Protein kinases are highly evolved signal transduction enzymes that regulate almost every biological process known. In the immune system, kinases control the ability to differentiate self from non-self. Autoimmune disorders such as arthritis, some forms of diabetes, organ-transplant rejection, and other conditions are known to result from aberrant regulation of protein kinase pathways. Yet, drugs which target protein kinases to treat these disorders have been difficult to develop because of the ubiquitous and highly conserved active sites of protein kinases.Through development of a chemical genetic strategy, it has become possible to create the first mono-specific inhibitors of any protein kinases and to use these reagents to study the effects of specific kinase inhibitors on T cell signal transduction. These reagents have revealed the presence of previously unexpected thresholds of kinase activity which are required for signaling. The current proposal seeks to quantify these thresholds by measurement of the quantitative dependence of T cell receptor signal transduction on the catalytic activity of three receptor proximal kinases, Lck, Fyn, and Zap-70. A novel chemical genetic approach will be used to reveal the activity of a single kinase in the T cell necessary for downstream T cell signal transduction events such as interleukin-2 (IL-2) production. A quantitative map of T cell signal transduction will allow for precise selection of the best kinase targets for drug discovery toward the treatment of many autoimmune disorders which result from aberrant T cell signaling.
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