This work is designed to understand the role of the Lck tyrosine protein kinase in T cell function. There is compelling evidence that this cytoplasmic tyrosine protein kinase plays an indispensable role in both T cell maturation and T cell activation. It is likely that what is learned about the Lck kinase will increase our understanding of the biochemistry of signal transduction and of the function of the Src-like tyrosine protein kinases as a class. The general goals of the work are to understand how the Lck protein is regulated by upstream modulators and how it interacts with downstream effectors.
Three specific aims will be pursued. First, the mechanism by which agents that induce oxidative stress activate the Lck kinase will be examined by a combination of molecular genetics and protein chemistry. Particular emphasis will be given to understanding the role of tyrosine phosphorylation in the activation of the kinase. Second, two apparently novel tyrosine phosphorylated proteins in activated T cells, one of which shows cell cycle-dependent nuclear localization, will be identified and characterized using recently isolated monoclonal antibodies. Third, the importance of the palmitylation of Lck and the phosphorylation of the kinase at serine 42, serine 59, and tyrosine 192, all of which lie outside the catalytic domain, will be examined in functional T cells. These modifications are unlikely to affect enzymatic activity, but they may affect the interaction of the kinase with regulators or substrates and this may be apparent in functional assays of lymphoid cells.
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