Much has been learned in recent years regarding the biochemical events most critical for signal transduction mediated by numerous cell surface receptors on immune cells. A key second messenger is diacylglycerol (DAG), which is formed when engaged ITAM-bearing receptors activate the phosphatidylinositol cascade. DAG, in turn, stimulates at least two critical signaling cascades; the Ras pathway and several protein kinase C family members. Thus, understanding the formation of DAG and its metabolism is key to understanding immune cell activation. One means by which DAG function is terminated is the conversion of DAG to phosphatidic acid by DAG kinases (DGKs). This proposal focuses on DGKzeta, one of two DGKs expressed at high levels in hematopoietic cells. Our preliminary data indicate that DGKzeta is an important in vivo negative regulator of T cell and mast cell function. The experiments described in this proposal will make use of cell lines and genetically altered mice to investigate how DGKzeta serves this key role.
Three specific aims will be pursued. First, we propose a cell biologic and biochemical analysis of DGKzeta to determine its subcellular localization and features most critical for affecting signaling pathways.
The second aim will investigate the impact of DGKzeta deficiency on in vivo T cell function and the third aim will examine similar questions in the mast cell compartment.
Both aims 2 and 3 will extend the structure/function analysis to determine features of this enzyme most essential for responses to immunologic challenges. We anticipate that this work will shed additional light on the complex regulation of T cell and mast cell function and will hopefully suggest novel approaches to modulate activity of these cell types.
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