Understanding the role of Tec in Fcgamma receptor mediated phagocytosis

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The recognition and destruction of bacterial pathogens and other foreign particles by specific immune cells (macrophages) is principally mediated by the Fcgamma class of cell surface antibody receptors. This proposal aims to understand the molecular mechanisms which link receptor activation to the cellular rearrangements required to invaginate or swallow the offending particle. We have used immunofluorescent microscopy and biochemical methods to show that the intracellular tyrosine kinase Tec is an important component of the phagocytosis mechanism. Here we plan to use highly selective gene targeting methods to generate a mouse cell culture model system which is devoid of Tec protein. This will allow us to determine whether Tec is essential for Fcgamma-mediated phagocytosis. Reintroduction of mutant versions of the Tec protein into this null background will provide detailed information on the molecular partners of Tec and the individual roles of the various domains within the Tec protein. By studying the molecular mechanism of phagocytosis, we expect to gain an understanding of how to influence the Fcgamma signalling pathway, either to enhance the ability to deal with pathogens, or to restrict the consequences of excessive phagocytosis associated with autoimmune diseases. Tec is an enzyme likely to play an important role between the Fcgamma receptor and actin cytoskeleton rearrangements and therefore is a potentially important drug target.