intracellular machinery initiated by other mitogens, research on insulin signal transduction can hopefully be accelerated. The purpose of this proposal is to investigate the mechanisms of glucose uptake stimulation in fibroblasts and adipocytes expressing polyoma middle T antigen.
Two specific aims will be addressed: (1) the cellular content and subcellular distribution of specific glucose transporter isoforms will be evaluated in fibroblasts and adipocytes expressing polyoma middle T antigen; and, (2) the relative contribution of other proteins such as Src, Shc, and phosphatidylinositol 3-kinase will be investigated in cells expressing polyoma middle T antigen mutants incapable of activating specific signal transduction cascades. Ultimately, such research could lead to clinically useful information on the altered glucose uptake rates found in cancerous tissue and diabetics.
| Zhou, H; Summers, S A; Birnbaum, M J et al. (1998) Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis. J Biol Chem 273:16568-75 |
| Summers, S A; Birnbaum, M J (1997) A role for the serine/threonine kinase, Akt, in insulin-stimulated glucose uptake. Biochem Soc Trans 25:981-8 |
