Analysis of serine kinase function and regulation in T lymphocytes. (360G-Wellcome-065975_Z_01_A)

Previous studies have shown that a network of serine kinases has essential functions in T cells. Accordingly, we plan to establish the molecular basis for the actions of four key serine kinases in T lymphocytes. Genetics, biochemistry, immunology and cell biology will be used to characterise the role of Phosphoinositide dependent kinase 1 ( PDK1), LKB1 and the AMP dependent protein kinase in peripheral T cell activation and function and to analyse the role of LKB1 and AMPK in regulating T lymphocyte metabolism. Diacylglycerol binding kinases of the Protein Kinase D family are specific targets for antigen receptors in lymphocytes and temporally and spatially disseminate antigen receptor signals away from the plasma membrane into the cell interior. Functions for PKDs in lymphocytes include the control of the phosphorylation and localization of class II histone deacetylases, key regulatory enzymes that control chromatin and repress gene expression. . We have also identified actin regulatory proteins and adapter molecules as PKD substrates. The key issues we will address are the mechanisms that regulate the subcellular localisation of PKDs; the role of PKDs in regulating the lymphocyte cytoskeleton; the function of different PKD isoforms in lymphocytes.