T lymphocytes play a critical role in immune responses to both extracellular pathogens and transformed cells. Regulation of lymphocyte proliferation and differentiation is a multistep process that integrates a cascade of activation signals. The molecular mechanisms that link primary activation events occurring at the plasma membrane to alterations in the pattern and function of cytoplasmic and nuclear elements remain poorly understood. Recent data has focused attention on the role of glycosylated-phosphatidylinositol (GPI) molecules as key elements in the generation of intracellular messenger molecules and regulation of cellular proliferation. GPI molecules serve important dual functions in eukaryotic cells as membrane anchors for proteins and as precursors to insulin sensitive pharmacologically active inositolphosphoglycans (IPG). Both forms of GPI are utilized in the regulation of T cell growth. Aggregation of GPI anchored proteins such as Thy-1 can initiate a mitogenic response, and free GPI has been proposed as a precursor to second messengers of interleukin 2 and insulin action. The goal of this proposal is to elucidate the biochemical basis and molecular mechanisms of GPI controlled signaling processes during the early phases of T cell proliferation.
The specific aims are: 1) Analysis of the relationship between heterogeneous GPI structure and function, 2) Examination of GPI structure-function relationships using antibody probes, and 3) Examination of the roles of gpi molecules in T cell signalling.
| Merida, I; Williamson, P; Kuziel, W A et al. (1993) The serine-rich cytoplasmic domain of the interleukin-2 receptor beta chain is essential for interleukin-2-dependent tyrosine protein kinase and phosphatidylinositol-3-kinase activation. J Biol Chem 268:6765-70 |
| Merida, I; Williamson, P; Smith, K et al. (1993) The role of diacylglycerol kinase activation and phosphatidate accumulation in interleukin-2-dependent lymphocyte proliferation. DNA Cell Biol 12:473-9 |
| Taichman, R; Merida, I; Torigoe, T et al. (1993) Evidence that protein tyrosine kinase p56-Lck regulates the activity of phosphatidylinositol-3'-kinase in interleukin-2-dependent T-cells. J Biol Chem 268:20031-6 |
| Gaulton, G N (1991) Differential regulation of glycosylated phosphatidylinositol subtypes by insulin. Diabetes 40:1297-304 |
